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CHEMISTRY (632 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 14)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 28)
ACS Catalysis     Hybrid Journal   (Followers: 46)
ACS Chemical Neuroscience     Hybrid Journal   (Followers: 22)
ACS Combinatorial Science     Hybrid Journal   (Followers: 23)
ACS Macro Letters     Hybrid Journal   (Followers: 27)
ACS Medicinal Chemistry Letters     Hybrid Journal   (Followers: 42)
ACS Nano     Hybrid Journal   (Followers: 310)
ACS Photonics     Hybrid Journal   (Followers: 14)
ACS Symposium Series     Full-text available via subscription  
ACS Synthetic Biology     Hybrid Journal   (Followers: 25)
Acta Chemica Iasi     Open Access   (Followers: 5)
Acta Chimica Slovaca     Open Access   (Followers: 2)
Acta Chimica Slovenica     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 8)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 7)
Acta Scientifica Naturalis     Open Access   (Followers: 3)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 8)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 9)
Adsorption Science & Technology     Open Access   (Followers: 6)
Advanced Functional Materials     Hybrid Journal   (Followers: 60)
Advanced Science Focus     Free   (Followers: 5)
Advances in Chemical Engineering and Science     Open Access   (Followers: 75)
Advances in Chemical Science     Open Access   (Followers: 19)
Advances in Chemistry     Open Access   (Followers: 24)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19)
Advances in Drug Research     Full-text available via subscription   (Followers: 25)
Advances in Environmental Chemistry     Open Access   (Followers: 7)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 12)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 27)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Polymer Science     Hybrid Journal   (Followers: 45)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 3)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 8)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Al-Kimia : Jurnal Penelitian Sains Kimia     Open Access  
Alchemy : Journal of Chemistry     Open Access   (Followers: 3)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 68)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 22)
American Journal of Chemistry     Open Access   (Followers: 32)
American Journal of Plant Physiology     Open Access   (Followers: 13)
American Mineralogist     Hybrid Journal   (Followers: 16)
Anadolu University Journal of Science and Technology A : Applied Sciences and Engineering     Open Access  
Analyst     Full-text available via subscription   (Followers: 37)
Angewandte Chemie     Hybrid Journal   (Followers: 182)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 260)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 4)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 9)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 13)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Open Access   (Followers: 2)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 9)
Applied Spectroscopy     Full-text available via subscription   (Followers: 26)
Applied Surface Science     Hybrid Journal   (Followers: 34)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 3)
Asian Journal of Chemistry and Pharmaceutical Sciences     Open Access  
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 3)
Avances en Quimica     Open Access  
Biochemical Pharmacology     Hybrid Journal   (Followers: 11)
Biochemistry     Hybrid Journal   (Followers: 380)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 11)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 2)
Biomacromolecules     Hybrid Journal   (Followers: 23)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 140)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 90)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 1)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 24)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 3)
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 2)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 11)
Canadian Mineralogist     Full-text available via subscription   (Followers: 6)
Carbohydrate Research     Hybrid Journal   (Followers: 25)
Carbon     Hybrid Journal   (Followers: 71)
Catalysis for Sustainable Energy     Open Access   (Followers: 8)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 7)
Catalysis Science and Technology     Free   (Followers: 8)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 12)
Cellulose     Hybrid Journal   (Followers: 10)
Cereal Chemistry     Full-text available via subscription   (Followers: 5)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 21)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 75)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 27)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 22)
Chemical Reviews     Hybrid Journal   (Followers: 206)
Chemical Science     Open Access   (Followers: 28)
Chemical Technology     Open Access   (Followers: 34)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 57)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 23)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 7)
Chemistry & Biology     Full-text available via subscription   (Followers: 33)
Chemistry & Industry     Hybrid Journal   (Followers: 8)
Chemistry - A European Journal     Hybrid Journal   (Followers: 170)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 16)
Chemistry and Materials Research     Open Access   (Followers: 21)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Open Access   (Followers: 3)
Chemistry Letters     Full-text available via subscription   (Followers: 45)
Chemistry of Materials     Hybrid Journal   (Followers: 270)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 20)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 1)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 3)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 12)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 11)
Chromatographia     Hybrid Journal   (Followers: 22)
Chromatography     Open Access   (Followers: 2)
Chromatography Research International     Open Access   (Followers: 6)
Cogent Chemistry     Open Access   (Followers: 2)
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 11)
Colloids and Interfaces     Open Access  
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 7)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 23)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Communications Chemistry     Open Access  
Composite Interfaces     Hybrid Journal   (Followers: 7)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 1)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 12)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 10)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 4)
Copernican Letters     Open Access   (Followers: 1)
Corrosion Series     Full-text available via subscription   (Followers: 7)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 8)
Croatica Chemica Acta     Open Access  
Crystal Structure Theory and Applications     Open Access   (Followers: 4)
CrystEngComm     Full-text available via subscription   (Followers: 13)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Chromatography     Hybrid Journal  
Current Green Chemistry     Hybrid Journal   (Followers: 1)
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Microwave Chemistry     Hybrid Journal  
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 14)
Current Research in Chemistry     Open Access   (Followers: 9)
Current Science     Open Access   (Followers: 73)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 2)
Dalton Transactions     Full-text available via subscription   (Followers: 23)
Detection     Open Access   (Followers: 4)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)

        1 2 3 4 | Last

Journal Cover
Bioorganic Chemistry
Journal Prestige (SJR): 0.85
Citation Impact (citeScore): 4
Number of Followers: 10  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0045-2068 - ISSN (Online) 1090-2120
Published by Elsevier Homepage  [3157 journals]
  • Studies on Lysozyme Modifications Induced by Substituted p-Benzoquinones
    • Abstract: Publication date: Available online 14 January 2019Source: Bioorganic ChemistryAuthor(s): Jisook Kim, Charles A. Thomas, Jacob M. Ewald, Neethu M. Kurien, Mary E. Booker, Hendrik J. Greve, Titus V. Albu Protein misfolding can facilitate a protein damaging process and makes it susceptible to a series of events such as unfolding, adduct formation, oligomerization, or aggregation. Loss of a protein’s native structure may result in its biological malfunction and/or cellular toxicity that could cause associated diseases. Several factors were identified for causing structural changes of a protein, however quinone-induced protein modifications received very little attention whether for amyloidal or non-amyloidal proteins. In this paper, we report our investigation on lysozyme modifications upon treatment with selected benzoquinones (BQs), utilizing fluorescence spectroscopy including anisotropy determination, UV-Vis spectroscopy, and SDS-PAGE. Lysozyme was reacted with substituted BQs in order to examine substituent effects on protein modifications. In addition, we evaluated lysozyme modifications induced by 1,4-benzoquinone in concentration-, pH-, temperature-, and time-dependent studies. Our study shows that all BQs can readily modify lysozyme in a complex manner through adduct formation, oligomerization, polymeric aggregation, and/or fibrilization. Electrochemical properties of selected BQs were monitored using cyclic voltammetry in phosphate buffered aqueous solution, and it was found that quinone reduction potentials correlate well with their reactivity trend toward lysozyme.Graphical abstractGraphical abstract for this article
  • EGFR inhibitors from cancer to inflammation: Discovery of
           4-fluoro-N-(4-(3-(trifluoromethyl)phenoxy)pyrimidin-5-yl)benzamide as a
           novel anti-inflammatory EGFR inhibitor
    • Abstract: Publication date: Available online 12 January 2019Source: Bioorganic ChemistryAuthor(s): Ahmed Elkamhawy, Ahmed H.E. Hassan, Sora Paik, Yong Sup Lee, Hwi-Ho Lee, Ji-Sun Shin, Kyung-Tae Lee, Eun Joo Roh EGFR inhibitors are well-known as anticancer agents. Quite differently, we report our effort to develop EGFR inhibitors as anti-inflammatory agents. Pyrimidinamide EGFR inhibitors eliciting low micromolar IC50 and the structurally close non-EGFR inhibitor urea analog were synthesized. Comparing their nitric oxide (NO) production inhibitory activity in peritoneal macrophages and RAW 246.7 macrophages indicated that their anti-inflammatory activity in peritoneal macrophages might be a sequence of EGFR inhibition. Further evaluations proved that compound 4d significantly and dose-dependently inhibits LPS-induced iNOS expression and IL-1β, IL-6, and TNF-α production via NF-κB inactivation in peritoneal macrophages. Compound 4d might serve as a lead compound for development of a novel class of anti-inflammatory EGFR inhibitors.Graphical abstractGraphical abstract for this article
  • Bioactive Cytosporone Derivatives Isolated from the Mangrove-derived
           Fungus Dothiorella sp. ML002
    • Abstract: Publication date: Available online 12 January 2019Source: Bioorganic ChemistryAuthor(s): Cai-Juan Zheng, Guo-Lei Huang, Hai-Xia Liao, Rong-Qing Mei, You-Ping Luo, Guang-Ying Chen, Qing-Ying Zhang Three new cytosporone derivatives dothiorelones K–M (1, 2, 7), together with six known ones (3–6, 8, 9) were isolated from the mangrove-derived fungus Dothiorella sp. ML002. Their structures were determined by comprehensive 1D, 2D NMR spectroscopic and HR-ESI-MS spectroscopic data. Compounds 1, 2 and 5 displayed inhibitory activity against α-glucosidase with the IC50 values of 22.0, 77.9 and 5.4 μg/mL, respectively. Additionally, compounds 1, 2, and 5 also exhibited antibacterial activities against Staphylococcus aureus (ATCC 6538) with the same MIC values of 50 μg/mL, respectively. The results indicated that cytosporone derivatives will be useful to as diabetes control agents.Graphical abstractGraphical abstract for this article
  • A Combinatorial Approach of Structure-Based Virtual Screening and
           Molecular Dynamics Simulation towards the Discovery of a Highly Selective
           Inhibitor for VP9 Coat Protein of Banna Virus
    • Abstract: Publication date: Available online 12 January 2019Source: Bioorganic ChemistryAuthor(s): Parikshit Moitra Structure based virtual screening of two libraries containing 27628 numbers of antiviral compounds was used to discover a few of the potent inhibitor molecules against Banna virus (BAV). Cross-docking studies with many common interfering proteins provided five of the highly selective inhibitor for BAV. Analyses of the leading molecules with ADME-Tox filtering tool and atomistic molecular dynamics simulation studies finally discovered a benzoxazolone derivative as one of the most promising molecules towards the highly selective inhibition of BAV. The theoretical calculations are also supported by the experimental evidences where the interactions between the hit ligand and a model peptide sequence, mimicking the VP9 protein of BAV, were studied. Overall the development of a personalized therapeutic towards the highly selective inhibition of BAV is discussed herein for the first time in literature.Graphical abstractGraphical abstract for this article
  • Synthesis of 1-(α-aminoalkyl)-2-naphthol and α-aminonitrile derivatives
           with molybdenum Schiff base complex covalently bonded on silica-coated
           magnetic nanoparticles and DNA interaction study of one type of
           derivatives using computational and spectroscopic methods
    • Abstract: Publication date: Available online 11 January 2019Source: Bioorganic ChemistryAuthor(s): Jamshid Rakhtshah, Behrooz Shaabani, Sadegh Salehzadeh, Neda Hosseinpour Moghadam An air- and moisture-stable molybdenum Schiff base complexes immobilized on magnetic iron oxide nanoparticles with a core-shell structure was developed for utilization as a new heterogeneous catalyst. The surface, structural and magnetic characteristics of the nanomaterials were characterized by using Fourier transform infrared (FT-IR) spectroscopy, X-ray powder diffraction (XRD), vibrating sample magnetometry (VSM), scanning electron microscopy (SEM), energy dispersive X-ray (EDX) and inductively coupled plasma atomic emission spectroscopy (ICP-AES). In application point of view, an ultrasonic assisted one-pot multicomponent protocol for the synthesis of 1-(α-aminoalkyl)-2-naphthol derivatives have been demonstrated under mild condition with short reaction times, high yields and TON values up to 570. To survey the generality of the procedure, we studied the synthesis of α-aminonitrile derivatives with different aldehydes, trimethylsilyl cyanide (TMSCN) and aniline under the same conditions. Additionally, binding interaction of 1-(phenyl(pyridin-2-ylamino)methyl)naphthalen-2-ol (AMAN-1) with various types of rigid DNA and HSA has been investigated by molecular modeling study. In vitro studies under physiological conditions showed that the desired derivative interacts with calf-thymus DNA (ct-DNA) via an intercalative binding mode.Graphical abstractGraphical abstract for this article
  • Innovative nano-carriers in anticancer drug delivery-A comprehensive
    • Abstract: Publication date: Available online 10 January 2019Source: Bioorganic ChemistryAuthor(s): Peng Dong, K.P. Rakesh, H.M. Manukumar, Yasser Hussein Eissa Mohammed, C.S. Karthik, S. Sumathi, P. Mallu, Hua-Li Qin In the scientific field, nanotechnology has offered multipurpose and designated functional nanoparticles (NPs) for the development of applications in nano-medicine. This present review focuseson cutting edge of nanotechnology in biomedical applications as drug carries in cancer treatment. The nanotechnology overcomes several limitations of drug delivery systems used in distinct therapeutic approaches of cancer treatment. The serious effect of conventional chemotherapeutics by nonspecific targeting, the lack of solubility, and the inability of chemotherapeutics entry to cancer cells which, offersa great opportunityfor nanotechnology to play significant roles in cancer biology. The selective delivery of nano-drugs to the targeted cancer cells by the programmed way and avoiding nonspecific interactions to the healthy cells. The present review focuses on the methods of improving the size, shape and characteristics of nanomaterials which can be exploited for cancer therapy. The successful designing of nanocarriers can be tailored for cancer treatment for upcoming future as nano-medicines.Graphical abstractGraphical abstract for this article
  • Discovery of atorvastatin as a tetramer stabilizer of nuclear receptor
           RXRα through structure-based virtual screening
    • Abstract: Publication date: Available online 10 January 2019Source: Bioorganic ChemistryAuthor(s): Xin Wang, Shuyi Chong, Huiyun Lin, Zhiqiang Yan, Fengyu Huang, Zhiping Zeng, Xiaokun Zhang, Ying Su Retinoid X receptor alpha (RXRα), a central member of the nuclear receptor superfamily and a key regulator of many signal transduction pathways, has been an attractive drug target. We previously discovered that an N-terminally truncated form of RXRα can be induced by specific ligands to form homotetramers, which, as a result of conformational selection, forms the basis for inhibiting the nongenomic activation of RXRα. Here, we report the identification and characterization of atorvastatin as a new RXRα tetramer stabilizer by using structure-based virtual screening and demonstrate that virtual library screening can be used to aid in identifying RXRα ligands that can induce its tetramerization. In this study, docking was applied to screen the FDA-approved small molecule drugs in the DrugBank 4.0 collection. Two compounds were selected and purchased for testing. We showed that the selected atorvastatin could bind to RXRα to promote RXRα-LBD tetramerization. We also showed that atorvastatin possessed RXRα-dependent apoptotic effects. In addition, we used a chemical approach to aid in the studies of the binding mode of atorvastatin.Graphical abstractGraphical abstract for this article
  • Orobanone analogues from acid-promoted aromatization rearrangement of
           curcumol inhibit hypoxia-inducible factor-1 (HIF-1) in cell-based reporter
    • Abstract: Publication date: Available online 10 January 2019Source: Bioorganic ChemistryAuthor(s): Yue-qing Li, Guang-zhe Li, Yi Dong, Xu Ma, Hui-juan Dong, Qian-qian Wu, Wei-jie Zhao In this paper, the mechanism of orobanone analogues formation via aromatization rearrangement of curcumol was minutely explored. Aromatization of curcumol with acetone under acidic condition was selected as the model reaction. The formation of a stable aromatic system was the driving force for this reaction. Based on the model reaction, other four new orobanone analogues were prepared through curcumol reacting with different carbonyl compounds. The results showed that the stability of carbocation, which was generated from the carbonyl compounds, and the steric hindrance were main factors affecting the aromatization. We also synthesized the analogue of aromaticane B using compound 2. In vitro anti-proliferative activity of some derivatives were tested by MTT assay. Two derivatives showed weak anti-tumor effect on two cancer cell lines (HepG2 and MCF7) under normoxia. Four orobanone analogue 2, 5, 6 and 9 significantly inhibited hypoxia-induced HIF-1 luciferase reporter activity in HeLa cells with the IC50 values of 13.6, 6.6, 2.4 and 18.2μM, respectively.Graphical abstractGraphical abstract for this article
  • Synthesis, characterization, antioxidant power and acute toxicity of some
           new azo-benzamide and azo-imidazolone derivatives with in vivo and in
           vitro antimicrobial evaluation
    • Abstract: Publication date: Available online 9 January 2019Source: Bioorganic ChemistryAuthor(s): Mohammed kareem samad, Farouq Emam Hawaiz In this research paper, a stepwise chemical reaction was conducted to synthesize and develop of a new potent azo-oxazolone, which was used as prototypical molecule for production of two series of azo-benzimide (5a-j) and azo-imidazolone (6a-j). FT-IR, 1H-NMR, 13C-NMR and CHN analysis were used for the structural elucidation. The high biological efficiency of newly obtained compounds was confirmed by in vitro antioxidant efficacy and in vitro antimicrobial activity against gram-positive and gram-negative bacteria via disc diffusion and tube dilution techniques. In addition, in vivo anti-microbial activity of some of the synthesized compounds was determined by using burnt rats which infected by Staphylococcus aureus. Tested compounds have shown high anti-microbial activity and wound healing in comparison to ucederm as a control. In vivo acute toxicity was carried out by up and down method for the compounds 4, 5d and 6d. The limited test dose was 2000mg/kg, while the maximum tolerated dose was 5000mg/kg which has administered no lethality recorded.Graphical abstractGraphical abstract for this article
  • Design, synthesis, molecular docking and biological activity evaluation of
           some novel indole derivatives as potent anticancer active agents and
           apoptosis inducers
    • Abstract: Publication date: Available online 8 January 2019Source: Bioorganic ChemistryAuthor(s): Ahmed. M.Sh. El-Sharief, Yousry A. Ammar, Amany Belal, Marwa A.M. Sh. El-Sharie, Yehia A. Mohamed, Ahmed B.M. Mehany, Gameel A M Elhag ali, Ahmed Ragab Reaction of 5-morphilinosulfonylisatin (1) with acetophenones (2a–e) afforded 3-hydroxy-3-substituted-2-oxoindoles 3a-e, when treated with acetic acid the expected 3-phenacylidene-2-oxoindoles 4a-d and 4-hydroxy-5'-(morpholinosulfonyl) spiro [chromene-2, 3'-indolin]-2'-one 6 were obtained. Isatin derivative (1) was stirred with cyano derivatives to produce the arylidines (7a-c), while under reflux condition, it gave pyrrolo[2,3–b]indoles (8, 9). Moreover, istain (1) reacted with pyrazolo-5-one or 3-substituted phenol in presence of malononitrile to afford spiroxindole derivatives (10a,b) and (11a,b). Also, compounds (10a,b) and (11a,b) were obtained through cyclization of (7a) with pyrazolo-5-one or 3-substituted phenol. The obtained compounds were identified by IR, 1H NMR, 13C NMR and elemental analysis. Anticancer activity against three cancer cell lines (HepG-2, HCT-116 and MCF-7) were evaluated using sulforhodamine B assay method. Compounds 4b, 4c, 7a, 7c and 9 showed broad spectrum anticancer activity on the three tested cell lines with IC50 values less than 10 µM. Cell cycle analysis was performed for the most promising derivatives, compounds 4b and 7c arrested HepG-2 cells at G2-M phase, while compounds 7a and 9 accumulated cells at G0-G1 phase, all of them induced apoptosis at priG1 phase in the range of (11.32 to 19.17%). Additionally compounds 4b, 7a and 9 showed more potent activity against EGFR than Lapatinib, their IC50 values are from 0.019 to 0.026 µM while IC50 of Lapatinib is 0.028 µM. Molecular docking studies were conducted to investigate the binding mode, amino acid interactions and free binding energy of these potent derivatives.Graphical abstractGraphical abstract for this article
  • Piperazine-Azole-Fluoroquinolone Hybrids: Conventional and Microwave
           Irradiated Synthesis, Biological Activity Screening and Molecular Docking
    • Abstract: Publication date: Available online 8 January 2019Source: Bioorganic ChemistryAuthor(s): Arif Mermer, Ozlem Faiz, Ahmet Demirbas, Neslihan Demirbas, Manikandan Alagumuthu, Sivakumar Arumugam A series of new 1,2,4-triazole and 1,3,4-oxadiazole derivatives was obtained via several steps sequential reactions of phenyl piperazine. Then, these compounds were converted to the corresponding fluoroquinolone hybrids via one pot three component Mannich reaction. All the reactions were examined under conventional and microwave mediated conditions, and optimum conditions were determined. The effect of different solvents and microwave power on microwave prompted reactions was investigated as well. All the newly synthesized compounds were characterized by FTIR, 1H NMR, 13C NMR and EI MS spectral techniques. The antimicrobial activity, DNA gyrase and Topoisomerase IV inhibition potentials were performed. The results obtained showed that fluoroquinolone hybrids possess good antimicrobial activity. Moreover, Fluoroquinolone-azole-piperazine hybrids synthesized in the present study displayed excellent DNA gyrase inhibition. To unveil the interaction mode of compounds to receptor, a molecular docking study was performed. With an average least binding energy of -9.5 kcal/mol, all compounds were found to have remarkable inhibitory potentials against DNA gyrase (E. coli).Graphical abstractGraphical abstract for this article
  • Design, Synthesis, Biological Evaluation and Molecular Modelling Studies
           of Indole Glyoxylamides as a New Class of Potential Pancreatic Lipase
    • Abstract: Publication date: Available online 8 January 2019Source: Bioorganic ChemistryAuthor(s): S.N.C. Sridhar, Saksham Palawat, Atish T. Paul A series of eighteen indole glyoxylamide analogues were synthesized, characterized and evaluated for their pancreatic lipase inhibitory activity. Porcine pancreatic lipase (Type II) was used with 4-nitrophenyl butyrate (as substrate) for the in vitro assay. Compound 8f exhibited competitive inhibition against pancreatic lipase with IC50 value of 4.92 µM, comparable to that of the standard drug, orlistat (IC50 = 0.99 µM). Compounds 7a-i and 8a-i were subjected to molecular docking into the active site of human PL (PDB ID: 1LPB) wherein compound 8f possessed a potential MolDock score of -153.037 kcal/mol. Molecular dynamics simulation of 8f complexed with pancreatic lipase, confirmed the role of aromatic substitution in stabilizing the ligand through hydrophobic interactions (maximum observed RMSD = 3.5 Å).Graphical abstractGraphical abstract for this article
  • Synthesis and biological evaluation of some novel thiobenzimidazole
           derivatives as anti-renal cancer agents through inhibition of c-MET kinase
    • Abstract: Publication date: Available online 8 January 2019Source: Bioorganic ChemistryAuthor(s): Hany S. Ibrahim, Mohamed E. Albakri, Walaa R. Mahmoud, Heba Abdelrasheed Allam, Ahmed M. Reda, Hatem A. Abdel-Aziz Benzimidazole is an interesting scaffold constituting a main core in many anticancer agents against variable cell lines as Carbendazim (I) and Nocodazole (II). Accordingly, eighteen compounds of 2-((1H-benzoimidazol-2-yl)thio)-1-(aryl/heteroaryl)ethan-1-ones, in their sulphate salt and free forms, were designed and investigated as anticancer agents. In vitro preliminary screening of selected compounds by the National Cancer Institute (NCI) on a panel of 60 cell lines revealed renal cancer cell line (A498) as the most vulnerable cell line; accordingly, IC50 values against A498 cell line were determined for compounds with the best results. The best inhibitory activity was for compound 4a with (IC50= 6.97 µM) compared to sunitinib as a reference drug (IC50= 6.99 µM). Compound 4a was further subjected to cell cycle analysis that indicated the decrease in cell population in the G2/M phase when compared to the untreated control cells. In addition, it showed significant increase in the late apoptosis in Annexin-V FTIC study compared to the control cells. An enzymatic inhibitory study on compound 4a against c-Met and MAP kinases revealed its better activity against c-Met kinase with (IC50 = 0.27 µM) compared to sunitinib (IC50 = 0.18 µM). Molecular docking study was conducted to reveal the interactions of compound 4a in the active site of c-Met kinase. Computational ADME study was performed to insure that compound 4a has proper pharmacokinetic and drug-likeness properties.Graphical abstractGraphical abstract for this article
  • Wedtrilosides A and B, two new diterpenoid glycosides from the leaves of
           Wedelia trilobata (L.) Hitchc. with α-amylase and α-glucosidase
           inhibitory activities
    • Abstract: Publication date: Available online 8 January 2019Source: Bioorganic ChemistryAuthor(s): Nguyen Thi Luyen, Pham Thanh Binh, Pham Thi Tham, Ta Manh Hung, Nguyen Hai Dang, Nguyen Tien Dat, Nguyen Phuong Thao In the ongoing research to find new diabetes constituents from the genus Wedelia, the chemical constituent of Wedelia trilobata leaves, a Vietnamese medicinal plant species used to treat type 2 diabetes mellitus, was selected for detailed investigation. From a methanolic extract, two new ent-kaurane diterpenoids, wedtrilosides A and B (1 and 2), along with five known metabolites (3-7), were isolated from W. trilobata. The chemical structures of (1-7) were assigned via spectroscopic techniques (IR, 1D, 2D NMR and HR-QTOF-MS data) and chemical methods. The isolates were evaluated for α-amylase and α-glucosidase inhibitory activities compared to the clinical drug acarbose. Among them, compounds 4, 6, and 7 showed the most potent against α-glucosidase enzyme with IC50 values of 27.54 ± 1.12, 173.78 ± 2.37, and 190.40 ± 2.01 μg/mL. While moderate inhibitory effect against α-amylase was observed with compounds 6 and 7 (with IC50 = 181.97 ± 2.62 and 52.08 ± 0.56 μg/mL, respectively). The results suggested that the antidiabetic properties from the leaves of W. trilobata are not simply a result of each isolated compound, but are due to other factors such as the accessibility of polyphenolic groups to α-amylase and α-glucosidase activities.Graphic abstractGraphical abstract for this article
  • Discovery of a novel series of hDHODH inhibitors with anti-pulmonary
           fibrotic activities
    • Abstract: Publication date: Available online 7 January 2019Source: Bioorganic ChemistryAuthor(s): Kuan Lu, Yanfang Zhao, Guodong Wu, Hao Hu, Mingzhong Wang, Guowei Gong, Yuyang Jiang Human dihydroorotate dehydrogenase (hDHODH) is a flavin-dependent enzyme essential to pyrimidine de novo biosynthesis, which serves as an attractive therapeutic target for the treatment of autoimmune disorders. A novel series of hDHODH inhibitors was developed based on a lead which was obtained by a medicinal chemistry exploration. Most compounds showed moderate to significant potency against hDHODH, compounds 5d, 5e, and 6a effectively inhibited the activities of hDHODH with IC50 values from 0.9 to 2.8 μM. Further studies showed that compound 5e also effectively suppressed proliferation of the activated PBMCs (IC50 = 20.35 μM). Surprisingly, compound 5e also showed anti-pulmonary fibrotic activity similar to that of pirfenidone in vitro assay. Therefore, compound 5e might have potential to be developed as a novel hDHODH inhibitors for autoimmune diseases therapy.Graphical abstractGraphical abstract for this article
  • O-Linked Melatonin Dimers as Bivalent Ligands Targeting Dimeric Melatonin
    • Abstract: Publication date: Available online 4 January 2019Source: Bioorganic ChemistryAuthor(s): Angeliki Karamitri, Mirna S. Sadek, Anne-Sophie Journé, Florence Gbahou, Romain Gerbier, Mai B. Osman, Samy A. M. Habib, Ralf Jockers, Darius P. Zlotos A series of dimeric melatonin analogues 3a-e obtained by connecting two melatonin molecules through the methoxy oxygen atoms with spacers spanning 16-24 atoms and the agomelatine dimer 7 were synthesized and characterized in 2-[125-I]-iodomelatonin binding assays, bioluminescence resonance energy transfer (BRET) experiments, and in functional cAMP and β-arrestin recruitment assays at MT1 and MT2 receptors. The binding affinity of 3a-e generally increased with increasing linker length. Bivalent ligands 3a-e increased BRET signals of MT1 dimers up to 3-fold compared to the monomeric control ligand indicating the simultaneous binding of the two pharmacophores to dimeric receptors. Bivalent ligands 3c and 7 exhibited important changes in functional properties on the Gi/cAMP pathway but not on the β-arrestins pathway compared to their monomeric counterparts. Interestingly, 3c (20 atoms spacer) shows inverse agonistic properties at MT2 on the Gi/cAMP pathway. In conclusion, these findings indicate that O-linked melatonin dimers are promising tools to develop signalling pathway-based bivalent melatonin receptor ligands.Graphical abstractGraphical abstract for this article
  • Lanceoleins A−G, hydroxychalcones, from the flowers of Coreopsis
           lanceolata and their chemopreventive effects against human colon cancer
    • Abstract: Publication date: Available online 4 January 2019Source: Bioorganic ChemistryAuthor(s): Hyoung-Geun Kim, Hyun-Ji Oh, Jung-Hwan Ko, Hae Seong Song, Yeong-Geun Lee, Se Chan Kang, Dae Young Lee, Nam-In Baek Seven new chalcones, lanceolein A−G (compounds 5 and 7−12), as well as five known chalcones (1−4 and 6), were isolated from the methanolic extract of Coreopsis lanceolata flowers. The chemical structures of 5 and 7−12 were determined on the basis of spectroscopic data interpretation. All compounds inhibited the production of nitrite oxide (NO) induced by LPS in RAW264.7 macrophage cells. Also, compounds 1−6 showed moderated cytotoxicity against human colon cancer cell lines, while compounds 7−12 hardly showed the cytotoxicity. Especially, compounds 2, 5, and 6 exhibited a little higher cytotoxicity on HCT15 cells, with IC50 values of 43.7 ± 2.17 μM, 35.6 ± 0.24 μM, and 47.9 ± 1.18 μM, respectively. In the Tali assay, compounds 2 and 5 increased the numeral of apoptotic cells. These compounds also significantly promoted the expression of apoptotic proteins including PARP and caspase-3.Graphical abstractGraphical abstract for this article
  • Identification of 1,2,4-triazoles as new thymidine phosphorylase
           inhibitors: Future anti-tumor drugs
    • Abstract: Publication date: Available online 4 January 2019Source: Bioorganic ChemistryAuthor(s): Sohail Anjum Shahzad, Muhammad Yar, Zulfiqar Ali Khan, Lubna Shahzadi, Syed Ali Raza Naqvi, Adeem Mahmood, Sami Ullah, Ahson Jabbar Shaikh, Tauqir Ali Sherazi, Adebayo Tajudeen Bale, Jędrzej Kukułowicz, Marek Bajda Thymidine phosphorylase (TP) is over expressed in several solid tumors and its inhibition can offer unique target suitable for drug discovery in cancer. A series of 1,2,4-triazoles 3a–3l has been synthesized in good yields and subsequently inhibitory potential of synthesized triazoles 3a–3l against thymidine phosphorylase enzyme was evaluated. Out of these twelve analogs five analogues 3b, 3c, 3f, 3l and 3l exhibited a good inhibitory potential against thymidine phosphorylase. Inhibitory potential in term of IC50 values were found in the range of 61.98 ± 0.43 to 273.43 ± 0.96 μM and 7-Deazaxanthine was taken as a standard inhibitor with IC50 = 38.68 ± 4.42 μM. Encouraged by these results, more analogues 1,2,4-triazole-3-mercaptocarboxylic acids 4a–4g were synthesized and their inhibitory potential against thymidine phosphorylase was evaluated. In this series, six analogues 4b–4g exhibited a good inhibitory potential in the range of 43.86 ± 1.11 to 163.43 ± 2.03 μM. Angiogenic response of 1,2,4-triazole acid 4d was estimated using the chick chorionic allantoic membrane (CAM) assay. In the light of these findings, structure activity relationship and molecular docking studies of selected triazoles to determine the key binding interactions was discussed. Docking studies demonstrate that synthesized analogues interacted with active site residues of thymidine phosphorylase enzyme through π-π stacking, thiolate and hydrogen bonding interactions.Graphical abstractGraphical abstract for this article
  • Mitochondria-targeted triphenylphosphonium conjugated glycyrrhetinic acid
           derivatives as potent anticancer drugs
    • Abstract: Publication date: Available online 3 January 2019Source: Bioorganic ChemistryAuthor(s): Le Jin, Lumei Dai, Min Ji, Hengshan Wang Glycyrrhetinic acid has been usually studied for their anti-tumor activities. However, the low bioavailability and poor aqueous solubility as well as limited intracellular accumulation have limited their utility. In this present study, a series of new glycyrrhetinic acid conjugates with a triphenylphosphonium cation (TTP+) moiety, meant to specifically target them to tumor cells mitochondria, have been designed and synthesized. Among them, compound 2f possessed excellent antitumor activities against the tested human cancer cells, and simultaneously exhibited better cell selectivity between cancer cells and normal cells than glycyrrhetinic acid and HCPT. Moreover, 2f significantly induced cell cycle arrest at the G2/M phase, and effectively inhibited cancer cells proliferation and migration. Mechanism studies revealed that 2f triggered apoptosis through the mitochondrial pathway via the collapse of mitochondrial membrane potential, reactive oxygen species production and the activation of caspase-9 and caspase-3.Graphical abstractGraphical abstract for this article
  • Synthesis of novel benzenesulfonamide bearing 1,2,3-triazole linked
           hydroxy-trifluoromethylpyrazolines and hydrazones as selective carbonic
           anhydrase isoforms IX and XII inhibitors
    • Abstract: Publication date: Available online 3 January 2019Source: Bioorganic ChemistryAuthor(s): Vikas Sharma, Rajiv Kumar, Silvia Bua, Claudiu T. Supuran, Pawan K. Sharma A series of twenty four hydroxy-trifluoromethylpyrazoline-carbonyl-1,2,3-triazoles and four hydrazones bearing benzenesulfonamide moieties was obtained by condensation of carboxyhydrazides with substituted 1,3-diketones. All the newly synthesized compounds were investigated as inhibitors of physiologically and pharmacologically relevant human (h) carbonic anhydrsae (CA, EC cytosolic isoforms hCA I and II, as well as transmembrane tumor-assosciated isoforms hCA IX and XII. These compounds exhibited excellent CA inhibitory potency against the four CA isoenzymes as compared to clinically used reference drug acetazolamide (AAZ). Some compounds bearing bulkier group at C-5ˈ position of 1,2,3-triazoles ring were weaker inhibitors of hCA I. Inhibition assay against hCA II indicates, that several derivatives exhibited upto 27-fold more effective inhibitory activity compared to AAZ. Five of the assayed compounds displayed low nanomolar potency (Ki≤ 10 nM) against hCA IX, whereas five compounds were found to be endowed with excellent inhibitory potencies (Ki≤ 5 nM) against hCA XII. The biological activity profile presented herein will be useful for designing new leads and provide candidates for preclinical investigations.Graphical abstract9a, 9d, 9e, 10a, 10f Ki (nM) < 60 against hCA I9a-9d, 10a, 12a Ki (nM) < 1 against hCA II10f, 11f, 12a, 12c, 12f Ki (nM) < 15 against hCA IX10f, 11e, 12a-12c Ki (nM) < 6 against hCA XIIGraphical abstract for this article
  • Exploring the antimalarial potential of the methoxy-thiazinoquinone
           scaffold: identification of a new lead candidate
    • Abstract: Publication date: Available online 3 January 2019Source: Bioorganic ChemistryAuthor(s): Concetta Imperatore, Marco Persico, Maria Senese, Anna Aiello, Marcello Casertano, Paolo Luciano, Nicoletta Basilico, Silvia Parapini, Antonella Paladino, Caterina Fattorusso, Marialuisa Menna A small library of antiplasmodial methoxy-thiazinoquinones, rationally designed on the model of the previously identified hit 1, has been prepared by a simple and inexpensive procedure. The synthetic derivatives have been subjected to in vitro pharmacological screening, including antiplasmodial and toxicity assays. These studies afforded a new lead candidate, compound 9, endowed with higher antiplasmodial potency compared to 1, a good selectivity index when tested against a panel of mammalian cells, no toxicity against RBCs, a synergistic antiplasmodial action in combination with dihydroartemisinin, and a promising inhibitory activity on stage V gametocyte growth. Computational studies provided useful insights into the structural requirements needed for the antiplasmodial activity of thiazinoquinone compounds and on their putative mechanism of action.Graphical abstractGraphical abstract for this article
  • Synthesis, anticancer effect and molecular modeling of new
           thiazolopyrazolyl coumarin derivatives targeting VEGFR-2 kinase and
           inducing cell cycle arrest and apoptosis
    • Abstract: Publication date: Available online 3 January 2019Source: Bioorganic ChemistryAuthor(s): Tahia K. Mohamed, Rasha Z. Batran, Samia A. Elseginy, Mamdouh M. Ali, Abeer E. Mahmoud New thiazolopyrazolyl coumarin derivatives were synthesized and tested for their anticancer potential in vitro against five different human cell lines, including breast MCF-7, lung A549, prostate PC3, liver HepG2 and normal melanocyte HFB4. Breast carcinoma revealed higher sensitivity towards compounds 7a, 8c, 9b, 9c and 9d with IC50 values ranging from 5.41-10.75μM in comparison to the reference drug doxorubicin (IC50= 6.73 μM). In addition, no noticeable toxicity was exhibited towards normal cells HFB4. Moreover, in vitro studies of the VEGFR-2 inhibition in human breast cancer MCF-7 cell line for the promising cytotoxic compounds showed that compounds 7a, 8c, 9b, 9c and 9d were potent inhibitors at low micromolar concentrations (IC50= 0.034-0.582 μM) compared to the reference drug, sorafenib (IC50= 0.019 μM). Several theoretical and experimental studies were done to reveal the molecular mechanisms that control breast carcinoma metastasis. The mechanistic effectiveness in cell cycle progression, apoptotic induction and gene regulation was assessed for the promising compound 9d due to its remarkable cytotoxic activity against MCF-7 and significant VEGFR-2 inhibition. Flow cytometeric analysis showed that compound 9d induced cell growth cessation at G2/M phase and increased the percentage of cells at pre-G1 phase that stimulates the apoptotic death of MCF-7 cells. Furthermore, real time PCR assay illustrated that compound 9d up regulated p53 gene expression and elevated Bax/Bcl-2 ratio which confirmed the mechanistic pathway of compound 9d. Moreover, the apoptotic induction of breast cancer cells MCF-7 was enhanced effectively through activation of caspases-7 and 9 by compound 9d. On the other hand, a set of in silico methods such as molecular docking, molecular dynamics simulation, QSAR analysis as well as ADMET analysis was performed in order to study the protein-ligand interactions and the relationship between the physicochemical properties and the inhibitory activity of the promising compounds 7a, 8c and 9d. Based on the aforementioned findings, compound 9d could be considered as effective apoptosis modulator and promising lead for future development of new anti-breast cancer agents.Graphical abstractGraphical abstract for this article
  • The mechanism of interactions between flavan-3-ols against a-glucosidase
           and their in vivo antihyperglycemic effects
    • Abstract: Publication date: Available online 3 January 2019Source: Bioorganic ChemistryAuthor(s): Ling-Ling Zhang, Lin Han, Shi-Yi Yang, Xue-Mei Meng, Wen-Fang Ma, Min Wang Catechin and epicatechin are flavan-3-ols, with (+)-catechin (C) and (−)-epicatechin (EC) being the most common optical isomers found in nature. In this study, we found that C and EC showed notable inhibitory activity against a-glucosidase (AGH), and that both inhibition activities reversible and competitive. Additionally, we observed that C and EC quenched the intrinsic fluorescence of AGH through a static quenching mechanism, and that the electrostatic force was the predominant driving factor in the binding reaction. Molecular docking studies indicated that the benzene-ring-4′-hydroxyphenyl construct on flavan-3-ol plays an important role in AGH inhibition, and that the inhibition increases along with increased binding of amino acid residues at this site. Furthemore, C and EC inhibited glucose absorption in everted intestine sleeves in vitro and suppressed increases in postprandial blood glucose levels in vivo. Our results suggest that C and EC are useful to protect against hyperglycemia through inhibiting the activity of a-glucosidase.Graphical abstractGraphical abstract for this article
  • Targeting Microbial Resistance: Synthesis, Antibacterial Evaluation, DNA
           Binding and Modeling Study of New Chalcone-Based Dithiocarbamate
    • Abstract: Publication date: Available online 3 January 2019Source: Bioorganic ChemistryAuthor(s): Marwa Ayman, Shahenda M. El-Messery, Elsayed E. Habib, Sara T. Al-Rashood, Abdulrahman A. Almehizia, Hamad M. Alkahtani, Ghada S. Hassan New dithiocarbamate chalcone-based derivatives were synthesized, their structures were elucidated using different spectroscopic techniques. They were subjected to antimicrobial screening against selected Gram negative bacteria focusing on microbial resistance. Bacterial resistance was targeted via phosphoethanolamine transferase enzyme. Most of the synthesized compounds showed equal or higher activity to colistin standard. Compound 24 proved to be the most active candidate with MIC of 8 µg/ml against both Ps12 and K4 and MBC of 32 µg/ml against Ps12 and 16 µg/ml against K4 Molecular docking study showed that 20, 22,24 and 25 had good binding affinity with active site residues via Thr280. DNA macromolecule was further targeted. Compounds 28 and 34 were recorded to have better DNA binding than doxurubucin with IC50 of 27.48 and 30.97 µg/ml respectively, suggesting that it could have a role in their higher antibacterial effect. Their docking into DNA has shown a clear intercalation matching with antibacterial data. Pharmacokinetics parameters of active compounds showed that they have better absorption through GIT.Graphical abstractGraphical abstract for this article
  • Synthesis and Biological Evaluation of Novel Tris-Chalcones as Potent
           Carbonic Anhydrase, Acetylcholinesterase, Butyrylcholinesterase and
           α-Glycosidase Inhibitors
    • Abstract: Publication date: Available online 2 January 2019Source: Bioorganic ChemistryAuthor(s): Serdar Burmaoglu, Ali Osman Yilmaz, M. Fatih Polat, Rüya Kaya, İlhami Gulcin, Oztekin Algul A novel class of fluoro-substituted tris-chalcones derivatives (5a-5i) was synthesized from phloroglucinol and corresponding benzaldehydes. A three step synthesis method was followed for the production of these tris-chalcone compounds. The structures of the newly synthesized compounds (5a-5i) were confirmed on the basis of IR, 1H NMR, 13C NMR, and elemental analysis. The compounds’ inhibitory activities were tested against human carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase (α-Gly). These chalcone derivatives had Ki values in the range of 19.58-78.73 nM for hCA I, 12.23-41.70 nM for hCA II, 1.09-6.84 nM for AChE, 8.30-32.30 nM for BChE and 0.93±0.20-18.53±5.06 nM against α-glycosidase. These results strongly support the promising nature of the tris-chalcone scaffold as selective carbonic anhydrase, acetylcholine esterase, butyrylcholinesterase, and α-glycosidase inhibitor. Overall, due to these derivatives’ inhibitory potential on the tested enzymes, they are promising drug candidates for the treatment of diseases like glaucoma, leukemia, epilepsy; Alzheimer’s disease; type-2 diabetes mellitus that are associated with high enzymatic activity of carbonic anhydrase, acetylcholine esterase, butyrylcholinesterase, and α-glycosidase.Graphical abstractGraphical abstract for this article
  • Synthesis and biological activity of a potent optically pure autoinducer-2
           quorum sensing agonist
    • Abstract: Publication date: April 2019Source: Bioorganic Chemistry, Volume 85Author(s): Osvaldo S. Ascenso, Inês M. Torcato, Ana Sofia Miguel, João C. Marques, Karina B. Xavier, M. Rita Ventura, Christopher D. Maycock Quorum sensing (QS) regulates population-dependent bacterial behaviours, such as toxin production, biofilm formation and virulence. Autoinducer-2 (AI-2) is to date the only signalling molecule known to foster inter-species bacterial communication across distantly related bacterial species. In this work, the synthesis of pure enantiomers of C4-propoxy-HPD and C4-ethoxy-HPD, known AI-2 analogues, has been developed. The optimised synthesis is efficient, reproducible and short. The (4S) enantiomer of C4-propoxy-HPD was the most active compound being approximately twice as efficient as (4S)-DPD and ten-times more potent than the (4R) enantiomer. Additionally, the specificity of this analogue to bacteria with LuxP receptors makes it a good candidate for clinical applications, because it is not susceptible to scavenging by LsrB-containing bacteria that degrade the natural AI-2. All in all, this study provides a new brief and effective synthesis of isomerically pure analogues for QS modulation that include the most active AI-2 agonist described so far.Graphical abstractBoth enantiomers of Propoxy-DPD have been synthesised and tested. The (4S) enantiomer was the mostactive AI-2 agonist described so far.Graphical abstract for this article
  • A molecular hybrid producing simultaneously singlet oxygen and nitric
           oxide by single photon excitation with green light
    • Abstract: Publication date: April 2019Source: Bioorganic Chemistry, Volume 85Author(s): Cristina Parisi, Mariacristina Failla, Aurore Fraix, Antonio Rescifina, Barbara Rolando, Loretta Lazzarato, Venera Cardile, Adriana C.E. Graziano, Roberta Fruttero, Alberto Gasco, Salvatore Sortino Combination of photosensitizers (PS) for photodynamic therapy with NO photodonors (NOPD) is opening intriguing horizons towards new and still underexplored multimodal anticancer and antibacterial treatments not based on “conventional” drugs and entirely controlled by light stimuli. In this contribution, we report an intriguing molecular hybrid based on a BODIPY light-harvesting antenna that acts simultaneously as PS and NOPD upon single photon excitation with the highly biocompatible green light. The presented hybrid offers a combination of superior advantages with respect to the other rare cases reported to date, meeting most of the key criteria for both PSs and NOPDs in the same molecular entity such as: (i) capability to generate 1O2 and NO with single photon excitation of biocompatible visible light, (ii) excellent 1O2 quantum yield and NO quantum efficiency, (iii) photogeneration of NO independent from the presence of oxygen, (iv) large light harvesting properties in the green region. Furthermore, this compound together with its stable photoproduct, is well tolerated by both normal and cancer cells in the dark and exhibits bimodal photomortality of cancer cells under green light excitation due to the combined action of the cytotoxic 1O2 and NO.Graphical abstractGraphical abstract for this article
  • Expansion of the scaffold diversity for the development of highly
           selective butyrylcholinesterase (BChE) inhibitors: Discovery of new hits
           through the pharmacophore model generation, virtual screening and
           molecular dynamics simulation
    • Abstract: Publication date: April 2019Source: Bioorganic Chemistry, Volume 85Author(s): Xin Lu, Hongyu Yang, Qihang Li, Yao Chen, Qi Li, You Zhou, Feng Feng, Wenyuan Liu, Qinglong Guo, Haopeng Sun Butyrylcholinesterase (BChE) is recently considered as a new target for the treatment of Alzheimer’s disease (AD). There is an increasing interest in the development of BChE inhibitors. In the present study, a set of pharmacophore models for BChE was developed and validated. Based on the models, virtual screening was performed on five compound collections, from which seventeen potential hits were retained for biological investigation. In total, eight of these seventeen potential hits showed selective BChE inhibitory activity. Moreover, four compounds displayed IC50 values in sub-micromolar range on eqBChE and three displayed IC50 values
  • Synthesis of novel quinoline-based thiadiazole, evaluation of their
           antileishmanial potential and molecular docking studies
    • Abstract: Publication date: April 2019Source: Bioorganic Chemistry, Volume 85Author(s): Noor Barak Almandil, Muhammad Taha, Fazal Rahim, Abdul Wadood, Syahrul Imran, Mohammed A. Alqahtani, Yasser A. Bamarouf, Mohamed Ibrahim, Ashik Mosaddik, Mohammed Gollapalli New series of quinoline-based thiadiazole analogs (1–20) were synthesized, characterized by EI-MS, 1H NMR and 13C NMR. All synthesized compounds were subjected to their antileishmanial potential. Sixteen analogs 1–10, 12, 13, 16, 17, 18 and 19 with IC50 values in the range of 0.04 ± 0.01 to 5.60 ± 0.21 µM showed tremendously potent inhibition as compared to the standard pentamidine with IC50 value 7.02 ± 0.09 µM. Analogs 11, 14, 15 and 20 with IC50 8.20 ± 0.35, 9.20 ± 0.40, 7.20 ± 0.20 and 9.60 ± 0.40 µM respectively showed good inhibition when compared with the standard. Structure-activity relationships have been also established for all compounds. Molecular docking studies were performed to determine the binding interaction of the compounds with the active site target.Graphical abstractNew series of quinoline based thiadiazole analogs (1–20) were synthesized and evaluated for antileishmanial potential.Graphical abstract for this article
  • In vitro and in silico evaluation of new thiazole compounds as monoamine
           oxidase inhibitors
    • Abstract: Publication date: April 2019Source: Bioorganic Chemistry, Volume 85Author(s): Begüm Nurpelin Sağlık, Betül Kaya Çavuşoğlu, Derya Osmaniye, Serkan Levent, Ulviye Acar Çevik, Sinem Ilgın, Yusuf Özkay, Zafer Asım Kaplancıklı, Yusuf Öztürk New twenty compounds bearing thiazole ring (3a-3t) were designed and synthesized as monoamine oxidase (MAO) inhibitors. The fluorometric enzyme inhibition assay was used to determine the biological effects of synthesized compounds. Most of them showed remarkable inhibitory activity against both MAO-A and MAO-B. By comparing their IC50 values, it can be seen that active derivatives displayed generally selectivity on MAO-B enzyme. Compounds 3j and 3t, which bear dihydroxy moiety at the 3rd and 4th position of phenyl ring, were the most active derivatives in the series against both isoenzymes. Compounds 3j and 3t showed significant inhibition profile on MAO-A with the IC50 values of 0.134 ± 0.004 µM and 0.123 ± 0.005 µM, respectively, while they performed selectivity against MAO-B with the IC50 values of 0.027 ± 0.001 µM and 0.025 ± 0.001 µM, respectively. Also, docking studies about these compounds were carried out to evaluate their binding modes on the active regions of MAO-A and MAO-B.Graphical abstractThe most active compound 3t in the active region of hMAO-B (PDB ID: 2V5Z).Graphical abstract for this article
  • Biphenyl-3-oxo-1,2,4-triazine linked piperazine derivatives as potential
           cholinesterase inhibitors with anti-oxidant property to improve the
           learning and memory
    • Abstract: Publication date: April 2019Source: Bioorganic Chemistry, Volume 85Author(s): Prabhash Nath Tripathi, Pavan Srivastava, Piyoosh Sharma, Manish Kumar Tripathi, Ankit Seth, Avanish Tripathi, Sachchida Nand Rai, Surya Pratap Singh, Sushant K. Shrivastava A series of novel piperazine tethered biphenyl-3-oxo-1,2,4-triazine derivatives were designed, and synthesized. Amongst the synthesized analogs, compound 6g showed significant non-competitive inhibitory potential against acetylcholinesterase (AChE, IC50; 0.2 ± 0.01 μM) compared to standard donepezil (AChE, IC50: 0.1 ± 0.002 μM). Compound 6g also exhibited significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE (22.22 ± 1.11%) and showed good CNS permeability in PAMPA-BBB assay (Pe(exp), 6.93 ± 0.46). The in vivo behavioral studies of compound 6g indicated significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. Further, ex vivo studies showed a significant AChE inhibition and reversal of the scopolamine-induced oxidative stress by compound 6g. Moreover, molecular docking and dynamics simulations of compound 6g showed a consensual binding affinity and active site interactions with the PAS and active catalytic site (CAS) residues of AChE.Graphical abstractGraphical abstract for this article
  • The first synthesis, carbonic anhydrase inhibition and anticholinergic
           activities of some bromophenol derivatives with S including natural
    • Abstract: Publication date: April 2019Source: Bioorganic Chemistry, Volume 85Author(s): Cetin Bayrak, Parham Taslimi, Halide Sedef Karaman, Ilhami Gulcin, Abdullah Menzek Starting from vanillin, known four benzyl bromides with Br were synthesized. The first synthesis of natural product 3,4-dibromo-5-((methylsulfonyl)methyl)benzene-1,2-diol (2) and 3,4,6-tribromo-5-((methylsulfonyl)methyl)benzene-1,2-diol (3) and derivatives were carried out by demethylation, acetylatilation, oxidation and hydrolysis reactions of the benzyl bromides. Also, these compounds were tested against some important enzymes like acetylcholinesterase and butyrylcholinesterase enzymes, carbonic anhydrase I, and II isoenzymes. The novel bromophenols showed Ki values of in range of 53.75 ± 12.54–234.68 ± 46.76 nM against hCA I, 42.84 ± 9.36 and 200.54 ± 57.25 nM against hCA II, 0.84 ± 0.12–14.63 ± 3.06 nM against AChE and 0.93 ± 0.20–18.53 ± 5.06 nM against BChE. Induced fit docking process performed on the compounds inhibiting hCA I, hCA II, AChE, and BChE receptors. Hydroxyl group should exist at the aromatic ring of the compounds for inhibition of the enzymes. The moieties reported in this study will be useful for design of more potent and selective inhibitors against the enzymes.Graphical abstractGraphical abstract for this article
  • The monoamine oxidase inhibition properties of C6-mono- and
           N3/C6-disubstituted derivatives of 4(3H)-quinazolinone
    • Abstract: Publication date: April 2019Source: Bioorganic Chemistry, Volume 85Author(s): Malikotsi A. Qhobosheane, Lesetja J. Legoabe, Anél Petzer, Jacobus P. Petzer Parkinson’s disease is characterised by the death of the nigrostriatal neurons and depletion of striatal dopamine. The standard symptomatic therapy consists of dopamine replacement with l-dopa, the metabolic precursor of dopamine, which represents the most effective treatment. Since monoamine oxidase (MAO) B is a key dopamine metabolising enzyme in the brain, MAO-B inhibitors are often used as adjuvants to l-dopa. In addition to the symptomatic benefits offered by MAO-B inhibitors, these drugs may also possess neuroprotective properties and possibly delay the progression of Parkinson’s disease. Based on the therapeutic use of MAO-B inhibitors, the present study evaluates a series of mono- and disubstituted derivatives of 4(3H)-quinazolinone as potential inhibitors of recombinant human MAO-A and MAO-B. Twelve C6-monosubstituted and nine N3/C6-disubstituted 4(3H)-quinazolinone derivatives were synthesised, which led to the discovery of novel quinazolinone derivatives with micromolar and submicromolar activities as inhibitors of MAO-B. The most potent mono- and disubstituted derivatives exhibited IC50 values of 6.35 μM (7f) and 0.685 μM (8b), respectively. This study identifies suitable substitution patterns for the design of 4(3H)-quinazolinone derivatives as MAO-B inhibitors.Graphical abstractGraphical abstract for this article
  • Synthesis, molecular properties prediction and biological evaluation of
           indole-vinyl sulfone derivatives as novel tubulin polymerization
           inhibitors targeting the colchicine binding site
    • Abstract: Publication date: April 2019Source: Bioorganic Chemistry, Volume 85Author(s): Wenlong Li, Honghao Sun, Feijie Xu, Wen Shuai, Jie Liu, Shengtao Xu, Hequan Yao, Cong Ma, Zheying Zhu, Jinyi Xu Twenty-two novel indole-vinyl sulfone derivatives were designed, synthesized and evaluated as tubulin polymerization inhibitors. The physicochemical and drug-likeness properties of all target compounds were predicted by Osiris calculations. All compounds were evaluated for their antiproliferative activities, among them, compound 7f exhibited the most potent activity against a panel of cancer cell lines, which was 2–7 folds more potent than our previously reported compound 4. Especially, 7f displayed about 8-fold improvement of selective index as compared with compound 4, indicating that 7f might have lower toxicity. Besides, 7f inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Further investigations showed that compound 7f effectively disrupted microtubule network, caused cell cycle arrest at G2/M phase and induced cell apoptosis in K562 cells. Moreover, 7f reduced the cell migration and disrupted capillary-like tube formation in HUVEC cells. Importantly, the in vivo anti-tumor activity of 7f was validated in H22 liver cancer xenograft mouse model without apparent toxicity, suggesting that 7f is a promising anti-tubulin agent for cancer therapy.Graphical abstractGraphical abstract for this article
  • Synthesis of benzothiazole derivatives as a potent α-glucosidase
    • Abstract: Publication date: April 2019Source: Bioorganic Chemistry, Volume 85Author(s): Mohammed Gollapalli, Muhammad Taha, Muhammad Tariq Javid, Noor Barak Almandil, Fazal Rahim, Abdul Wadood, Ashik Mosaddik, Mohamed Ibrahim, Mohammed A. Alqahtani, Yasser A. Bamarouf Diabetes is one of the pre-dominant metabolic disorders all over the world. It is the prime reason of mortality and morbidity due to hyperglycemia which is link with numerus obstacles. Delaying absorption and digestion of carbohydrate has great therapeutic impact for governing postprandial hyperglycemia. Consequently, alpha glucosidase is one of the potential therapeutic approaches that reduce absorption of glucose and delay carbohydrate digestion hence maintaining blood glucose level. In this regard we have synthesized benzothiazole based oxadiazole in search of potent anti-diabetic agent as α-glucosidase Inhibitors. Benzothiazole based oxadiazole derivatives 1–23 have been synthesized, characterized by 1HNMR, 13CNMR, and MS and evaluated for α-glucosidase Inhibition. All analogs exhibited a varying degree of α-glucosidase inhibitory activity with IC50 values ranging in between 0.5 ± 0.01–30.90 ± 0.70 μM when compared with the standard acarbose (IC50 = 866.30 ± 3.20 μM). Structure activity relationship has been established for all compounds. Molecular docking studies were performed to predict the binding interaction of the compounds with the active site of enzyme.Graphical abstractGraphical abstract for this article
  • Ursolic and oleanolic acid derivatives with cholinesterase inhibiting
    • Abstract: Publication date: April 2019Source: Bioorganic Chemistry, Volume 85Author(s): Anne Loesche, Alexander Köwitsch, Susana D. Lucas, Zayan Al-Halabi, Wolfgang Sippl, Ahmed Al-Harrasi, René Csuk Triterpenoids are in the focus of scientific interest, and they were evaluated for many pharmacological applications among them their ability to act as inhibitors of cholinesterases. These inhibitors are still of interest as drugs that improve the life quality of patients suffering from age-related dementia illnesses especially of Alzheimer’s disease. Herein, we prepared several derivatives of ursolic and oleanolic acid and screened them in Ellman’s assays for their ability to inhibit acetylcholinesterase and/or butyrylcholinesterase, and for each of the active compounds the type of inhibition was determined. As a result, several compounds were shown as good inhibitors for acetylcholinesterase and butyrylcholinesterase even in a micromolar range. An ursolic acid derived hydroxyl-propinyl derivative 10 was a competitive inhibitor for butyrylcholinesterase with an inhibition constant of Ki = 4.29 μM, and therefore being twice as active as gold standard galantamine hydrobromide. The best inhibitor for acetylcholinesterase, however, was 2-methyl-3-oxo-methyl-ursoloate (18), acting as a mixed-type inhibitor showing Ki = 1.72 µM and Ki′ = 1.28 μM, respectively.Graphical abstractGraphical abstract for this article
  • Syntheses and evaluation of new Quinoline derivatives for inhibition of
           hnRNP K in regulating oncogene c-myc transcription
    • Abstract: Publication date: April 2019Source: Bioorganic Chemistry, Volume 85Author(s): Bing Shu, Ping Zeng, Shuangshuang Kang, Peng-Hui Li, Dexuan Hu, Guotao Kuang, Jiaojiao Cao, Xiaoya Li, Meiling Zhang, Lin-Kun An, Zhi-Shu Huang, Ding Li Aberrant overexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a key feature in oncogenesis and progression of many human cancers. hnRNP K has been found to be a transcriptional activator to up-regulate c-myc gene transcription, a critical proto-oncogene for regulation of cell growth and differentiation. Therefore, down-regulation of c-myc transcription by inhibiting hnRNP K through disrupting its binding to c-myc gene promoter is a potential approach for cancer therapy. In the present study, we synthesized and screened a series of Quinoline derivatives and evaluated their binding affinity for hnRNP K. Among these derivatives, (E)-1-(4-methoxyphenyl)-3-(4-morpholino-6-nitroquinolin-2-yl)prop-2-en-1-one (compound 25) was determined to be the first-reported hnRNP K binding ligand with its KD values of 4.6 and 2.6 μM measured with SPR and MST, respectively. Subsequent evaluation showed that the binding of compound 25 to hnRNP K could disrupt its unfolding of c-myc promoter i-motif, resulting in down-regulation of c-myc transcription. Compound 25 showed a selective anti-proliferative effect on human cancer cell lines with IC50 values ranged from 1.36 to 3.59 μM. Compound 25 exhibited good tumor growth inhibition in a Hela xenograft tumor model, which might be related to its binding with hnRNP K. These findings illustrated that inhibition of DNA-binding protein hnRNP K by compound 25 could be a new and selective strategy of regulating oncogene transcription instead of targeting promoter DNA secondary structures such as G-quadruplexes or i-motifs.Graphical abstractA new series of Quinoline derivatives were synthesized for specific binding with hnRNP K. Subsequent evaluation showed that compound 25 could bind to hnRNP K and disrupt its activity of unfolding c-myc oncogene promoter i-motif. This down-regulated c-myc transcription and expression, resulting in tumor cells apoptosis.Graphical abstract for this article
  • Bio-guided search of active indole alkaloids from Tabernaemontana
           catharinensis: Antitumour activity, toxicity in silico and molecular
           modelling studies
    • Abstract: Publication date: April 2019Source: Bioorganic Chemistry, Volume 85Author(s): Pauline Fagundes Rosales, Flavio Ferreira Marinho, Adriana Gower, Marilda Chiarello, Bianca Canci, Mariana Roesch-Ely, Favero Reisdorfer Paula, Sidnei Moura Active plant metabolites have been used as prototype drugs. In this context, Tabernaemontana catharinensis (Apocynaceae) has been highlighted because of the presence of active indole alkaloids. Thus, this study aims the bio-guided search of T. catharinensis cytotoxic alkaloids. The chemical composition was identified by high-resolution mass spectrometry, and fractionation was performed by open column and preparative thin-layer chromatography, from plant stems. The enriched fractions were tested in vitro in tumour cells A375 (melanoma cell line) and A549 (adenocarcinomic human alveolar basal epithelial cells), and non-tumour Vero cells (African green monkey kidney epithelial cells). The alkaloids identified as active were submitted to in silico toxicity prediction by ADME-Tox and OSIRIS programs and, also, to molecular docking, using topoisomerase I (PDB ID: 1SC7) by iGEMDOCK. As a result, six sub-fractions were obtained, which were identified as containing 16-epi-affinine, 12-methoxy-n-methyl-voachalotine, affinisine, voachalotine, coronaridine hydroxyindoline and ibogamine, respectively. The affinisine-containing sub-fraction showed selective toxicity against A375, with an IC50 of 11.73 µg mL−1, and no cytotoxicity against normal cells (Vero). From the in silico toxicity test results, all indole alkaloid compounds had a low toxicity risk. The molecular docking data provided structural models and binding affinities of the plant’s indole alkaloids and topoisomerase I. In summary, this bio-guided search revealed that the indole alkaloids from T. catharinensis display selective cytotoxicity in A375 tumour cells and toxicity in silico. Particularly, affinisine might be a chemotherapeutic for A375 melanoma cells.Graphical abstractGraphical abstract for this article
  • Synthesis and bioactivities of pyrazoline benzensulfonamides as carbonic
           anhydrase and acetylcholinesterase inhibitors with low cytotoxicity
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Dilan Ozmen Ozgun, Halise Inci Gul, Cem Yamali, Hiroshi Sakagami, Ilhami Gulcin, Murat Sukuroglu, Claudiu T. Supuran 4-(3-Substitutedphenyl-5-polymethoxyphenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamides (9–16) were synthesized and their chemical structures were elucidated by 1H NMR, 13C NMR, and HRMS. The compounds designed include pyrazoline and sulfonamide pharmacophores in a single molecule by hibrit molecule approach which is a useful technique in medicinal chemistry in designing new compounds with potent activity for the desired several bioactivities. Inhibition potency of the sulfonamides were evaluated against human CA isoenzymes (hCA I and hCA II) and acetylcholinesterase (AChE) enzyme and also their cytotoxicities were investigated towards oral squamous cancer cell carcinoma (OSCC) cell lines (Ca9-22, HSC-2, HSC-3, and HSC-4) and non-tumor cells (HGF, HPLF, and HPC). Cytosolic hCA I and hCA II isoenzymes were inhibited by the sulfonamide derivatives (9–16) and Ki values were found in the range of 27.9 ± 3.2–74.3 ± 28.9 nM and 27.4 ± 1.4–54.5 ± 11.6 nM, respectively. AChE enzyme was strongly inhibited by the sulfonamide derivatives with Ki values in the range of 37.7 ± 14.4–89.2 ± 30.2 nM The CC50 values of the compounds were found between 15 and 200 µM towards OSCC malign cell lines. Their tumor selectivities were also calculated with two ways. Compound’s selectivities towards cancer cell line were found generally low, except compounds bearing 3,4-dimethoxyphenyl 14 (TS1 = 1.3, TS2 = 1.4) and 10 (TS2 = 1.4). All sulfonamide derivatives studied here can be considered as good candidates to develop novel CAs or AChE inhibitor candidates based on the enzyme inhibition potencies with their low cytotoxicity and tumor selectivity.Graphical abstractGraphical abstract for this article
  • Bioactive butylphthalide derivatives from Ligusticum chuanxiong
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Xu Zhang, Zi-ming Feng, Ya-nan Yang, Jian-shuang Jiang, Pei-cheng Zhang Seven new butylphthalide derivatives, ligusticumolide A-G (1–7), together with two known butylphthalide derivatives (8–9) were isolated from an ethanol extract of Ligusticum chuanxiong Hort. The structures of these derivatives were elucidated from analysis of 1D/2D NMR, UV, IR and HRESIMS data. The absolute configurations of these derivatives were determined by electronic circular dichroism (ECD) calculations and Mosher′s method. Ligusticumolide A (1) and ligusticumolide B (2) are enantiomers that were obtained by chiral separation. Ligusticumolide C (3) and ligusticumolide D (4) are diastereomers. All of the compounds were evaluated for their hepatoprotective activity against N-acetyl-p-aminophenol-induced HepG2 cell injury. Compounds 4, 5, and 7–9 showed more significant hepatoprotective activity than that of the positive control drug (bicyclol) at a concentration of 10 μM (p 
  • Docking- and Pharmacophore-Based Virtual Screening for the Identification
           of Novel Mycobacterium tuberculosis Protein Tyrosine Phosphatase B (MptpB)
           Inhibitor with A Thiobarbiturate Scaffold
    • Abstract: Publication date: Available online 31 December 2018Source: Bioorganic ChemistryAuthor(s): Dongfeng Zhang, Yun Lin, Xi Chen, Wenting Zhao, Dongni Chen, Meng Gao, Qinglin Wang, Bin Wang, Haihong Huang, Yongjun Lu, Yu Lu Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatase B (MptpB) is an important virulence factor for Mtb that contributes to survival of the bacteria in macrophages. The absence of a human ortholog makes MptpB an attractive target for new therapeutics to treat tuberculosis. MptpB inhibitors could be an effective treatment to overcome emerging TB drug resistance. Adopting a structure-based virtual screening strategy, we successfully identified thiobarbiturate-based drug-like MptpB inhibitor 15 with an IC50 of 22.4 μM, and as a non-competitive inhibitor with a Ki of 24.7 μM. Importantly, not only did it exhibit moderate cell membrane permeability, compound 15 also displayed potent inhibition of intracellular TB growth in the macrophage, making it an excellent lead compound for anti-TB drug discovery. To the best of our knowledge, this novel thiobarbiturate is the first class of MptpB inhibitor reported so far that leveraged docking- and pharmacophore-based virtual screening approaches. The results of preliminary structure-activity relationship demonstrated that compound 15 identified herein was not a singleton and may inspire the design of novel selective and drug-like MptpB inhibitors.Graphical abstractGraphical abstract for this article
  • Design and synthesis of new phthalazine-based derivatives as potential
           EGFR inhibitors for the treatment of hepatocellular carcinoma
    • Abstract: Publication date: Available online 31 December 2018Source: Bioorganic ChemistryAuthor(s): Ahmed T.A. Boraei, Hanaa K. Ashour, El Sayed H. El Tamany, Nahla Abdelmoaty, Abdullah I. El-Falouji, Mohamed S. Gomaa Searching for new leads in the battle of cancer will never ends, we herein disclose the design and synthesis of new phthalazine derivatives and their in vitro and in vivo testing for their antiproliferative activity. Phthalazine was selected as a privilege moiety that is incorporated in a big number of anticancer drugs in clinical use or that are still under clinical or preclinical studies. We utilized the drug extension strategy to tailor the designed compounds to fit the EGFR hydrophobic sub pocket and cleft region. The designed phthalazine derivatives was synthesized by linking phthalazine moiety with 1,3,4-oxadiazole-thione and 1,2,4-triazole-thione. Alkylation and glycosylation of the new heterocyclic systems were successfully performed to be used in the drug extension. Coupling of some phthalazine derivatives with different amino acids was also performed to improve the drug selectivity.The synthesized compounds were tested for their antiproliferative activity against cancer cells both in vivo and in vitro. The in vitro activity against hepatocellular carcinoma (HepG2 cell line) ranged from 5.7 µg/mL to 43.4 µg/mL. Compounds 31a and 16 were the most active with an IC50 5.7 µg/mL and 7.1 µg/mL, respectively compared to the standard compound doxorubicin (4.0 µg/mL). In vivo, compounds 10 and 16 showed IC50 values 7.25 μM and 7.5 μM, respectively compared to the standard compound cisplatin (IC50 9.0 μM). In silico, testing of the phthalazine derivatives showed that they are good inhibitors for EGFR. The docking studies substantiated compounds 4, 10, 16 and 31a as new lead compounds and identified Arg841 as a key residue in the cleft region for binding stronger inhibitors.Graphical abstractGraphical abstract for this article
  • Radicicol Rescues Yeast Cell Death Triggered by Expression of Human
           α-Synuclein and its A53T Mutant, but not by Human βA4 Peptide and
           Proapoptotic Protein Bax
    • Abstract: Publication date: Available online 28 December 2018Source: Bioorganic ChemistryAuthor(s): Asma Derf, Shilpa A. Verekar, Shreyans K. Jain, Sunil K. Deshmukh, Sandip B. Bharate, Bhabatosh Chaudhuri Aggregation/misfolding of α-synuclein and βA4 proteins cause neuronal cell death (NCD) associated with Parkinson’s and Alzheimer’s disease. It has been suggested that a heat shock protein-90 (Hsp90) inhibitor can prevent NCD by activating the heat shock transcription factor-1 which, in turn, upregulates molecular chaperones such as Hsp70 that targets aggregated/misfolded proteins for refolding/degradation. We have isolated radicicol, an Hsp90 inhibitor, from a fungus occurring in the crevices of marble rocks of Central India. Radicicol, which was found to be a strong antioxidant, was tested for its ability to rescue yeast cells from death induced by expression of wild-type α-synuclein, its more toxic A53T mutant, and βA4. It effectively overcomes wild-type/mutant α-synuclein mediated yeast cell death, concomitantly diminishes ROS levels, reverses mitochondrial dysfunction and prevents nuclear DNA-fragmentation, a hallmark of apoptosis. Surprisingly however, radicicol is unable to rescue yeast cells from death triggered by expression of secreted βA4. Moreover, although radicicol acts as an antioxidant it fails to prevent yeast cell death inflicted by the proapoptotic protein, Bax. Our results indicate that radicicol specifically targets aggregated/misfolded α-synuclein’s toxicity and opens up the possibility of using multiple yeast assays to screen natural product libraries for compounds that would unambiguously target α-synuclein aggregation/misfolding.Graphical abstractGraphical abstract for this article
  • Antimicrobial characteristics and biocompatibility of the surgical sutures
           coated with biosynthesized silver nanoparticles
    • Abstract: Publication date: Available online 27 December 2018Source: Bioorganic ChemistryAuthor(s): Tuba Baygar, Nurdan Sarac, Aysel Ugur, Inci Rana Karaca Surgical sutures play important role during the wound healing of the surgical sites which are known to be sensitive to microbial infections. Silver nanoparticles (AgNPs) have been recently used as promising agents against multiple-drug resistant microorganisms. This study was designed to coat the sutures with silver nanoparticles obtained via a green synthesis approach. Microbial-mediated biological synthesis of AgNPs were carried out ecofriendly using Streptomyces sp. AU2 cell-free extract and deposited on silk sutures through an in situ process. Sutures coated with biosyntehsized AgNP (bio-AgNP coated sutures) were characterized using Scanning Electron Microscopy (SEM) and elemantal analysis were carried out using Energy Dispersive X-ray Spectroscopy (EDS). The silver amount released by the bio-AgNP coated sutures was calculated by Inductively Coupled Plasma-Mass Spectroscopy (ICP-MS) throughout a degradation process. Antimicrobial potential of the bio-AgNP coated sutures was determined against common pathogenic microorganisms Candida albicans, Escherichia coli and Staphylococcus aureus. To determine the biocompatibility/cytotoxicty of the bio-AgNP coated sutures, the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) assay was used through an indirect test method; that the elutions obtained by the extraction of the sutures at 1, 4, 8 and 10. days and were placed in contact with 3T3 fibroblast cell culture. To best of our knowledge, this is the first report about coating of the nonabsorbable silk sutures with silver nanoparticles biosynthesized using a microbial extract.Graphical abstractGraphical abstract for this article
  • Cloning, overexpression and characterization of a thermostable
           β-xylosidase from Thermotoga petrophila and cooperated transformation of
           ginsenoside extract to ginsenoside 20(S)-Rg3 with a β-glucosidase
    • Abstract: Publication date: Available online 26 December 2018Source: Bioorganic ChemistryAuthor(s): Shanshan Zhang, Jingcong Xie, Linguo Zhao, Jianjun Pei, Erzheng Su, Wei Xiao, Zhenzhong Wang A thermostable β-xylosidase gene Tpexyl3 from Thermotoga petrophila DSM 13995 was cloned and overexpressed by Escherichia coli. Recombinant Tpexyl3 was purified, and its molecular weight was approximately 86.7 kDa. Its optimal activity was exhibited at pH 6.0 and 90°C. It had broad specificity to xylopyranosyl, arabinopyranosyl, arabinofuranosyl and glucopyranosyl moieties. The β-xylosidase activity of the recombinant Tpexyl3 was 6.81 U/mL in the LB medium and 151.4 U/mL in a 7.5 L bio-reactor. It was applied to transform ginsenoside extract into the pharmacologically active minor ginsenoside 20(S)-Rg3, which was combined with thermostable β-glucosidase Tpebgl3. After transforming under optimal condition, the 20 g/L of ginsenoside extract was transformed into 6.28 g/L of Rg3 within 90 min, with a corresponding molar conversion of 95.0% and Rg3 productivity of 1793.49 mg/L/h, respectively. This study is the highest report of a GH3 family glycosidase with arabinopyranosidase activity and also the first report on the high substrate concentration bioconversion of ginsenoside extract to ginsenoside 20(S)-Rg3 by using two thermostable glycosidases.Graphical abstractGraphical abstract for this article
  • 3, 9-Di-O-substituted coumestrols incorporating basic amine side chains
    • Abstract: Publication date: Available online 22 December 2018Source: Bioorganic ChemistryAuthor(s): Guoshun Luo, Zhengpu Tang, Xinyu Li, Qiangqiang Hou, Yu Chen, Kejing Lao, Hua Xiang There is much interest in the use of phytoestrogens such as coumestrol in breast cancer intervention due to their antiestrogenic activity and multiple modes of tumor cell death. However, the clear beneficial effects of naturally occurring estrogen mimetic coumestrol remain controversial due to experimental evidence that it has been shown to stimulate MCF-7 cell proliferation via agonist effect on estrogen receptor at low concentration. Herein, to disconnect the ER interaction and apoptosis-specific mechanism of coumestrol, various 3, 9-di-O-substituted coumestrols (7a-7e) and their furan ring-opened analogs (5a-5e) were synthesized and assessed for antiproliferative properties. Attachment of a dimethylamine-containing side chain to 3-O of coumestrol led to the most promising compound 7e with improved antiproliferative activity (1.7-fold increase) against MCF-7 cells, decreased estrogen activity (> 20 times weaker ERα binder) and a novel action to induce apoptosis. Mechanistic studies revealed that 7e is a tubulin polymerization inhibitor, which could arrest cell cycle at G2/M phase and induce apoptosis along with the decrease of mitochondrial membrane potential. In summary, such subtle modifications to the 3, 9-di-hydroxyl groups of coumestrol allow the generation of a novel apoptosis inducer with distinct pharmacological properties, providing an excellent starting point to future development of novel tumor-vascular disrupting agents targeting tubulin.Graphical abstractGraphical abstract for this article
  • Synthesis, antioxidant and Aβ anti-aggregation properties of new ferulic,
           caffeic and lipoic acid derivatives obtained by the Ugi four-component
    • Abstract: Publication date: Available online 21 December 2018Source: Bioorganic ChemistryAuthor(s): Mohamed Benchekroun, Irene Pachón-Angona, Vincent Luzet, Helene Martin, María-Jesús Oset-Gasque, José Marco-Contelles, Lhassane Ismaili We report herein the synthesis antioxidant and Aβ anti-aggregation capacity of (E)-N-benzyl-N-[2-(benzylamino)-2-oxoethyl]-3-(aryl)acrylamides and related (R)-N-benzyl-N-(2-(benzylamino)-2-oxoethyl)-5-(1,2-dithiolan-3-yl)pentanamides 1-12. These compounds have been obtained, via Ugi four-component reaction, from modest to good yields. Their antioxidant analysis, using the DPPH and ORAC assays, allowed us to identify compounds 8 and 9, as potent antioxidant agents, showing also strong Aβ1-40 self-aggregation inhibition, two biological properties of interest in pathologies linked to the oxidative stress, such as Alzheimer’s disease.Graphical abstractGraphical abstract for this article
  • Identification of a pyrimidinetrione derivative as the potent DprE1
           inhibitor by structure-based virtual ligand screening
    • Abstract: Publication date: Available online 13 December 2018Source: Bioorganic ChemistryAuthor(s): Ya Gao, Jinshan Xie, Ruotian Tang, Kaiyin Yang, Yahan Zhang, Lixia Chen, Hua Li Despite the increasing need of new antituberculosis drugs, the number of agents approved for the market has fallen to an all-time low. In response to the emerging drug resistance followed, structurally unique chemical entities will be highlighted. decaprenylphosphoryl-β-D-ribose oxidase (DprE1) participating in the biosynthesis of mycobacterium cell wall is a highly vulnerable and validated antituberculosis target. On the basis of it, a systematic strategy was applied to identify a high-quality lead compound (compound 50) that inhibits the essential enzyme DprE1, thus blocking the synthesis of the mycobacterial cell wall to kill M. tuberculosis in vitro and in vivo. Correspondingly, the rational design and synthetic strategy for compound 50 was reported. Notably, the compound 50 has been confirmed to be no toxicity. Altogether, our data suggest the compound 50 targeting DprE1 is a promising candidate for the tuberculosis (TB) therapy.Graphical abstractGraphical abstract for this article
  • One-pot four-component synthesis of thiazolidin-2-imines using CuI/ZnII
           dual catalysis: a new class of acetylcholinesterase inhibitors
    • Abstract: Publication date: Available online 5 December 2018Source: Bioorganic ChemistryAuthor(s): Syeda Aaliya Shehzadi, Imtiaz Khan, Aamer Saeed, Fayaz Ali Larik, Pervaiz Ali Channar, Mubashir Hassan, Hussain Raza, Qamar Abbas, Sung-Yum Seo An efficient one-pot four-component strategy involving aldehydes, amines, alkynes and isothiocyanates has been developed to access a novel series of thiazolidine-2-imines (5a-x). This process operates under the action of a cooperative catalysis composed of Cu(I) and Zn(II) delivering the desired five-membered heterocyclic compounds in good to excellent yields. Notably, this transformation avoids the use of pre-formed imines or propargylamines and proceeds via an intramolecular 5-exo-dig hydrothiolation reaction of the in situ formed propargyl thiourea. Furthermore, the biological application of these motifs was demonstrated in terms of their strong acetylcholinesterase (AChE) inhibitory activity where compound 5s was identified as the lead AChE inhibitor with an IC50 value of 0.0023 ± 0.0002 μM, 88-folds stronger inhibition than standard drug (neostigmine methyl sulphate; IC50 = 0.203 ± 0.004 μM). Molecular docking analysis reinforced the in vitro biological activity results revealing the formation of several useful interactions of the potent lead with amino acid residues in the active site of the enzyme.Graphical abstractGraphical abstract for this article
  • Structure-activity relationship of pyrazolo pyrimidine derivatives as
           inhibitors of mitotic kinesin Eg5 and anticancer agents
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): P. Muthuraja, V. Veeramani, S. Prakash, M. Himesh, U. Venkatasubramanian, P. Manisankar Human kinesin Eg5 is a potential inhibiting site for cancer chemotherapy. Blocking metaphase by binding foreign inhibitors with Eg5 eventually leads to apoptotic cell death. Here, we report the pyrazolopyrimidine derivates as potent inhibitors of Eg5 that prevents mitotic kinesin progression. IC50 values were evaluated against the motor domain of Eg5 using steady-state ATPase assay. To better understanding, we have performed molecular docking simulation. It reveals that the interactions of the proposed inhibitors with both the allosteric sites (helices α2, α3 and loopL5, and helices α4 & α6). Out of fifteen pyrazolopyrimidine derivates, three compounds (12, 25, and 27) have shown significant inhibition of Eg5. The synthesized compounds (12, 25, and 27) were tested for their in-vitro anticancer activity against cervical cancer cell line (HeLa).Graphical abstractGraphical abstract for this article
  • Design and analysis of EphA2-SAM peptide ligands: A multi-disciplinary
           screening approach
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Flavia Anna Mercurio, Concetta Di Natale, Luciano Pirone, Daniela Marasco, Enrica Calce, Marian Vincenzi, Emilia Maria Pedone, Stefania De Luca, Marilisa Leone EphA2 receptor plays a critical and debatable function in cancer and is considered a target in drug discovery. Lately, there has been a growing interest in its cytosolic C-terminal SAM domain (EphA2-SAM) as it engages protein modulators of receptor endocytosis and stability. Interestingly, EphA2-SAM binds the SAM domain from the lipid phosphatase Ship2 (Ship2-SAM) mainly producing pro-oncogenic outcomes. In an attempt to discover novel inhibitors of the EphA2-SAM/Ship2-SAM complex with possible anticancer properties, we focused on the central region of Ship2-SAM (known as Mid-Loop interface) responsible for its binding to EphA2-SAM. Starting from the amino acid sequence of the Mid-Loop interface virtual peptide libraries were built through ad hoc inserted mutations with either l- or d- amino acids and screened against EphA2-SAM by docking techniques. A few virtual hits were synthesized and experimentally tested by a variety of direct and competition-type interaction assays relying on NMR (Nuclear Magnetic Resonance), SPR (Surface Plasmon Resonance), MST (Microscale Thermophoresis) techniques. These studies guided the discovery of an original EphA2-SAM ligand antagonist of its interaction with Ship2-SAM.Graphical abstractGraphical abstract for this article
  • Synthesis, ADME, docking studies and in vivo anti-hyperglycaemic potential
           estimation of novel Schiff base derivatives from octadec-9-enoic acid
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Garima Kapoor, Dharam Pal Pathak, Rubina Bhutani, Asif Husain, Sandeep Jain, Md. Azhar Iqbal A new series of octadec-9-enoic acid schiff base entities (S1-S30) were designed and synthesized targeting peroxisome proliferator activated receptor-gamma for agonist action. Molinspiration software (online) was used to estimate drug like molecular properties of the metabolites. Docking disquisition on co-crystallized protein of PPAR-γ (PDB ID 1FM9) was carried out which showed S21, S10 and S7 as best situated in the vital sites of receptor having docking scores −9.19, −8.68 and −8.64 respectively. Free binding energy measured using model of Maestro 9.0 and was in range of from −40.01 and −80.54 kcal/mol, significant when compared with pioglitazone (−51.58 Kcal/mol). Seven best docked derivatives were assessed for in-vivo oral glucose tolerance on normal rats and anti-hyperglycaemic activity by streptozotocin induced diabetes model. S21 unveiled to be the best measured analogue among all the synthesized entities. Encouraging outcomes motivates fatty acids for further development of more effective and safer compounds.Graphical abstractGraphical abstract for this article
  • Design, synthesis and biological evaluation of novel β-pinene-based
           thiazole derivatives as potential anticancer agents via
           mitochondrial-mediated apoptosis pathway
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Yunyun Wang, Chenliang Wu, Qiangjian Zhang, Yu Shan, Wen Gu, Shifa Wang A series of novel β-pinene-based thiazole derivatives were synthesized and characterized by HRMS, 1H NMR, and 13C NMR analyses as potential antineoplastic agents. Derivatives were evaluated for their anticancer activities in vitro, and the data manifested that most target compounds showed potent anti-proliferative activities against three human cancer cell lines. Especially, compound 5g displayed excellent cytotoxic activity against Hela, CT-26, and SMMC-7721 cell lines with IC50 values of 3.48 ± 0.14, 8.84 ± 0.16, and 6.69 ± 0.15 µM, respectively. To determine the underlying mechanism of compound 5g on cell viability, DAPI staining, Annexin-V/PI staining, JC-1 staining, DCFDA staining, and Western blot analysis were performed. Our data showed that compound 5g inhibited cell proliferation by inducing apoptosis and cell cycle arrest of Hela cells at the G0/G1 phase in a dose dependent manner. Further studies revealed that compound 5g enhanced levels of reactive oxygen species (ROS), caused a decrease in mitochondrial membrane potential, increased the release of mitochondrial cytochrome C, and affected the expression of Bax, Bcl-2, caspase-3 and caspase-9. Thus, our findings indicated that compound 5g induced apoptosis in Hela through ROS-mediated mitochondrial dysfunction signaling pathways.Graphical abstractGraphical abstract for this article
  • Design, synthesis, DNA assessment and molecular docking study of novel
           2-(pyridin-2-ylimino)thiazolidin-4-one derivatives as potent antifungal
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Nadia Hanafy Metwally, Ibrahim Taha Radwan, Walaa Salah El-Serwy, Mohamed Ahmed Mohamed A series of novel 2-imino-4-thiazolidinone derivatives 4a,b was synthesized through reaction of unsymmetrical thioureas 3a,b with chloroacetic acid. Condensation of 4a,b with aromatic aldehydes 5a-eyielded the corresponding 5-arylidene derivatives 6a-j. In addition, the reaction of 4a,b with 4-arylazo-3-hydroxybenzaldehydes 8a-c furnished the respective mono-arylazo-4-thiazolidinones10a-f. All the newly synthesized compounds were confirmed by their elemental analysis and spectral data. The antifungal activity of the newly synthesized compounds was assessed and the compounds 6d, 6e, 6i, 6j, 9a,b and 10a-frevealedhigher antifungal activity towards Alternaria solani than to the standard Ridomil gold plus. Moreover, the DNA toxicity of 4-thiazolidinone derivatives 6d, 9a, 10b, 10c and 10f on the nucleic acid of Alternaria solani (KT354939) was performed and the results showed qualitatively more than 70% cleavage. Also, compounds 6i, 6j, 9b, 10c and 10f were docked inside the active site of 1ZOYenzyme and suitable binding with the active site of amino acids, were displayed according to their bond lengths, angles and conformational energy.Graphical abstractCompound 10c has a high potent activity against Alternaria Solani.Graphical abstract for this article
  • Antiproliferative 3-deoxysphingomyelin analogs: Design, synthesis,
           biological evaluation and molecular docking of pyrrolidine-based
           3-deoxysphingomyelin analogs as anticancer agents
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Ahmed H.E. Hassan, Hye Rim Park, Yoon Mi Yoon, Hye In Kim, Sung Yeun Yoo, Kun Won Lee, Yong Sup Lee Sphingomyelins and glycerophospholipids are structurally related phospholipids. Nevertheless, glycerophospholipids analogs are known as antitumor agents while sphingomyelin analogs were reported as cytoprotective agents. Herein, we have addressed the development of 3-deoxysphingomyelin analogs as cytotoxic agents possessing modified sphingobases. Thus, pyrrolidine-based 3-deoxysphingomyelin analogs were synthesized and evaluated against a panel of cell lines representing four major types of cancers. Compounds 3d, 4d and 6d elicited better GI50 values than the FDA approved drug miltefosine. Investigation of their impact on Akt phosphorylation as a possible mechanism for the antiproliferative activity of this class of compounds revealed that these compounds might elicit a concentration-dependent mechanism via inhibition of Akt phosphorylation at the lower concentration. Molecular docking predicted their binding modes to Akt to involve polar head binding to the Pleckstrin homology domain and hydrophobic tail extension into a hydrophobic pocket connecting the Pleckstrin homology domain and the kinase domain. As a whole, the described work suggests compounds 3d, 4d and 6d as promising pyrrolidine-based 3-deoxysphingomyelin analogs for development of novel cancer therapies.Graphical abstractGraphical abstract for this article
  • A new class of diamide scaffold: Design, synthesis and biological
           evaluation as potent antimitotic agents, tubulin polymerization inhibition
           and apoptosis inducing activity studies
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Khaled O. Mohamed, Islam Zaki, Ibrahim M. El-Deen, Mohammed K. Abdelhameid A new series of diamide functional compounds has been designed, synthesized and confirmed by spectroscopic methods and elemental analyses. All the synthesized compounds were evaluated for their antiproliferative activity on HepG2 cell line. Compounds 3k and 3l were proved to have potent anticancer activity equipotent or more potent than reference compound Combretastatin A-4. The results of DNA flow cytometry analysis demonstrated cell cycle arrest at G2/M phase. The extent of apoptosis induced by 3k and 3l was also determined. Moreover, the compounds produced a significant reduction in cellular microtubules for microtubule loss and potently inhibited the binding of [3H]colchicine to tubulin. Compounds 3k and 3l were proved to upregulate expression of proteins triggering apoptosis, such as p53, Bax, and decreased Bcl-2 overexpression as well as increased the expression of effector caspase- 3/7.Graphical abstractGraphical abstract for this article
  • l-fucitols+as+fucosidase+inhibitors:+Synthesis,+molecular+modelling+and+activity+against+cancer+cell+lines&rft.title=Bioorganic+Chemistry&rft.issn=0045-2068&">N-Alkyl-1,5-dideoxy-1,5-imino-l-fucitols as fucosidase inhibitors:
           Synthesis, molecular modelling and activity against cancer cell lines
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Jian Zhou, Arvind Negi, Styliana I. Mirallai, Rolf Warta, Christel Herold-Mende, Michael P. Carty, Xin-Shan Ye, Paul V. Murphy 1,5-Dideoxy-1,5-imino-l-fucitol (1-deoxyfuconojirimycin, DFJ) is an iminosugar that inhibits fucosidases. Herein, N-alkyl DFJs have been synthesised and tested against the α-fucosidases of T. maritima (bacterial origin) and B. taurus (bovine origin). The N-alkyl derivatives were inactive against the bacterial fucosidase, while inhibiting the bovine enzyme. Docking of inhibitors to homology models, generated for the bovine and human fucosidases, was carried out. N-Decyl-DFJ was toxic to cancer cell lines and was more potent than the other N-alkyl DFJs studied.Graphical abstractGraphical abstract for this article
  • Design, synthesis and biological evaluation of novel indole derivatives as
           potential HDAC/BRD4 dual inhibitors and anti-leukemia agents
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Gaoliang Cheng, Zhi Wang, Jinyu Yang, Yu Bao, Qihao Xu, Linxiang Zhao, Dan Liu HDAC inhibitors and BRD4 inhibitors were considered to be potent anti-cancer agents. Recent studies have demonstrated that HDAC and BRD4 participate in the regulation of some signal paths like PI3K-AKT. In this work, a series of indole derivatives that combine the inhibitory activities of BRD4 and HDAC into one molecule were designed and synthesized through the structure-based design method. Most compounds showed potent HDAC inhibitory activity and moderate BRD4 inhibitory activity. In vitro anti-proliferation activities of the synthesized compounds were also evaluated. Among them, 19f was the most potent inhibitor against HDAC3 with IC50 value of 5 nM and BRD4 inhibition rate of 88% at 10 μM. It was confirmed that 19f could up-regulate the expression of Ac-H3 and reduce the expression of c-Myc by western blot analysis. These results indicated that 19f was a potent dual HDAC/BRD4 inhibitor and deserved further investigation.Graphical abstractGraphical abstract for this article
  • Synthesis of a new disulfide Fmoc monomer for creating biologically
           susceptible linkages in peptide nucleic acid oligomers
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Brandon Campbell, Taylor Hood, Nathaniel Shank Peptide nucleic acids (PNA) are one of many synthetic mimics of DNA and RNA that have found applications as biological probes, as nano-scaffold components, and in diagnostics. In an effort to use PNA as constructs for cellular delivery we investigated the possibility of installing a biologically susceptible disulfide bond in the backbone of a PNA oligomer. Here we report the synthesis of a new abasic Fmoc monomer containing a disulfide bond that can be incorporated into a PNA oligomer (DS-PNA) using standard solid phase peptide synthesis. The disulfide bond survives cleavage from the resin and DS-PNA forms duplexes with complementary PNA oligomers. Initial studies aimed at determining if the disulfide bond is cleavable to reducing agents while in a duplex are explored using UV thermal analysis and HPLC.Graphical abstractGraphical abstract for this article
  • Antibody recognition by a novel microgel photonic crystal
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Na Sai, Zhong Sun, Yuntang Wu, Guowei Huang In this study, a easy-to-prepare biosensor for the sensitive detection of the antibody (Ab) protein was developed using a novel microgel photonic crystal (MPC). The MPC was fabricated by the spin-coated self-assembly method with the monodisperse Ab-sensitive poly (methyl methacrylate-acrylamide-glutaraldehyde-hapten) (P(MMA-AM-GA-HP)) microgels. Morphology characterization showed that the P(MMA-AM-GA-HP) microgels possessed round shapes and the large specific surface area, and the formed MPC had a highly ordered three dimensional (3D) periodically-ordered structure with the desired structural color. The Ab-response event of the P(MMA-AM-GA-HP) microgels can be directly transferred into a readable optical signal through a change in Bragg reflection of the periodic structure of the MPC. With the sensory system, the sensitive and selective detection of Ab was achieved without labeling techniques and expensive instruments. Therefore, this easy and sensitive detection system has great potential for next generation of the bioassay platform for clinical diagnosis and other applications.Graphical abstractGraphical abstract for this article
  • Hydrolases-mediated transformation of oleuropein into demethyloleuropein
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Luca Cariati, Manuela Oliverio, Francesco G. Mutti, Sonia Bonacci, Tanja Knaus, Paola Costanzo, Antonio Procopio Phenolic compounds present in extra virgin olive oil have recently attracted considerable attention due to their pharmacological activities. Among them oleacein (3,4-DHPEA-EDA), structurally related to oleochantal (4-HPEA-EDA), is one of the most studied. 3,4-DHPEA-EDA has been synthesized through decarboxylation of demethyloleuropein catalyzed by Er(OTf)3. Demethyloleuropein is extracted from black olives drupes in very limited amounts and only in particular periods of the year. The availability of demethyloleuropein could be increased by a selective hydrolysis of the methyl ester moiety of oleuropein, a secoiridoid present in large amount in olive leaves. In this work we describe a new enzymatic method for carrying out a selective hydrolysis of oleuropein via the screening of a panel of hydrolases (lipases, esterases and proteases). Among all the enzymes tested the best results was obtained using α-chymotrypsyn from bovine pancreas as biocatalyst, thus revealing a classic example of catalytic enzyme promiscuity.Graphical abstractGraphical abstract for this article
  • Synthesis and identification of novel pyridazinylpyrazolone based diazo
           compounds as inhibitors of human islet amyloid polypeptide aggregation
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Syed Usama Bin Farrukh, Ibrahim Javed, Abdul Qayyum Ather, Abdul-Hamid Emwas, Meshari Alazmi, Xin Gao, Ghayoor Abbas Chotana, Thomas P. Davis, Pu Chun Ke, Rahman Shah Zaib Saleem We have carried out a docking inspired synthesis and screening of a library of diazenyl-derivatives of pyridazinylpyrazolone molecules for their ability to modulate the amyloidogenic self-assembly of human islet amyloid polypeptide (hIAPP). hIAPP is a 37-residue peptide which is involved in glycemic control along with insulin. Its extracellular fibrillar assemblies in pancreatic β-cells are responsible for type 2 diabetes. A three-step synthetic scheme was used to prepare these novel compounds using 2-(6-chloropyridazin-3-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one as a key intermediate that was reacted with various diazo electrophiles to generate a library of compounds with yields ranging from 64 to 85%. The effect of the compounds on hIAPP amyloid fibril formation was evaluated with a thioflavin T (ThT) fluorescence-based kinetic assay. Furthermore, TEM imaging was carried out to corroborate the interactions of the compounds with hIAPP and subsequent hIAPP inhibition at the different level of fibrillization. The CD spectroscopy showed that upon incubation with SSE15314 for 12 h, the percentage of α-helices was maintained to a level of hIAPP at 0 h. The current study presents identification and characterization of SSE15314 as the hit, which completely inhibited the fibril formation and can be further optimized into a lead compound.Graphical abstractGraphical abstract for this article
  • Xanthenone-based hydrazones as potent α-glucosidase inhibitors:
           Synthesis, solid state self-assembly and in silico studies
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Qamar-un-Nisa Tariq, Sana Malik, Ajmal Khan, Muhammad Moazzam Naseer, Shafi Ullah Khan, Abida Ashraf, Muhammad Ashraf, Muhammad Rafiq, Khalid Mahmood, Muhammad Nawaz Tahir, Zahid Shafiq Xanthenone based hydrazone derivatives (5a–n) have been synthesized as potential α-glucosidase inhibitors. All synthesized compounds (5a–n) are characterized by their FTIR, 1H NMR, 13C NMR and HRMS, and in case of 5g also by X-ray crystallographic technique. The compounds unveiled a varying degree of α-glucosidase inhibitory activity when compared with standard acarbose (IC50 = 375.38 ± 0.12 µM). Amongst the series, compound 5l (IC50 = 62.25 ± 0.11 µM) bearing a trifluoromethyl phenyl group is found to be the most active compound. Molecular modelling is performed to establish the binding pattern of the more active compound 5l, which revealed the significance of substitution pattern. The pharmacological properties of molecules are also calculated by MedChem Designer which determines the ADME (absorption, distribution, metabolism, excretion) properties of molecules. The solid state self-assembly of compound 5g is discussed to show the conformation and role of iminoamide moiety in the molecular packing.Graphical abstractGraphical abstract for this article
  • Multi-target inhibitors against Alzheimer disease derived from
           3-hydrazinyl 1,2,4-triazine scaffold containing pendant phenoxy
           methyl-1,2,3-triazole: Design, synthesis and biological evaluation
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Mahnaz Yazdani, Najmeh Edraki, Rashid Badri, Mehdi Khoshneviszadeh, Aida Iraji, Omidreza Firuzi Alzheimer's disease (AD) is a complex neurological disorder with diverse underlying pathological processes. Several lines of evidence suggest that BACE1 is a key enzyme in the pathogenesis of AD and its inhibition is of particular importance in AD treatment. Ten new 3-hydrazinyl-1,2,4-triazines bearing pendant aryl phenoxy methyl-1,2,3-triazole were synthesized as multifunctional ligands against AD. We show that compounds containing Cl and NO2 groups at the para position of the phenyl ring, namely compounds 7c (IC50 = 8.55 ± 3.37 µM) and 7d (IC50 = 11.42 ± 2.01 µM), possess promising BACE1 inhibitory potential. Furthermore, we assessed the neuroprotective activities of 7c and 7d derivatives in PC12 neuronal cell line, which showed moderate protection against amyloid β peptide toxicity. In addition, compound 7d demonstrated metal chelating activity and moderate antioxidant potential (IC50 = 44.42 ± 7.33 µM). Molecular docking studies of these molecules revealed high-affinity binding to several amino acids of BACE1, which are essential for efficient inhibition. These results demonstrate that 1,2,4-triazine derivatives bearing an aryl phenoxy methyl-1,2,3-triazole have promising properties as therapeutic agents for AD.Graphical abstractGraphical abstract for this article
  • Combined molecular modeling and cholinesterase inhibition studies on some
           natural and semisynthetic O-alkylcoumarin derivatives
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Ilkay Erdogan Orhan, F. Sezer Senol Deniz, Ramin Ekhteiari Salmas, Serdar Durdagi, Francesco Epifano, Salvatore Genovese, Serena Fiorito Coumarins of synthetic or natural origins are an important chemical class exerting diverse pharmacological activities. In the present study, 26 novel O-alkylcoumarin derivatives were synthesized and have been tested at 100 µM for their in vitro inhibitory potential against acetylcholinesterase (AChE) and butyrlcholinesterase (BChE) targets which are the key enzymes playing role in the pathogenesis of Alzheimer’s disease. Among the tested coumarins, none of them could inhibit AChE, whereas 12 of them exerted a marked and selective inhibition against BChE as compared to the reference (galanthamine, IC50 = 46.58 ± 0.91 µM). In fact, 10 of the active coumarins showed higher inhibition (IC50 = 7.01 ± 0.28 µM – 43.31 ± 3.63 µM) than that of galanthamine. The most active ones were revealed to be 7-styryloxycoumarin (IC50 = 7.01 ± 0.28 µM) and 7-isopentenyloxy-4-methylcoumarin (IC50 = 8.18 ± 0.74 µM). In addition to the in vitro tests, MetaCore/MetaDrug binary QSAR models and docking simulations were applied to evaluate the active compounds by ligand-based and target-driven approaches. The predicted pharmacokinetic profiles of the compounds suggested that the compounds reveal lipophilic character and permeate blood brain barrier (BBB) and the ADME models predict higher human serum protein binding percentages (>50%) for the compounds. The calculated docking scores indicated that the coumarins showing remarkable BChE inhibition possessed favorable free binding energies in interacting with the ligand-binding domain of the target. Therefore, our results disclose that O-alkylcoumarins are promising selective inhibitors of cholinesterase enzymes, particularly BChE in our case, which definitely deserve further studies.Graphical abstractGraphical abstract for this article
  • The synthesis and anticancer activities of chiral epoxy-substituted
           chromone analogs
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Hyunji Cho, Seung Hee Seo, Younghwa Na, Youngjoo Kwon Human DNA topoisomerases (topos) have been recognized as a good target molecule for the development of anticancer drugs because they play an important role in solving DNA topological problems caused by DNA strand separation during replication and transcription. In this study, we designed and synthesized 11 novel chromone backbone compounds possessing epoxy and halohydrin substituents with chirality. In the topos inhibition test, compounds 2, 9, 10, and 11 showed comparable topo I inhibitory activity at concentration of 100 μM compared to camptothecin, and all of the synthesized compounds showed moderate topo IIα inhibitory activity. Among them, compounds 9, 10 and 11 were more potent than the others in both topo I and IIα inhibitory activity. Compound 11 showed the most potent cell antiproliferative activity against all tested cancer cell lines with particularly strong inhibition (an IC50 of 0.04 µM) of K562 myelogenous leukemia cancer cell proliferation. In the brief structure-activity relationship analysis, there was no clear correlation between stereochemistry and topos inhibitory and cytotoxic activity. 5(R),7(S)-bisepoxy-substituted compound 11 was the most potent DNA cross-linker and induced G2/M arrest in a cell cycle assay in a dose- and time-dependent manner. After the treatment time period induced apoptosis in K562 cells without increasing G2/M-phase cells. Overall, compound 11 showed good consistent inhibitory biological activity related to cancer cell proliferation.Graphical abstractGraphical abstract for this article
  • Synthesis of 8-hydroxyquinoline glycoconjugates and preliminary assay of
           their β1,4-GalT inhibitory and anti-cancer properties
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Monika Krawczyk, Gabriela Pastuch-Gawolek, Anna Mrozek-Wilczkiewicz, Michal Kuczak, Magdalena Skonieczna, Robert Musiol 8-Hydroxyquinoline scaffold is a privileged structure used in designing a new active agents with therapeutic potential. Its connections with the sugar unit is formed to improve the pharmacokinetic properties. The broad spectrum of activity of quinoline derivatives, especially glycoconjugates, is often associated with the ability to chelate metal ions or with the ability to intercalate into DNA. Simple and effective methods of synthesis glycoconjugates of 8-hydroxyquinoline and 8-hydroxyquinaldine derivatives, containing an O-glycosidic bond or a 1,2,3-triazole linker in their structure, have been developed. The obtained glycoconjugates were tested for their ability to inhibit β-1,4-Galactosyltransferase, as well as inhibit cancer cell proliferation. It was found that used glycoconjugation strategy influenced both improvement of activity and improvement of the bioavailability of 8-HQ derivatives. Their activity depends on type of attached sugar, presence of protecting groups in sugar moiety and presence of a linker between sugar and quinolone aglycone.Graphical abstractGraphical abstract for this article
  • Design, synthesis and structure-activity relationship optimization of
           phenanthridine derivatives as new Wnt/β-catenin signalling pathway
    • Abstract: Publication date: March 2019Source: Bioorganic Chemistry, Volume 84Author(s): Duo-zhi Chen, Bi-juan Yang, Xiao-li He, Shi-rui Fan, Jie-yun Cai, Chen-xu Jing, Heng Zhang, Yu Zhang, Lin Li, Xiao-jiang Hao Phenanthridine derivativeHLY78 has previously been identified as the first Wnt/β-catenin signalling pathway agonist that targets the DAX domain of axin. However, due to the relatively weak activation on the Wnt/β-catenin signalling pathway, HLY78 is insufficient for further pharmacological study. Herein, the structural optimization of HLY78 and analyses of the structure-activity relationships (SARs) of HLY78-derived phenanthridine derivatives as agonists of the Wnt/β-catenin signalling pathway are presented. In this work, 36 derivatives were designed and synthesized with some derivatives exhibiting stronger Wnt activity than the activity of HLY78. In particular, one of them, 8-((1,3-dimethy-pyrazol-5-yl)methoxy)-5-ethyl-4-methyl-5,6-dihydro-phenanthridin-9-ol, exhibited strong Wnt active activity and is 10 times more potent than HLY78. The following SAR analysis suggests that a pyrazole group, especially at the C-8 position, is important for Wnt activation; a methyl group at the C-4position seems to be more beneficial for Wnt activation than ethyl; and oxidation of the C-6 position reduces the Wnt activation.Graphical abstractGraphical abstract for this article
  • Artemisianins A-D, New Stereoisomers of Seco-guaianolide Involved
           Heterodimeric [4+2] Adducts from Artemisia argyi Induce Apoptosis via
           Enhancement of Endoplasmic Reticulum Stress
    • Abstract: Publication date: Available online 1 December 2018Source: Bioorganic ChemistryAuthor(s): Gui-Min Xue, Dong-Rong Zhu, Chao Han, Xiao-Bing Wang, Jian-Guang Luo, Ling-Yi Kong Artemisianins A-D (1-4), four stereoisomers of sesquiterpenoid dimers, forming via [4+2] cycloaddition from a 1, 10-seco-guaianolide dienophile and a guaianolide diene, along with two biosynthetically related precurors 5 and 6, were isolated from the famous traditional Chinese medicine Artemisia argyi. The structures of 1-4, including their absolute configurations, were elucidated by extensive spectroscopic data and ECD/TDDFT calculation analysis. Compounds 1-4 exhibited cytotoxicity with IC50 values ranging from 7.2 to 23.3 μM. The accumulation of Ca2+ in cytoplasm and enlarged endoplasmic reticulum (ER) indicated that 1 mediated HT-29 cancer cell apoptosis through improvement of ER-stress, which was further proved by unfolded protein response (UPR) pathway on basis of the upregulation of IRE1α, p-PERK, ATF6, and CHOP.Graphical abstractFour novel stereoisomers of sesquiterpenoid dimers, artemisianins A-D (1-4), induced cancer cell apoptosis via enhancement of endoplasmic reticulum stress were isolated from the famous traditional Chinese medicine Artemisia argyi.Graphical abstract for this article
  • 3D-QSAR assisted identification of FABP4 inhibitors: an effective scaffold
           hopping analysis/QSAR evaluation
    • Abstract: Publication date: Available online 29 November 2018Source: Bioorganic ChemistryAuthor(s): Giuseppe Floresta, Agostino Cilibrizzi, Vincenzo Abbate, Ambra Spampinato, Chiara Zagni, Antonio Rescifina Following on the recent publication of pharmacologically relevant effects, small molecule inhibitors of adipocyte fatty-acid binding protein 4 (FABP4) have attracted high interest. FABP4 is mainly expressed in macrophages and adipose tissue, where it regulates fatty acid storage and lipolysis, being also an important mediator of inflammation. In this regard, FABP4 recently demonstrated an interesting molecular target for the treatment of type 2 diabetes, other metabolic diseases and some type of cancers. In the past years, hundreds of effective FABP4 inhibitors have been synthesized. In this paper, a quantitative structure-activity relationship (QSAR) model has been produced, in order to predict the bioactivity of FABP4 inhibitors. The methodology has been combined with a scaffold-hopping approach, allowing to identify three new molecules that act as effective inhibitors of this protein. These molecules, synthesized and tested for their FABP4 inhibitor activity, showed IC50 values between 3.70 and 5.59 μM, with a high level of agreement with the predicted values.Graphical abstractGraphical abstract for this article
  • Synthesis, molecular docking and cholinesterase inhibitory activity of
           hydroxylated 2-phenylbenzofuran derivatives
    • Abstract: Publication date: Available online 29 November 2018Source: Bioorganic ChemistryAuthor(s): Antonella Fais, Amit Kumar, Rosaria Medda, Francesca Pintus, Francesco Delogu, Maria J. Matos, Benedetta Era, Giovanna L. Delogu We have designed, synthesized and evaluated a series of hydroxylated 2-phenylbenzofuran derivatives as potential cholinesterase inhibitors. Starting from a series of 2-phenylbenzofurans previously published, in this paper we present a complete synthesis and the influence on the activity of one or two hydroxyl groups located in meta or in meta and para positions respectively of the 2-phenyl ring and highlight the importance of position of hydroxyl groups. Moreover, simultaneous introduction of halogen at position 7 of the benzofuran scaffold resulted in an improved inhibitory activity against the enzyme. To further provide molecular insight and to identify the most probable ligand-binding site of the protein, docking studies were performed for the top-ranked compounds. Docking results revealed conserved ligand-binding residues and supported the role of catalytic site residues in enzyme inhibition.Graphical abstractGraphical abstract for this article
  • New tirucallane triterpenoids from Picrasma quassioides with their
           potential antiproliferative activities on hepatoma cells
    • Abstract: Publication date: Available online 28 November 2018Source: Bioorganic ChemistryAuthor(s): Wen-Yu Zhao, Jing-Jie Chen, Chun-Xin Zou, Ying-Ying Zhang, Guo-Dong Yao, Xiao-Bo Wang, Xiao-Xiao Huang, Bin Lin, Shao-Jiang Song Seven new tirucallane-type triterpenoids (1-7), kumuquassin A-G, along with 20 known analogues (8-27) were isolated from the stems of Picrasma quassioides. The structures and the absolute configurations of new compounds were elucidated by spectroscopic data, electronic circular dichroism (ECD) spectroscopic analyses and quantum ECD calculations. Notably, kumuquassin A (1) contains a rare Δ17, 20 double bond, kumuquassin B (2) is the first example of tirucallane triterpenoid possessing a 5/3 biheterocyclic ring system at the side chain. All the compounds were screened for the cytotoxicity against two human hepatoma cell lines, HepG2 and Hep3B, and several compounds exhibited promising activity. The most potential compound 3 was selected for cell cycle analysis, which showed that 3 could cause an accumulation of HepG2 cells at subG1 peak. Annexin V-FITC/PI staining further confirmed that compound 3 caused death of hepatoma cells through apoptosis induction.Graphical abstractGraphical abstract for this article
  • TDP-43 Specific Reduction Induced by Di-hydrophobic tags conjugated
    • Abstract: Publication date: Available online 27 November 2018Source: Bioorganic ChemistryAuthor(s): Na Gao, Yun-Peng Huang, Ting-Ting Chu, Qian-Qian Li, Bing Zhou, Yong-Xiang Chen, Yu-Fen Zhao, Yan-Mei Li TAR DNA binding protein 43 (TDP-43) is a key target in amyotrophic lateral sclerosis (ALS) treatment. Here, based on hydrophobic tagging strategy, we designed and synthesized a series of single or double hydrophobic tags conjugated peptides D1-D8. Among them, it was found that D4 displayed strongest ability to induce TDP-43 degradation in cells. D4 could reduce TDP-43 induced cytotoxicity. Besides, D4 could reduce TDP-43 levels in a transgenic drosophila model.Graphical abstractGraphical abstract for this article
  • Phenylpropanoids and lignans from Prunus tomentosa seeds as efficient
           β-amyloid (Aβ) aggregation inhibitors
    • Abstract: Publication date: Available online 26 November 2018Source: Bioorganic ChemistryAuthor(s): Qingbo Liu, Jie Wang, Bin Lin, Zhuo-Yang Cheng, Ming Bai, Shaochun Shi, Xiao-Xiao Huang, Shao-Jiang Song Alzheimer’s disease (AD) is characterized by the progressive accumulation of extracellular β-amyloid (Aβ) aggregates. Recently, lignans and phenylpropanoids are attracting increasing attention to discovery useful agents of inhibition on Aβ aggregation. In the present study, to develop potential agents for slowing the progression of AD, Prunus tomentosa seeds were selected as a raw material for bioactive compounds, which led to the separation of two pairs of new enantiomeric lignans and phenylpropanoids using chiral HPLC. The planar structures of these compounds were elucidated by spectroscopic data analyses. And their absolute configurations were determined by comparing of experimental and calculated electronic circular dichroism (ECD). The biosynthesis pathway was also discussed. Additionally, the inhibitory activity on Aβ aggregation of all optical pure compounds was tested by thioflavin T (ThT) assay. The isolates (1a, 1b, 2a and 2b) showed more potent inhibitory activity than positive control curcumin with inhibitory rate of 73.89±3.41% 78.69±1.50%, 63.25±2.68%, and 67.13±0.90% at 20 μM, respectively. More importantly, the inhibition profiles were explained by molecular dynamics and docking simulation studies.Graphical abstractGraphical abstract for this article
  • Synthesis and computer-aided analysis of the role of linker for novel
           ligands of the 5-HT6 serotonin receptor among substituted
    • Abstract: Publication date: Available online 26 November 2018Source: Bioorganic ChemistryAuthor(s): Dorota Łażewska, Rafał Kurczab, Małgorzata Więcek, Grzegorz Satała, Katarzyna Kieć-Kononowicz, Jadwiga Handzlik A series of 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazines was designed based on previously published 2-amino-4-benzyl-(4-methylpiperazin-1-yl)-1,3,5-triazines in order to evaluate the role of a linker between the triazine moiety and an aromatic substituent for the human serotonin 5-HT6 receptor affinity. As new linkers two carbon atoms (ethyl or ethenyl) or an oxyalkyl chain (methoxy, 2-ethoxy, 2-propoxy) were introduced. Affinities of the compounds for the 5-HT6R as the main target, and for the 5-HT1AR, 5-HT7R and D2R as competitive ones, were determined in the radioligand binding assays. Docking to the 5-HT6R homology model was performed to support SAR analysis. Results showed that the branching of the methoxyl linker increased affinity for the human 5-HT6R whereas an unsaturated bond within the linker dramatically reduced desirable activity. Both experimental and theoretical studies confirmed the previously postulated beneficial role of the aromatic size for interaction with the 5-HT6R. Thus, the largest naphthyl moiety yielded the highest activity. In particular, 4-(4-Methylpiperazin-1-yl)-6-(1-(naphthalen-1-yloxy)ethyl)-1,3,5-triazin-2-amine (24), the most potent 5-HT6R agent found (Ki = 23 nM), can be a new lead structure for further search and development.Graphical abstractGraphical abstract for this article
  • Antitrypanosomal activity of epi-polygodial from Drimys brasiliensis and
           its effects in cellular membrane models at the air-water interface
    • Abstract: Publication date: Available online 24 November 2018Source: Bioorganic ChemistryAuthor(s): Giulia Elisa Guimarães Gonçalves, Thiago Rahal Morais, Kaio Santos Gomes, Thais Alves Costa-Silva, Andre Gustavo Tempone, João Henrique Ghilardi Lago, Luciano Caseli Epi-polygodial, a drimane sesquiterpene was isolated from Drimys brasiliensis (Winteraceae). This compound demonstrated high parasite selectivity towards Trypanosoma cruzi trypomastigotes (IC50 = 5.01 μM) with a selectivity index higher than 40. These results were correlated with the effects observed when this compound was incorporated in cellular membrane models of protozoans, represented by Langmuir monolayers of dipalmitoylphosphoethanolamine (DPPE). Surface pressure-area isotherms showed that epi-polygodial expands DPPE monolayers at higher areas and condenses them at lower areas, which was attributed to the preferential interaction with the polar heads of the lipid. This mechanism of action could be corroborated with Polarization-Modulation Reflection-Absorption Spectroscopy and Brewster Angle Microscopy. These results pointed to the fact that the interaction of epi-polygodial with DPPE monolayers at the air-water interface affects the physical chemical properties of the mixed film, which may be important to comprehend the interaction of this drug with cellular membranes at the molecular level.Graphical abstractGraphical abstract for this article
  • 1-(2-Hydroxy-5-((trimethylsilyl)ethynyl)phenyl)ethanone based
           α,β-unsaturated derivatives an alternate to non-sulfonamide carbonic
           anhydrase II inhibitors, synthesis via Sonogashira coupling, binding
           analysis, Lipinsk’s rule validation
    • Abstract: Publication date: Available online 24 November 2018Source: Bioorganic ChemistryAuthor(s): Jamaluddin Mahar, Aamer Saeed, Kevin D. Belfield, Fayaz Ali Larik, Pervaiz Ali Channar, Mehar Ali Kazi, Qamar Abbas, Mubashir Hassan, Hussain Raza, Sung-Yum Seo A novel series of silyl-yne containing chalcone derivatives 5a-5j was synthesized by exploiting Sonogashira coupling reaction and Claisen-Schimdt condensation reaction. The synthesized derivative were characterized by spectroscopic and elemental analysis. The selective inhibition of carbonic anhydrases is considered critical in the field of medicinal chemistry because carbonic anhydrases exits in several isoforms. Synthesized compounds were subjected to carbonic anhydrase –II assay. Except 5j, the other derivatives exhibited better potential than standard acetazolamide. Compound 5e was found to be potent derivative in the series with IC50 value 0.054±0.001µM. Binding analysis revealed that most potent derivative 5e binds in the active site of CA-II and single π-π stacking interaction was observed between ring structure of ligand and Phe129 having bond length 4.90Å. Pharmacokinetics elicited that compounds obey Lipinski’s rule and show significant drug score.Graphical abstractGraphical abstract for this article
  • Novel salicylamide derivatives as potent multifunctional agents for the
           treatment of Alzheimer's disease: design, synthesis and biological
    • Abstract: Publication date: Available online 22 November 2018Source: Bioorganic ChemistryAuthor(s): Qing Song, Yan Li, Zhongcheng Cao, Xiaoming Qiang, Zhenghuai Tan, Yong Deng A series of salicylamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors. They showed good inhibitory activities of self- and Cu2+-induced Aβ1–42 aggregation, and significant antioxidant activities. Among them, compound 15b exhibited good inhibitory activity toward RatAChE and EeAChE with IC50 value of 10.4 μM and 15.2 μM, respectively. Moreover, 15b displayed high antioxidant activity (2.46 Trolox equivalents), good self- and Cu2+-induced Aβ1-42 aggregation inhibitory potency (42.5% and 31.4% at 25.0 μM, respectively) and moderate disaggregation ability to self- and Cu2+-induced Aβ1-42 aggregation fibrils (23.4% and 27.0% at 25 μM, respectively). Furthermore, 15b also showed biometal chelating abilities, anti-neuroinflammatory ability and BBB permeability. These multifunctional properties indicated compound 15b was worthy of being chosen for further pharmacokinetics, toxicity and behavioral researches to test its potential for AD treatment.Graphical abstractGraphical abstract for this article
  • Heterocyclic cellular lipid peroxidation inhibitors inspired by the marine
           antioxidant barettin
    • Abstract: Publication date: Available online 22 November 2018Source: Bioorganic ChemistryAuthor(s): Christophe Labrière, Jeanette H Andersen, Marte Albrigtsen, Jørn H Hansen, Johan Svenson The marine environment remains a rich source for the discovery and development of novel bioactive compounds. The present paper describes the design, synthesis and biological evaluation of a library of small molecule heterocyclic mimetics of the marine 2,5-diketopiperazine barettin which is a powerful natural antioxidant. By mainly focusing on the influence from the brominated indole and heterocyclic core of barettin, a library of 19 compounds was prepared. The compounds comprised a heterocyclic core, either a 2,5 diketopiperazine, an imidazolidinedione or a thioxothiazolidinone, which were mainly monosubstituted with ranging bulky substituents. The prepared compounds were screened for activity in a cellular lipid peroxidation assay using HepG2 cells. Several of the synthetic compounds showed antioxidant properties superior to the positive control barettin. Two of the prepared compounds displayed inhibitory activity similar to commercial antioxidants with significant inhibition at low µg/mL concentrations. The toxicity of the compounds was also investigated against MRC-5 lung fibroblasts and none of the included compounds displayed any toxicity at 50 µg/mL.Graphical abstractGraphical abstract for this article
  • 1,4-Dihydroquinazolin-3(2H)-yl benzamide derivatives as anti-inflammatory
           and analgesic agents with an improved gastric profile: Design, synthesis,
           COX-1/2 inhibitory activity and molecular docking study
    • Abstract: Publication date: Available online 22 November 2018Source: Bioorganic ChemistryAuthor(s): Asmaa Sakr, Hend Kothayer, Samy M. Ibrahim, Mohamed M. Baraka, Samar Rezq The design and synthesis of a new series of 1,4-dihydroquinazolin-3(2H)-yl benzamide derivatives (4a-o) as anti-inflammatory and analgesic agents and COX-1/2 inhibitors are reported. The target compounds (4a-o) were synthesized using a two-step scheme, and their chemical structures were confirmed with 1H NMR, 13C NMR, and mass spectra and elemental analysis. Compounds 4b, 4d, 4h, 4l, 4n and 4o showed the best in vitro COX-2 inhibitory activity (IC50 0.04-0.07 μM), which was nearly the same as that of the reference drug celecoxib (IC50 0.049 μM), but had a lower selectivity index, as dictated in our target design. In the in vivo anti-inflammatory inhibition assay, compounds 4b, 4c, 4e, 4f, 4m and 4o showed better oedema inhibition percentages, ranging from 38.1% to 54.1%, than did diclofenac sodium (37.8%). An in vivo analgesic assay revealed that compounds 4b and 4n had a potential analgesic effect 4- to 21-fold more potent than that of indomethacin and diclofenac sodium. All the tested compounds showed an improved ulcerogenic index when compared to indomethacin. In the synthesized series, compound 4b showed the best biological activity in all the experiments. The docking study results agreed with the in vitro COX inhibition assay results. Moreover, the predicted in silico studies of all the compounds support their potential as drug candidates.Graphical abstractGraphical abstract for this article
  • Biological Evaluation and Structure activity relationship of
           9-methyl-1-phenyl-9H-pyrido[3,4-b]indole derivatives as anti-leishmanial
    • Abstract: Publication date: Available online 22 November 2018Source: Bioorganic ChemistryAuthor(s): Penta Ashok, Subhash Chander, Terry K. Smith, Rajnish Prakash Singh, Prabhat Nath Jha, Murugesan Sankaranarayanan A series of piperazinyl-β-carboline-3-carboxamide derivatives were designed through a molecular hybridization approach. Designed analogues were synthesized, characterized and evaluated for anti-leishmanial activity against Leishmania infantum and Leishmania donovani. In L. infantum inhibition assay, compounds 7d, 7g and 7c displayed potent inhibition of promastigotes (EC50 1.59, 1.47 and 3.73 µM respectively) and amastigotes (EC50 1.4, 1.9 and 2.6 µM respectively). SAR studies revealed that, para substitution of methoxy, chloro groups and methyl group on ortho position favored anti-leishmanial activity against L. infantum. Among these analogues 7d, 7h, 7n and 7g exhibited potent inhibition against L. donovani promastigotes (EC50 0.91, 4.0, 4.57 and 5.02 µM respectively), axenic amastigotes (EC50 0.9, 3.5, 2.2 and 3.8 µM respectively) and intracellular amastigotes (EC50 1.3, 7.8, 5.6 and 6.3 µM respectively). SAR studies suggested that, para substitution of methoxy group, para and meta substitution of chloro groups and benzyl replacement recommended for significant anti-leishmanial against L. donovani.Graphical abstractAnti-leishmanial activity EC50 (µM)L. infantum: promastigotes 1.59 and axenic amastigotes 1.4.L.donovani: promastigotes 0.9, axenic amastigotes 1.4 and intracellular amstigotes 1.3Graphical abstract for this article
  • Ebsulfur as a potent scaffold for inhibition and labelling of New Delhi
           Metallo-β-lactamase-1 in vitro and in vivo
    • Abstract: Publication date: Available online 22 November 2018Source: Bioorganic ChemistryAuthor(s): Jianpeng Su, Jiayun Liu, Cheng Chen, Yuejuan Zhang, Kewu Yang The superbug infection caused by New Delhi metallo-β-lactamase (NDM-1) has grown into an emerging threat, labelling and inhibition of NDM-1 has proven challenging due to its shuttling between pathogenic bacteria. Here, we report a potent covalent scaffold, ebsulfur, for targeting the protein in vitro and in vivo. Enzymatic kinetic study indicated that eighteen ebsulfurs gained except 1a-b and 1f inhibited NDM-1, exhibiting an IC50 value ranging of 0.16-9 μM, and 1g was found to be the best, dose- and time-dependent inhibitor with an IC50 of 0.16 μM. Also, these ebsulfurs effectively restored the antibacterial activity of cefazolin against E. coli expressing NDM-1, and the best effect was observed to be from 1g, 1i and 1n, resulting in an 256-fold reduction in MIC of the antibiotic at a dose of 16 μg/mL. The equilibrium dialysis study implied that the ebsulfur disrupted the coordination of one Zn(II) ion at active site of NDM-1. Labelling of NDM-1 using a constructed fluorescent ebsulfur Ebs-R suggested that the inhibitor covalently bound to the target through SDS-PAGE analysis in vitro. Also, labelling NDM-1 in living E. coli cells with Ebs-R by confocal microscopic imaging showed the real-time distribution change process of intracellular recombinant protein NDM-1. Moreover, the cytotoxicity of these ebsulfurs against L929 mouse fibroblastic cells was tested, and their capability to restore antibacterial activity of antibiotic against clinical strains E.coli EC08 producing NDM-1 was determined. The ebsulfur scaffold proposed here is valuable for development of the covalent irreversible inhibitors of NDM-1, and also for labelling the target in vitro and in vivo.Graphical abstractGraphical abstract for this article
  • 1,3,4-Oxadiazole/chalcone hybrids: Design, synthesis, and inhibition of
           leukemia cell growth and EGFR, Src, IL-6 and STAT3 activities
    • Abstract: Publication date: Available online 22 November 2018Source: Bioorganic ChemistryAuthor(s): Marwa Ali A. Fathi, Amer Ali Abd El-Hafeez, Dalia Abdelhamid, Samar H. Abbas, Monica M. Montano, Mohamed Abdel-Aziz A new series of 1,3,4-oxadiazole/chalcone hybrids was designed, synthesized, identified with different spectroscopic techniques and biologically evaluated as inhibitors of EGFR, Src, and IL-6. The synthesized compounds showed promising anticancer activity, particularly against leukemia, with 8v being the most potent. The synthesized compounds exhibited strong to moderate cytotoxic activities against K-562, KG-1a, and Jurkat leukemia cell lines in MTT assays. Compound 8v showed the strongest cytotoxic activity with IC50 of 1.95 µM, 2.36 µM and 3.45 µM against K-562, Jurkat and KG-1a leukemia cell lines, respectively. Moreover; the synthesized compounds inhibited EGFR, Src, and IL-6. Compound 8v was most effective at inhibiting EGFR (IC50= 0.24 μM), Src (IC50= 0.96 μM), and IL-6 (% of control= 20%). Additionally, most of the compounds decreased STAT3 activation.Graphical abstractGraphical abstract for this article
  • Evaluation of blood-brain barrier penetration and examination of binding
           to human serum albumin of 7-O-arylpiperazinylcoumarins as potential
           antipsychotic agents
    • Abstract: Publication date: Available online 22 November 2018Source: Bioorganic ChemistryAuthor(s): Teresa Żołek, Orsolya Dömötör, Kinga Ostrowska, Éva A. Enyedy, Dorota Maciejewska The delivery of drugs to the brain is complicated by the multiple factors including low blood–brain barrier (BBB) passive permeability, active BBB efflux systems, and plasma protein binding. Thus, a detailed understanding of the transport of the new potent substances through the membranes is vitally important and their physico-chemical characteristics should be analyzed at first. This work presents an evaluation of drug likeness of eight 7-O-arylpiperazinylcoumarin derivatives with high affinity towards serotoninergic receptors 5-HT1A and 5-HT2A with particular analysis of the requirements for the CNS chemotherapeutics. The binding constants to human serum albumin (HSA) were determined at physiological pH using fluorescence spectroscopy, and then their mode of action was explained by analysis of theoretical HSA complexes. Dynamic simulation of systems allowed for reliable evaluation of the interaction strength. The analyzed coumarins were able to pass BBB, and they present good drug likeness properties. They showed high affinities to HSA (log KQ = 5.3 – 6.0 which corresponds to -8.12 – -7.15 kcal/mol of Gibbs free energy). The changes of the emission intensity upon binding to HSA were scrutinized showing the different mode of action for 4-phenylpiperazinylcoumarins. The values of computed Gibbs free energy and determined on the basis of experimentally obtained binding constants log KQ coincide suggesting a good quality of the theoretical model. Overall the 8-acetyl-7-O-arylpiperazinyl-4-methylcoumarin derivatives represent valuable lead compounds to be further tested in various preclinical assays as a possible chemotherapeutics against CNS diseases. Studied coumarins can be metabolized by cytochrome P450 to aldehydes and hydroxy derivatives. The existence of other binding sites inside HSA than Sudlow’s site 1 was postulated. The longer aliphatic linker between coumarin and piperazine moieties favored binding to HSA in other than Sudlow site 1 pocket.Graphical abstractGraphical abstract for this article
  • Synthesis and anti-inflammatory activity of sulfonamides and carboxylates
           incorporating trimellitimides: dual cyclooxygenase/carbonic anhydrase
           inhibitory actions
    • Abstract: Publication date: Available online 22 November 2018Source: Bioorganic ChemistryAuthor(s): Alaa A.M. Abdel-Aziz, Andrea Angeli, Adel S. El-Azab, Mohammed E.A. Hammouda, Magda A. El-Sherbeny, Claudiu T. Supuran Trimellitimides 6-21 were prepared and investigated in vivo for anti-inflammatory and ulcerogenic effects and in vitro for cytotoxicity. They were subjected to in vitro cyclooxygenase (COX-1/2) and carbonic anhydrase inhibition protocols. Compounds 6-11 and 18 exhibited anti-inflammatory activities and had median effective doses (ED50) of 34.3–49.8 mg kg-1 and 63.6-86.6% edema inhibition relative to the reference drug celecoxib (ED50: 33.9 mg kg-1 and 85.2% edema inhibition). Compounds 6-11 and 18 were weakly cytotoxic at 10 μM against 59 cell lines compared with the reference standard 5-fluorouracil (5-FU). Compounds 6-11 had optimal selectivity against COX-2. The selectivity index (SI) range was> 200−490 and was comparable to that for celecoxib [COX-2 (SI)> 416.7]. In contrast, compounds 12, 13, and 16-18 were nonselective COX inhibitors with a selectivity index range of 0.92-0.25. The carbonic anhydrase inhibition assay showed that sulfonamide incorporating trimellitimides 6-11 inhibited the cytosolic isoforms hCA I and hCA II, and tumor-associated isoform hCA IX. They were relatively more susceptible to inhibition by compounds 8, 9, and 11. The KI ranges were 54.1−81.9 nM for hCA I, 25.9–55.1 nM for hCA II, and 46.0–348.3 nM for hCA IX. © 2018 Elsevier Science. All rights reserved.Graphical abstractGraphical abstract for this article
  • Encapsulation of ciprofloxacin within modified xanthan gum- chitosan based
           hydrogel for drug delivery
    • Abstract: Publication date: Available online 22 November 2018Source: Bioorganic ChemistryAuthor(s): Demiana H. Hanna, Gamal R. Saad The aim of the present work was to investigate the preparation of polyelectrolyte hydrogel as potential drug carrier for antibacterial Ciprofloxacin drug (CFX), intended for controlled release formulation. Hydrogel of N -trimehtyl chitosan (TMC)/sodium carboxymethyl xanthan gum (CMXG) was prepared and ciprofloxacin was employed as a model drug to investigate the loading and release performance of the prepared hydrogel. FTIR, DSC, TGA and SEM analysis were used to characterize the TMC/CMXG hydrogel and its CFX loaded hydrogel. The results showed that the ciprofloxacin was successfully incorporated and released from the prepared hydrogel without the loss of structural integrity or the change in its functionality. The encapsulation efficiency of CFX within the prepared hydrogel was found to be increased with increasing the concentration of drug reaching about 93.8 ±2.1 % with concentration of CFX 250 µg/ml. It was shown also that the drug is entrapped within the gel without significant interaction as confirmed from FTIR spectra and DSC analysis. In vitro release study in phosphate buffer saline (PBS), indicated the steady rise in cumulative drug release with the highest release amount, reaching about 96.1 ±1.8 % up to 150 min, whereby the gel with high drug loading efficiency (3.52 ±0.07 %) displayed faster and higher release rate than that of gel containing a smaller amount of drug (0.44 ±0.01%). The release kinetics of loaded drug followed zero-order kinetics. CFX drug loaded hydrogel showed high activity against the gram positive and gram negative bacterial strains due to the successful released of CFX from the CFX loaded hydrogel into the tested bacterial strains with the highest diameter of inhibition zone against Escherichia coli (67.0 ±1.0) as compared to reference antibiotic, Gentamicin (28 ±0.5). Cytotoxicity of the prepared hydrogel was examined in vitro using lung human normal cell lines and showed the highest cell viability (97 ±0.5 %) at concentration up to 50 µg/ml. Consequently, TMC/CMXG hydrogel can be proposed as new controlled release drug delivery system.Graphical abstractGraphical abstract for this article
  • Discovery of a novel cathepsin inhibitor with dual autophagy-inducing and
           metastasis-inhibiting effects on breast cancer cells
    • Abstract: Publication date: Available online 22 November 2018Source: Bioorganic ChemistryAuthor(s): Lei Yuan, Jun Liu, Wenhui He, Youmei Bao, Lei Sheng, Chunyang Zou, Baichun Hu, Wentao Ge, Yang Liu, Jian Wang, Bin Lin, Yanchun Li, Enlong Ma Drug resistance and cancer cells metastasis have been the leading causes of chemotherapy failure and cancer-associated death in breast cancer patients. In present, various active molecules either exhibiting novel mechanism of action such as inducing autophagy or inhibiting metastasis have been developed to address these problems. However, the compounds exhibiting such dual functions have rarely been described. Previous work in our group showed that TSA, as a synthetic analog of asperphenamate, induced autophagic cell death in breast cancer cells instead of apoptosis. Furthermore, the target enzyme of TSA was predicted to be cathepin L (Cat L) by natural product consensus pharmacophore strategy. Accumulated evidences have shown that cathepsins are closely associated with migration and invasion of breast cancer cells. It seemed likely that TSA-like molecules may possess the dual functions of inducing autophagy and inhibiting metastasis. Therefore, sixty optically active derivatives were firstly designed and synthesized by replacing the A-ring moiety of TSA with other substituted-phenyl sulfonyl groups. Further cathepsin inhibitory activity assay showed that (S, S) and (S, R) isomers displayed no activity against four kinds of cathepsins (L, S, K, B), while all derivatives tested were inactive toward K and B subtypes. Compound 6a with meta-bromo substituent displayed the greatest inhibitory activity, and its inhibitory capability against Cat L and S was 3.9 and 11.5-fold more potent than that of TSA, respectively. Molecular docking also exhibited that 6a formed more hydrogen bonds or π-π contacts with Cat L or S than TSA. In order to determine whether 6a could play dual roles, its anti-cancer mechanism was further investigated. On the one hand, MDC staining experiment and western blotting analysis validated that 6a can induce autophagy in MDA-MB-231 cells. On the other hand, its metastatic inhibitory ability was also confirmed by wound healing and transwell chamber experiment.Graphical abstractGraphical abstract for this article
  • An alkali tolerant α-L-rhamnosidase from Fusarium moniliforme MTCC-2088
           used in de-rhamnosylation of natural glycosides
    • Abstract: Publication date: Available online 20 November 2018Source: Bioorganic ChemistryAuthor(s): Dhirendra Kumar, Sarita Yadav, Sudha Yadava, K.D.S. Yadav Analkali tolerant α-L-rhamnosidase has been purified to homogeneity from the culture filtrate of a new fungal strain, Fusarium moniliforme MTCC-2088,using concentration by ultrafiltration and cation exchange chromatography on CM cellulose column. The molecular mass of the purified enzyme has been found to be 36.0 kDa using SDS-PAGE analysis. The Km value using p-nitrophenyl-α-L-rhamnopyranosideas the variable substrate in 0.2M sodium phosphate buffer pH10.5 at50 0C was 0.50 mM. The catalytic rate constant was15.6 s-1giving the values of kcat/Kmis 3.12x 104M-1s-1. The pH and temperature optima of the enzyme were 10.5 and 50°C, respectively. The purified enzyme had better stability at 10°C in basic pH medium. The enzyme derhamnosylated natural glycosides like naringin to prunin, rutin to isoquercitrin and hesperidin to hesperetin glucoside. The purified α-L-rhamnosidase has potential for enhancement of wine aroma.Graphical abstractGraphical abstract for this article
  • The first target specific, highly diastereoselective synthesis, design and
           characterization of pyranoquinolinyl acrylic aciddiasteromers as potential
           α-glucosidase inhibitors
    • Abstract: Publication date: Available online 20 November 2018Source: Bioorganic ChemistryAuthor(s): G. Lavanya, K. Venkatapathy, C.J. Magesh, M. Ramanathan, R. Jayasudha In the present investigation we report the first target specific, highly diastereoselective synthesis of new class of pyranoquinolinyl/furoquinolinyl-acrylic acid diastereomers and evaluation of their invitro α-glucosidase inhibitory activity. All the products were thoroughly characterized by 1H-NMR, 13C-NMR, FT-IR, Mass spectral and CHN analysis. A highly diastereoselective target specific route of synthesis for the biologically active diastereomers were developed by usingchiral catalyst Europium tris[3-heptafluoropropylhydroxyl methylene]-(-)-camporate (A) or Europiumtris[3-(trifluoromethyl)hydroxylmethylene]-(+)-camporate (B). It was found that among a set of 4 diastereomeric products obtained, exodiasteromers of pyranoquinolinyl acrylic acid adducts exhibited relatively high α-glucosidase inhibitory activity. The newly synthesized compounds exhibited IC50 values in the range of (0.40 ± 0.02 - 30.3 ± 0.84μM) as compared to standard acarbose (IC50=0.65± 0.02μM). It was found that compounds 11a, 11c, 11d and 12d were found to be more active than standard acarbose. It was also found that unsubstituted compound (11a) or compounds with chlorine or methoxy substituent (11c, 11d, 12d) showed potential α-glucosidase inhibitory activity. However a reversal in activity was observed with Nitro substituent (11b, 13b) wherein the endodiastereomers were found to be more active than exodiastereomers. Molecular docking studies were used for design of the compound and understand the mode of binding between the compound and target enzyme. A plausible mechanism for the diastereoselective synthesis was also proposed.Graphical abstractGraphical abstract for this article
  • Synthesis and biological evaluation of
           7-(aminoalkyl)pyrazolo[1,5-a]pyrimidine derivatives as cathepsin K
    • Abstract: Publication date: Available online 19 November 2018Source: Bioorganic ChemistryAuthor(s): Nejc Petek, Bogdan Štefane, Marko Novinec, Jurij Svete A series of novel 7-aminoalkyl substituted pyrazolo[1,5-a]pyrimidine derivatives were synthesized and tested for inhibition of cathepsin K. The synthetic methodology comprises cyclization of 5-aminopyrazoles with N-Boc-α-amino acid-derived ynones followed by transformation of the ester and the Boc-amino functions. It allows for easy diversification of the pyrazolo[1,5-a]pyrimidine scaffold at various positions. Molecular docking studies with pyrazolo[1,5-a]pyrimidine derivatives were also performed to elucidate the binding mode in the active site of cathepsin K. The synthesized compounds exhibited moderate inhibition activity (Ki ≥ 77 μM).Graphical abstractGraphical abstract for this article
  • Immobilized Baliospermum montanum hydroxynitrile lyase catalyzed synthesis
           of chiral cyanohydrins
    • Abstract: Publication date: Available online 19 November 2018Source: Bioorganic ChemistryAuthor(s): Nisha Jangir, Santosh Kumar Padhi Hydroxynitrile lyase (HNL) catalyzed enantioselective C-C bond formation is an efficient approach to synthesize chiral cyanohydrins which are important building blocks in the synthesis of a number of fine chemicals, agrochemicals and pharmaceuticals. Immobilization of HNL is known to provide robustness, reusability and in some cases also enhances activity and selectivity.We optimized the preparation of immobilization of Baliospermium montanum HNL (BmHNL) by cross linking enzyme aggregate (CLEA) method and characterized it by SEM. Optimization of biocatalytic parameters was performed to obtain highest % conversion and ee of (S)-mandelonitrile from benzaldehyde using CLEA-BmHNL. The optimized reaction parameters were: 20 minutes of reaction time, 7 U of CLEA-BmHNL, 1.2 mM substrate, and 300 mM citrate buffer pH 4.2, that synthesized (S)-mandelonitrile in ∼99% ee and ∼60% conversion. Addition of organic solvent in CLEA-BmHNL biocatalysis did not improve in % ee or conversion of product unlike other CLEA-HNLs. CLEA-BmHNL could be successfully reused for eight consecutive cycles without loss of conversion or product formation and five cycles with a little loss in enantioselectivity. Eleven different chiral cyanohydrins were synthesized under optimal biocatalytic conditions in up to 99% ee and 59% conversion, however the % conversion and ee varied for different products. CLEA-BmHNL has improved the enantioselectivity of (S)-mandelonitrile synthesis compared to the use of purified BmHNL. Nine aldehydes not tested earlier with BmHNL were converted into their corresponding (S)-cyanohydrins for the first time using CLEA-BmHNL. Among the eleven (S)-cyanohydrins syntheses reported here, eight of them have not been synthesized by any CLEA-HNL. Overall, this study showed preparation, characterization of a stable, robust and recyclable biocatalyst i.e. CLEA-BmHNL and its biocatalytic application in the synthesis of different (S)-aromatic cyanohydrins.Graphical abstractGraphical abstract for this article
  • Anti-melanogenesis potential of a new series of Morita-Baylis-Hillman
           adducts in B16F10 melanoma cell line
    • Abstract: Publication date: Available online 19 November 2018Source: Bioorganic ChemistryAuthor(s): Emna Ketata, Haitham Elleuch, Aref Neifar, Wafa Mihoubi, Wajdi Ayadi, Naziha Marrakchi, Farhat Rezgui, Ali Gargouri Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radiation. An excessive synthesis of melanin leads to hyperpigmentation disorders. Tyrosinase catalyses the rate limiting steps on melanogenesis. Therefore, tyrosinase inhibitors have potential applications in medicine and cosmetic fields. We carried out herein the screening of a family of cyclic Morita-Baylis-Hillman adducts (MBH) to find out their effects on tyrosinase activity and on melanogenesis in murine melanoma B16F10 cell line. Kinetic analysis of tyrosinase inhibition showed that compounds 1a (2-hydroxymethyl) cyclohex-2-enone) and 3f (diethyl (1-(6-oxocyclohex-1-en-1-yl) ethyl-phosphonate) were competitive inhibitors, whereas the compound 2b (6-oxocyclohex-1-en-1-yl) ethyl acetate) was a non-competitive one. Additionally we have found that (1a, 2b and 3f) compounds had a strong melanogenesis inhibition effect in isobutylmethylxanthine (IBMX)-treated murine melanoma B16F10 cells when tested at low and non cytotoxic dose (10-50 µM), by attenuating the melanin production, intracellular tyrosinase activity and tyrosinase expression. Thus, we suggest that these compounds could be used as effective skin-whitening agents.Graphical abstractGraphical abstract for this article
  • Synthesis, molecular modeling and BACE-1 inhibitory study of
           tetrahydrobenzo[b] pyran derivatives
    • Abstract: Publication date: Available online 19 November 2018Source: Bioorganic ChemistryAuthor(s): Vijaya Bhaskar, Reshma Chowdary, Sheshagiri R. Dixit, Shrinivas D. Joshi β-Secretase (BACE1) has been broadly documented as one of the possible therapeutic targets for the treatment of Alzheimer’s disease. In this paper, we report the synthesis and the for β-secretase (BACE-1) inhibitory activity of new series of tetrahydrobenzo [b] pyran derivatives. One-pot synthesis of tetrahydrobenzo [b] pyrans was carried out by condensing aromatic aldehyde, malononitrile and 1,3-cyclohexanedione using ionic liquid 1-butyl-3-methyl imidazolium chloride ([bmIm]Cl-) in aqueous alcohol media. The addition of alcohol and water in the ratio of 1:2 keeps all the reactants in solution which facilitates the reaction and makes the product formation very easy. The synthesized compounds were subjected to BACE1 inhibition assay and six compounds, 4d, 4e, 4f, 4h, 4i, and 4p have shown significant IC50 values at micromolar level. Among these six active compounds, 4e was a potential inhibitor with its IC50 value in nanomolar range. All the synthesized compounds were docked onto the active site of β-Secretase enzyme.Graphical abstractGraphical abstract for this article
  • Design, synthesis and cytotoxicity of chimeric Erlotinib-Alkylphospholipid
    • Abstract: Publication date: Available online 19 November 2018Source: Bioorganic ChemistryAuthor(s): Md. Maqusood Alam, Ahmed H.E. Hassan, Kun Won Lee, Min Chang Cho, Ji Seul Yang, Jiho Song, Kyung Hoon Min, Jongki Hong, Dong-Hyun Kim, Yong Sup Lee Two series of erlotinib-alkylphospholipid hybrids were prepared and evaluated for their antiproliferative activities against a panel of four cell lines representing lung, breast, liver and skin cancers using erlotinib and miltefosine as reference standards. Amide analogs elicited more enhanced cytotoxic activity than analogous esters. Amide derivatives 8d and 8e exhibited promising broad-spectrum antiproliferative activity and higher efficacy than reference erlotinib and miltefosine. Their cellular GI50 values was in the ranges of 24.7∼46.9 μM and 26.8∼43.1 μM for 8e and 8d respectively. Assay results of the inhibitory activity of the prepared compounds on EGFR kinase reaction and Akt phosphorylation in conjugation with statistical correlation analysis indicated that other mechanisms might contribute to their elicited cytotoxicities. In addition, statistical correlation analysis revealed that mechanisms of elicited cytotoxicities for amide series might be different from ester series. In addition, correlation analysis indicated variations in the mechanisms according to the types of cell line.Graphical abstractGraphical abstract for this article
  • Repurposing Approach Identifies New Treatment Options for Invasive Fungal
    • Abstract: Publication date: Available online 19 November 2018Source: Bioorganic ChemistryAuthor(s): Isis Regina Grenier Capoci, Daniella Renata Faria, Karina Mayumi Sakita, Franciele Abigail Vilugron Rodrigues, Patricia de Souza Bonfim-Mendonça, Tania Cristina Alexandrino Becker, Érika Seki Kioshima, Terezinha Inez Estivalet Svidzinski, Bernard Maigret Drug repositioning is the process of discovery, validation and marketing of previously approved drugs for new indications. Our aim was drug repositioning, using ligand-based and structure-based computational methods, of compounds that are similar to two hit compounds previously selected by our group that show promising antifungal activity. Through the ligand-based method, 100 compounds from each of three databases (MDDR, DrugBank and TargetMol) were selected by the Tanimoto coefficient, as similar to LMM5 or LMM11. These compounds were analyzed by the scaffold trees, and up to 10 compounds from each database were selected. The structure-based method (molecular docking) using thioredoxin reductase as the target drug was performed as a complementary approach, resulting in six compounds that were tested in an in vitro assay. All compounds, particularly raltegravir, showed antifungal activity against the genus Paracoccidioides. Raltegravir, an antiviral drug, showed promising antifungal activity against the experimental murine paracoccidioidomycosis, with significant reduction of the fungal burden and decreased alterations in the lung structure of mice treated with 1 mg/kg of raltegravir. In conclusion, the combination of two in silico methods for drug repositioning was able to select an antiviral drug with promising antifungal activity for treatment of paracoccidioidomycosis.Graphical abstractGraphical abstract for this article
  • Nitric oxide inhibitory limonoids as potential anti-neuroinflammatory
           agents from Swietenia mahagoni
    • Abstract: Publication date: Available online 19 November 2018Source: Bioorganic ChemistryAuthor(s): Zhaoyu Shi, Lijun An, Xueyuan Yang, Yaru Xi, Chenyue Zhang, Yuan Shuo, Jie Zhang, Da-Qing Jin, Yasushi Ohizumi, Dongho Lee, Jing Xu, Yuanqiang Guo Recent studies have revealed that there is a close relationship between neuroinflammation and Alzheimer's disease (AD) and compounds with anti-neuroinflammatory effects are potentially useful for the treatment of AD. A phytochemical investigation to obtain new neuroinflammatory inhibitors resulted in the isolation of four new and three known limonoids from Swietenia mahagoni. The structures of these limonoids were established by NMR, MS, and electronic circular dichroism (ECD) data analysis. Compounds 1−3 feature complicated polycyclic caged structures of limonoid orthoester and represent new examples of phragmalin-type limonoids. All of the isolates showed anti-neuroinflammatory activities by inhibiting nitric oxide (NO) release in LPS-induced murine microglial BV-2 cells with compounds 1 and 3−6 having IC50 values of 26.8, 26.1, 26.0, 37.1, and 16.5 μM, respectively. The possible mechanism of NO inhibition of some bioactive compounds was also investigated using molecular docking, which revealed the interactions of bioactive compounds with the inducible nitric oxide synthase (iNOS) protein.Graphic abstractGraphical abstract for this article
  • Synthesis and Biological Evaluation of New Pyrazolone Schiff Bases as
           Monoamine Oxidase and Cholinesterase Inhibitors
    • Abstract: Publication date: Available online 17 November 2018Source: Bioorganic ChemistryAuthor(s): Fatih Tok, Bedia Koçyiğit-Kaymakçıoğlu, Begüm Nurpelin Sağlık, Serkan Levent, Yusuf Özkay, Zafer Asım Kaplancıklı In the current work, Schiff base derivatives of antipyrine were synthesized. The chemical characterization of the compounds was confirmed using IR, 1H-NMR, 13C-NMR and mass spectroscopies. The inhibitory potency of synthesized compounds was investigated towards acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidases A and B (MAO-A and MAO-B) enzymes. Some of the compounds displayed significant inhibitory activity against AChE and MAO-B enzymes, respectively. According to AChE enzyme inhibition assay, compounds 3e and 3g were found as the most potent derivatives with IC50 values of 0.285 µM and 0.057 µM, respectively. Also, compounds 3a (IC50 = 0.114 µM), 3h (IC50 = 0.049 µM), and 3i (IC50 =0.054 µM) were the most active derivatives against MAO-B enzyme activity. So as to understand inhibition type, enzyme kinetics studies were carried out. Furthermore, molecular docking studies were performed to define and evaluate the interaction mechanism between compounds 3g and 3h and related enzymes. ADME (Absorption, Distribution, Metabolism, and Excretion) and BBB (Blood, Brain, Barier) permeability predictions were applied to estimate pharmacokinetic profiles of synthesized compounds.Graphical abstractGraphical abstract for this article
  • Identification of osimertinib (AZD9291) as a lysine specific demethylase 1
    • Abstract: Publication date: Available online 16 November 2018Source: Bioorganic ChemistryAuthor(s): Zhong-Rui Li, Feng-Zhi Suo, Bo Hu, Yan-Jia Guo, Dong-Jun Fu, Bin Yu, Yi-Chao Zheng, Hong-Min Liu Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In this study, osimertinib was characterized as a LSD1 inhibitor for the first time with an IC50 of 3.98 ± 0.3 μM and showed LSD1 inhibitory effect at cellular level. These findings provide new molecular skeleton for dual inhibitor for LSD1 and EGFR. Osimertinib could serve as a lead compound for further development for anti-NSCLC drug discovery with dual targeting.Graphical abstractGraphical abstract for this article
  • Switching of Trp-214 intrinsic rotamer population in Human Serum Albumin:
           An insight into the aftermath of embracing therapeutic bioorganic
           luminophore Azapodophyllotoxin into Sudlow site I
    • Abstract: Publication date: Available online 16 November 2018Source: Bioorganic ChemistryAuthor(s): Soham Mukherjee, Kapil Ganorkar, Ajay Kumar, Naina Sehra, Sujit Kumar Ghosh Human serum albumin is perceived to be the most abundant protein in human blood plasma and functions as a major carrier of different enzymes and drugs inside human body. The present article puts in an effort to demonstrate the attitude adopted by human serum albumin towards a potential therapeutic luminophore 4-(2-Hydroxyethyl)-10-phenyl-3,4,6,7,8,10-hexahydro-1H-cyclopenta[g]furo[3,4-b]quinoline-1-one (HPFQ). HPFQ is a prodigy from azapodophyllotoxin class of compounds, which have been synthesized from the perspective of improved bioactivity than its prologue podophyllotoxins. While, HPFQ has proved to be highly bioactive against most cancer cell lines with best GI50 values of < 0.1 µM for a major number of cell lines; it also showed terrific fluorescent properties throughout the polarity scale, worthy of a promising imaging agent. The binding mechanism of HPFQ with HSA has been established by combining in vitro spectroscopic techniques, in silico molecular docking and induced fit docking (IFD). The competitive site-binding studies demonstrated that the otherwise anion-receptor sudlow site I of HSA nurtures neutral HPFQ with prudent affinity (Binding constant, Kb= 0.74 x 105 M-1). The time-resolve fluorescence studies reveal an appreciable reduction in HSA average radiative lifetime against an increase in HPFQ concentration and provided evidence for Forster’s resonance energy transfer (FRET) being responsible for the dominant quenching mechanism, escorted by minor structural deformations in the backbone of protein structure. HPFQ institutes itself near Trp-214 within protein matrix, and subsequently the “hydrophobic amino acids” dominated cybotactic environment of Trp-214 experiences a reduction in the micropolarity. The allosteric modulation triggered by the stronger association of HPFQ with HSA leads towards minor deformation in secondary structure of protein. Sudlow site I of HSA proficiently embraces a favourable conformation like malleable dough to furnish space for arriving bioactive HPFQ molecule. HPFQ is also believed to administer the conformational regulation in HSA domain by affecting inter-conversion of HSA rotamers, which may prove to be an enlightening area to decode the preferable interaction between them. The juxtaposed spectroscopic research described herein is expected to embolden design of azapodophyllotoxin based anti-proliferative clinical agents for efficient in vivo bio-distribution employing HSA-centred drug delivery and administration systems.Graphical abstractThe illustration depicts the favorable interaction initiated by introduction of a potential therapeutic bioorganic luminophore from the class of Azapodophyllotoxin into the sudlow site I of Human Serum Albumin and its ability to regulate the innate rotamers of Trp-214 residue in Human Serum AlbuminGraphical abstract for this article
  • Synthesis and antioxidant activity of new lipophilic dihydropyridines
    • Abstract: Publication date: Available online 13 November 2018Source: Bioorganic ChemistryAuthor(s): Diego da Costa Cabrera, Eduarda Santa-Helena, Heloisa P. Leal, Renata Rodrigues de Moura, Luiz Eduardo Maia Nery, Carla Amorim Neves Gonçalves, Dennis Russowsky, Marcelo G. Montes D'Oca Dihydropyridines (DHPs) obtained from Hantzsch multicomponent reactions are an important pharmaceutical class of compounds marketed as antihypertensive (e.g., nifedipine, nitrendipine, and amlodipine) drugs. This study synthesized new symmetrical and unsymmetrical long-chain fatty DHPs using multicomponent reactions under metal-free conditions with sulfamic acid as a catalyst. The DHPs were tested for antioxidant activity using three different methods. The insertion of a long chain into the DHP core contributed to antioxidant potential, and compounds derived from nitro aldehydes have better antioxidant potential than the antihypertensive drug nifedipine. In addition, fatty analogs to nifedipine derived from palmitic and oleic chains showed similar antioxidant activity to the common standards butylated hydroxytoluene and vitamin E. These results showed that our new synthesized products may find novel applications as antioxidant additives or for tools for use in drug discovery.Graphical abstractGraphical abstract for this article
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