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  Subjects -> CHEMISTRY (Total: 881 journals)
    - ANALYTICAL CHEMISTRY (54 journals)
    - CHEMISTRY (616 journals)
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CHEMISTRY (616 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: 26)
ACS Catalysis     Hybrid Journal   (Followers: 43)
ACS Chemical Neuroscience     Hybrid Journal   (Followers: 21)
ACS Combinatorial Science     Hybrid Journal   (Followers: 23)
ACS Macro Letters     Hybrid Journal   (Followers: 25)
ACS Medicinal Chemistry Letters     Hybrid Journal   (Followers: 41)
ACS Nano     Hybrid Journal   (Followers: 280)
ACS Photonics     Hybrid Journal   (Followers: 14)
ACS Symposium Series     Full-text available via subscription  
ACS Synthetic Biology     Hybrid Journal   (Followers: 24)
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: 9)
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: 7)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 9)
Adsorption Science & Technology     Open Access   (Followers: 6)
Advanced Functional Materials     Hybrid Journal   (Followers: 57)
Advanced Science Focus     Free   (Followers: 5)
Advances in Chemical Engineering and Science     Open Access   (Followers: 67)
Advances in Chemical Science     Open Access   (Followers: 18)
Advances in Chemistry     Open Access   (Followers: 21)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19)
Advances in Drug Research     Full-text available via subscription   (Followers: 24)
Advances in Environmental Chemistry     Open Access   (Followers: 5)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
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Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11)
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Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 16)
Advances in Polymer Science     Hybrid Journal   (Followers: 44)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
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: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Al-Kimia : Jurnal Penelitian Sains Kimia     Open Access  
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: 65)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 20)
American Journal of Chemistry     Open Access   (Followers: 30)
American Journal of Plant Physiology     Open Access   (Followers: 11)
American Mineralogist     Hybrid Journal   (Followers: 15)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 169)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 247)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 5)
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: 23)
Applied Surface Science     Hybrid Journal   (Followers: 32)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 2)
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access  
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Hybrid Journal   (Followers: 359)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 10)
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: 21)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 133)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 87)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 2)
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: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 6)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 70)
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: 10)
Cellulose     Hybrid Journal   (Followers: 7)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 20)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 74)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 26)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 22)
Chemical Reviews     Hybrid Journal   (Followers: 191)
Chemical Science     Open Access   (Followers: 25)
Chemical Technology     Open Access   (Followers: 26)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 56)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 24)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 7)
Chemistry & Biology     Full-text available via subscription   (Followers: 32)
Chemistry & Industry     Hybrid Journal   (Followers: 7)
Chemistry - A European Journal     Hybrid Journal   (Followers: 159)
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: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 43)
Chemistry of Materials     Hybrid Journal   (Followers: 259)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 19)
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: 4)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 14)
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: 24)
Chromatography     Open Access   (Followers: 2)
Chromatography Research International     Open Access   (Followers: 6)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access   (Followers: 1)
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: 6)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 22)
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  
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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: 6)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 6)
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  
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: 8)
Current Science     Open Access   (Followers: 69)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 3)
Dalton Transactions     Full-text available via subscription   (Followers: 23)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  

        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  [3159 journals]
  • Flurbiprofen derivatives as novel α-amylase inhibitors: Biology-oriented
           drug synthesis (BIODS), in vitro, and in silico evaluation
    • Abstract: Publication date: December 2018Source: Bioorganic Chemistry, Volume 81Author(s): Momin Khan, Aftab Alam, Khalid Mohammed Khan, Uzma Salar, Sridevi Chigurupati, Abdul Wadood, Farman Ali, Jahidul Islam Mohammad, Muhammad Riaz, Shahnaz PerveenNovel derivatives of flurbiprofen 1–18 including flurbiprofen hydrazide 1, substituted aroyl hydrazides 2–9, 2-mercapto oxadiazole derivative 10, phenacyl substituted 2-mercapto oxadiazole derivatives 11–15, and benzyl substituted 2-mercapto oxadiazole derivatives 16–18 were synthesized and characterized by EI-MS, 1H and 13C NMR spectroscopic techniques. All derivatives 1–18 were screened for α-amylase inhibitory activity and demonstrated a varying degree of potential ranging from IC50 = 1.04 ± 0.3 to 2.41 ± 0.09 µM as compared to the standard acarbose (IC50 = 0.9 ± 0.04 µM). Out of eighteen compounds, derivatives 2 (IC50 = 1.69 ± 0.1 µM), 3 (IC50 = 1.04 ± 0.3 µM), 9 (IC50 = 1.25 ± 1.05 µM), and 13 (IC50 = 1.6 ± 0.18 µM) found to be excellent inhibitors while rest of the compounds demonstrated comparable inhibition potential. A limited structure-activity relationship (SAR) was established by looking at the varying structural features of the library. In addition to that, in silico study was conducted to understand the binding interactions of the compounds (ligands) with the active site of α-amylase enzyme.Graphical abstractGraphical abstract for this article
       
  • Synthesis of new 3-phenylquinazolin-4(3H)-one derivatives as potent
           antibacterial agents effective against methicillin- and
           vancomycin-resistant Staphylococcus aureus (MRSA and VRSA)
    • Abstract: Publication date: December 2018Source: Bioorganic Chemistry, Volume 81Author(s): Srikanth Gatadi, Jitendra Gour, Grace Kaul, Manjulika Shukla, Arunava Dasgupta, Ravikumar Akunuri, Richa Tripathi, Y.V. Madhavi, Sidharth Chopra, Srinivas NanduriOccurrence of infections due to the drug resistant Staphylococcus aureus is on rise necessitating the need for rapid development of new antibacterial agents. In our present work, a series of new 3-phenylquinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP (E. coli, S. aureus, K. pneumoniae, A. baumannii, P. aeroginosa) pathogen panel and pathogenic mycobacterial strains. The study revealed that compounds 4a, 4c, 4e, 4f, 4g, 4i, 4o and 4p exhibited selective and potent inhibitory activity against Staphylococcus aureus with MIC values in the range of 0.125–8 µg/mL. Further, the compounds 4c, 4e and 4g were found to be non toxic to Vero cells (CC50 =>10–>100 µg/mL) and exhibited favourable selectivity index (SI = 40–>200). The compounds 4c, 4e and 4g also showed potent inhibitory activity against various MDR-S. aureus including VRSA. The promising results obtained indicated the potential use of the above series of compounds as promising antibacterial agents for the treatment of multidrug resistant Staphylococcus aureus infections.Graphical abstractGraphical abstract for this article
       
  • New Indole Based Hybrid Oxadiazole Scaffolds with N-Substituted
           Acetamides: As Potent Anti-diabetic Agents
    • Abstract: Publication date: Available online 18 August 2018Source: Bioorganic ChemistryAuthor(s): Majid Nazir, Muhammad Athar Abbasi, Aziz-ur-Rehman, Sabahat Zahra Siddiqui, Khalid Mohammed Khan, Kanwal, Uzma Salar, Muhammad Shahid, Muhammad Ashraf, Muhammad Arif Lodhi, Farman Ali KhanCurrent study is based on the sequential conversion of indolyl butanoic acid (1) into ethyl indolyl butanoate (2), indolyl butanohydrazide (3), and 1,3,4-oxadiazole-2-thiol analogs (4) by adopting chemical transformations. In a parallel series of reactions, 2-bromo-N-phenyl/arylacetamides (7a-l) were synthesized by reacting different amines derivatives (5a-l) with 2-bromoacetyl bromide (6) to serve as electrophile. Then, the synthesized electrophiles (7a-l) were treated with nucleophilic 1,3,4-oxadiazole-2-thiol analog (4) to afford a range of N-substituted derivatives (8a-l). The structural confirmation of all the synthetic compounds was carried out by IR, 1H-, 13C-NMR, EI-MS, and CHN analysis data. All synthesized molecules (8a-l) were tested for their antidiabetic potential via inhibition of the α-glucosidase enzyme followed by their in silico study. Their cytotoxicity profile was also ascertained via hemolytic activity and all of them possessed very low cytotoxicity. Compounds 8h and 8l were found most active having IC50 values 9.46 ± 0.03 µM and 9.37 ± 0.03 µM, respectively. However, all other molecules also exhibited good to moderate inhibition potential with IC50 values between 12.68 ± 0.04 - 37.82 ± 0.07, compared to standard acarbose (IC50 = 37.38 ± 0.12 µM), hence can be used as lead molecules for further research in order to get better antidiabetic agents.Graphical abstractGraphical abstract for this article
       
  • fSearching for improved mimetic peptides inhibitors preventing
           conformational transition of amyloid-β42 monomer
    • Abstract: Publication date: Available online 18 August 2018Source: Bioorganic ChemistryAuthor(s): János Gera, Titanilla Szögi, Zsolt Bozsó, Livia Fülöp, Exequiel E. Barrera, Ana M. Rodriguez, Luciana Méndez, Carina M.L. Delpiccolo, Ernesto G. Mata, Federica Cioffi, Kerensa Broersen, Gabor Paragi, Ricardo D. EnrizA series of novel mimetic peptides were designed, synthesised and biologically evaluated as inhibitors of Aβ42 aggregation. One of the synthesised peptidic compounds, termed compound 7 modulated Aβ42 aggregation as demonstrated by thioflavin T fluorescence, acting also as an inhibitor of the cytotoxicity exerted by Aβ42 aggregates. The early stage interaction between compound 7 and the Aβ42 monomer was investigated by replica exchange molecular dynamics (REMD) simulations and docking studies. Our theoretical results revealed that compound 7 can elongate the helical conformation state of an early stage Aβ42 monomer and it helps preventing the formation of β-sheet structures by interacting with key residues in the central hydrophobic cluster (CHC). This strategy where early “on-pathway” events are monitored by small molecules will help the development of new therapeutic strategies for Alzheimer’s disease.Graphical abstractGraphical abstract for this article
       
  • Issue TOC
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s):
       
  • Tyrosinase inhibition by some flavonoids: Inhibitory activity, mechanism
           by in vitro and in silico studies
    • Abstract: Publication date: Available online 15 August 2018Source: Bioorganic ChemistryAuthor(s): Didem Şöhretoğlu, Suat Sari, Burak Barut, Arzu ÖzelFlavonoids are main polyphenolic groups widely distributed to fruits, vegetables and beverages we consumed daily. They exhibit many biological effects. We tested tyrosinase inhibitor potential of structurally related (1-9) flavonoids and found that all the tested materials possessed tyrosinase inhibitory effect compared to the positive control, kojic acid. 2 exhibited the strongest tyrosinase inhibitory effect with an IC50 value of 40.94 ± 0.78 µM in a competitive manner. According to kinetic analysis 1, 4 and 7 were found to be competitive inhibitors, 3, 5, and 6 noncompetitive inhibitors of tyrosinase. According to the docking studies, A and C ring of the flavonoid structure, hydroxyl substituent at the 7th position, and hydroxyl substituents at para or para and meta position of ring B play key role for competitive inhibition of the enzyme.Graphical abstractGraphical abstract for this article
       
  • Highly functionalized 2-amino-4H-pyrans as potent cholinesterase
           inhibitors
    • Abstract: Publication date: Available online 12 August 2018Source: Bioorganic ChemistryAuthor(s): Raju Suresh Kumar, Abdulrahman I. Almansour, Natarajan Arumugam, Dhaifallah M. Al-thamili, Alireza Basiri, D. Kotresha, Thota Sai Manohar, S. Venketesh, Mohammad Asad, Abdullah M. AsiriNovel highly functionalized 2-amino-4H-pyrans were achieved in excellent yields under simple grinding at ambient temperature and were assessed for their potential for treating Alzheimer’s disease (AD). The 2-amino-4H-pyran bearing nitro groups on both the aryl rings showed the highest activity, with an IC50 of 1.98±0.09 µM against acetylcholinesterase (AChE) and 10.62±0.21 µM against butyrylcholinesterase (BChE), the inhibition mechanisms on AChE and BChE receptors were revealed by means of molecular docking simulations.Graphical abstractHighly functionalized 2-amino-4H-pyrans were achieved in excellent yields and assessed for their potential as inhibitors of AD. Compound bearing nitro groups on both the aryl rings showed the highest activity and this is also supported by its inhibition mechanisms on AChE and BChE receptors.Graphical abstract for this article
       
  • New bio-sensitive and biologically active single crystal of pyrimidine
           scaffold ligand and its gold and platinum complexes: DFT, antimicrobial,
           antioxidant, DNA interaction, molecular docking with DNA / BSA and
           anticancer studies
    • Abstract: Publication date: Available online 11 August 2018Source: Bioorganic ChemistryAuthor(s): Murugesan Sankarganesh, Jeyaraj Dhaveethu Raja, Karunganathan Sakthikumar, Rajadurai Vijay Solomon, Jegathalaprathaban Rajesh, Shanmuganarayanan Athimoolam, Vijaparthasarathi VijayakumarNovel gold and platinum complexes [AuL2].Cl, 1 and [PtL2].2Cl, 2 with ligand, 2-methoxy-6-((2-(4-(trifluoromethyl)pyrimidin-2-yl)hydrazono)methyl)phenol (HL) have been synthesized and screened for their antimicrobial, antioxidant, DNA binding and anticancer (in vitro) activities. The single crystal of ligand HL was obtained by slow evaporation technique. The molecular structure of HL was confirmed from single crystal X-ray technique. Density functional theory calculations have been performed to gain insights into the electronic structure of these metal complexes. Antimicrobial result shows that, HL and complexes (1 and 2) have good antimicrobial agents against E. coli (bacteria) and C. albicans (fungi) than others bacterial and fungal strains. Antioxidant assay results suggest that, HL and complexes (1 and 2) possess good radical scavenging activity against diverse free radicals (DPPH, SOD, NO and H2O2). The intercalative interactions of HL and complexes (1 and 2) with CT-DNA were confirmed from spectroscopic titrations and viscometric measurements. Furthermore, the interactions of prepared compounds with DNA were confirmed by molecular docking analysis. In order to understand the nature of interactions between these metal complexes and BSA protein results clearly shows that complex 1 binds better than that of complex 2. The antitumor activities of prepared products were tested against single normal and different tumor cell lines by MTT assay. These results reveal that prepared complexes (1 and 2) have significant cytotoxic effect against tumor cell lines.Graphical abstractGraphical abstract for this article
       
  • Polyamine derivatives from the bee pollen of Quercus mongolica with
           tyrosinase inhibitory activity
    • Abstract: Publication date: Available online 10 August 2018Source: Bioorganic ChemistryAuthor(s): Seon Beom Kim, Qing Liu, Jong Hoon Ahn, Yang Hee Jo, Ayman Turk, In Pyo Hong, Sang Mi Han, Bang Yeon Hwang, Mi Kyeong LeeEighteen constituents, including nine new compounds, were isolated from the bee pollen of Quercus mongolica. The structures of the new compounds were established on the basis of combined spectroscopic analysis. Structurally, the nine new compounds are polyamine derivatives with phenolic moieties which were assigned as one putrescine derivative, mogolicine A (2), seven spermidine derivatives, mongolidines A-G (3-5, 8, 12, 14, 17) and one spermine derivative, mogoline A (18). Evaluation of the biological activity of isolated compounds revealed that the polyamine derivatives with coumaroyl and caffeoyl moieties showed tyrosinase inhibition with IC50 values of 19.5 to 85.8 μM; however, the addition of a methoxy group to phenolic derivatives reduced the inhibitory activity.Graphical abstractGraphical abstract for this article
       
  • Synthesis of 1H-1,2,3-triazole derivatives as new α-glucosidase
           inhibitors and their molecular docking studies
    • Abstract: Publication date: Available online 7 August 2018Source: Bioorganic ChemistryAuthor(s): Satya Kumar Avula, Ajmal Khan, Najeeb Ur Rehman, Muhammad U. Anwar, Zahra Al-Abri, Abdul Wadood, Muhammad Riaz, Rene Csuk, Ahmed Al-HarrasiInhibition of α-glucosidase is an effective strategy for controlling the post-prandial hyperglycemia in diabetic patients. For the identification of new inhibitors of this enzyme, a series of new (R)-1-(2-(4-bromo-2-methoxyphenoxy) propyl)-4-(4-(trifluoromethyl) phenyl)-1H-1,2,3-triazole derivatives were synthesized (8a-d and 10a-e). The structures were confirmed by NMR, mass spectrometry and, in case of compound 8a, by single crystal X-ray crystallography. The α-glucosidase inhibitory activities were investigated in vitro. Most derivatives exhibited significant inhibitory activity against α-glucosidase enzyme. Their structure-activity relationship and molecular docking studies were performed to elucidate the active pharmacophore against this enzyme. Compound 10b was the most active analogue with IC50 value of 14.2 µM, while compound 6 was found to be the least active having 218.1 µM. A preliminary structure-activity relationship suggested that the presence of 1H-1,2,3-triazole ring in 1H-1,2,3-triazole derivatives is responsible for this activity and can be used as anti-diabetic drugs. The molecular docking studies of all active compounds were performed, in order to understand the mode of binding interaction and the energy of this class of compounds.Graphical abstractGraphical abstract for this article
       
  • Novel Thymol Bearing Oxypropanolamine Derivatives as Potent Some Metabolic
           Enzyme Inhibitors - Their Antidiabetic, Anticholinergic and Antibacterial
           Potentials
    • Abstract: Publication date: Available online 7 August 2018Source: Bioorganic ChemistryAuthor(s): Mustafa Zengin, Hayriye Genc, Parham Taslimi, Ali Kestane, Ertugrul Guclu, Aziz Ogutlu, Oguz Karabay, İlhami GulçinA series of classical and newly synthesized thymol bearing oxypropanolamine compounds were synthesized and characterized. Their in vitro antibacterial activity on A. baumannii, P. aeruginosa, E. coli and S. aureus strains were investigated with agar well diffusion method. The results were compared with commercially available drug active compounds. As well as 3a, 3b and 3c have the most significant antibacterial effect among all the tested compounds; approximately all of them have more antibacterial activity than the reference drugs. These novel thymol bearing oxypropanolamine derivatives were effective inhibitors of the α-glycosidase, cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase enzymes (AChE) with Ki values in the range of 463.85-851.05 µM for α-glycosidase, 1.11–17.34 µM for hCA I, 2.97-17.83 µM for hCA II, and 13.58-31.45 µM for AChE, respectively.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of
           N-aryl-2-phenyl-hydrazinecarbothioamides: Experimental and theoretical
           analysis on tyrosinase inhibition and interaction with HSA
    • Abstract: Publication date: Available online 6 August 2018Source: Bioorganic ChemistryAuthor(s): Danilo Sousa-Pereira, Otávio Augusto Chaves, Camilla Moretto dos Reis, Márcia C. C. de Oliveira, Carlos Maurício R. Sant'Anna, José Carlos Netto-Ferreira, Aurea EchevarriaA series of N-aryl-2-phenyl-hydrazinecarbothioamides have been investigated as possible inhibitors of tyrosinase, an enzyme involved in the development of melanomas. The hydrazinecarbothioamides 1-6 were synthesized from the reaction between phenylhydrazine and isothiocyanates, for which three different methods have been employed, namely stirring at room temperature, by microwave irradiation or by mechanochemical grinding. Quantitative yields were obtained for the later technique. Compound 4 showed the best valuefortyrosinase inhibition (IC50 = 22.6 µM), which occurs through an uncompetitive mechanism. Molecular docking results suggested that 4 can interact viaT-stacking with the substrate L-DOPA and via hydrogen bonding and hydrophobic forces with the amino acid residues Ala-79, His-243, Val-247, Phe-263, Val-282, and Glu-321. The interaction between human serum albumin (HSA) and compound 4 occurs through a ground state association and does not perturb the secondary structure of the albumin as well as the microenvironment around Tyr and Trp residues. The binding is spontaneous, moderate and occurs mainly in the Sudlow’s site I. Molecular docking results suggested hydrogen bonding, hydrophobic and electrostatic interactions as the main binding forces between the compound 4 and the amino acid residues Lys-198, Trp-214, Glu-449, Leu-452, and Leu-480.Graphical abstractGraphical abstract for this article
       
  • Synthesis of matrinic amide derivatives containing 1,3,4-thiadiazole
           scaffold as insecticidal/acaricidal agents
    • Abstract: Publication date: Available online 6 August 2018Source: Bioorganic ChemistryAuthor(s): Min Lv, Guangci Liu, Minghong Jia, Hui XuIn continuation of our program aimed at the development of natural product-based pesticidal agents, a series of matrinic amide derivatives containing 1,3,4-thiadiazole scaffold were prepared, and their insecticidal and acaricidal activities were evaluated against Mythimna separata and Tetranychus cinnabarinus. Some compounds exhibited potent insecticidal and acaricidal activities. It suggested that R1 as a nitro group and R2 as a fluorine atom, were important for the insecticidal activity; R1 as the electron-donating groups and R2 as the methyl group, were necessary for the acaricidal activity.Graphical abstractGraphical abstract for this article
       
  • An eco-friendly catalytic system for multicomponent, one-pot synthesis of
           novel spiro-chromeno indoline-triones and their anti-prostate cancer
           potentials evaluated via alkaline phosphatase inhibition mechanism
    • Abstract: Publication date: Available online 6 August 2018Source: Bioorganic ChemistryAuthor(s): M. Rajesh Kumar, A. Manikandan, A. Sivakumar, V. Violet DhayabaranA green and efficient straightforward tactic for the one-pot regioselective synthesis of novel 10,10-dimethyl-9,10,11,11a-tetrahydro-6H-spiro[chromeno[4,3–b]chromene-7,3'-indoline]-2',6,8 (7aH) -triones (4a-n) in one-pot modus has been established using eco-friendly p-toluenesulphonic acid as catalyst. Among the solvents that were used for synthesis, 4a-n were suitably synthesized with maximum yield (90-98 %) in water. We avoided column purification and the formed by-product in the process is environmental-friendly. Hence, this reaction may consider as an astonishing piece work in this study, why because, the reaction mechanism that depends on the nature of the group attached to the isatin ring nitrogen atom. The main advantage of this protocol includes short reaction time, good yield, easy to work-up, practical simplicity, high regioselectivity and reduced pollutant, cost and avoids tedious purification. These pharmaceutically important compounds (4a-n) were recognized for their alkaline phosphatase inhibition and prostate cancer medication capabilities. The selective activity relation between alkaline phosphatase and prostate cancer was unveiled through the interaction of 4a-n to Human alkaline phosphatase (PDB ID: 1EW2).Graphical abstractGraphical abstract for this article
       
  • Aryl fluorosulfate analogues as potent antimicrobial agents: SAR,
           cytotoxicity and docking studies
    • Abstract: Publication date: Available online 6 August 2018Source: Bioorganic ChemistryAuthor(s): Lekkala Ravindar, S.N.A. Bukhari, K.P. Rakesh, H.M. Manukumar, H.K. Vivek, N. Mallesha, Zhi-Zhong Xie, Hua-Li QinA series of aryl fluorosulfate analogues (1-37) were synthesized and tested for in vitro antibacterial and antifungal studies, and validated by docking studies. The compounds 9, 12, 14, 19, 25, 26, 35, 36 and 37 exhibited superior antibacterial potency against tested bacterial strains, while compounds 2, 4, 5, 15, 35, 36 and 37 were found to have better antifungal activity against tested fungal strains, compared to standard antibiotic gentamicin and ketoconazole respectively. Among all the synthesized 37 analogs, compounds 25, 26, 35, 36 and 37 displayed excellent anti-biofilm property against Staphylococcus aureus. The structure-activity relationship (SAR) revealed that the antimicrobial activity depends upon the presence of –OSO2F group and slender effect of different substituent’s on the phenyl rings. The electron donating (OCH3) groups in analogs increase the antibacterial activity, and interestingly the electron withdrawing (Cl, NO2, F and Br) groups increase the antifungal activity (except compound 35, 36 and 37). The mechanism of potent compounds showed membrane damage on bacteria confirmed by SEM. Compounds 35, 36 and 37 exhibited highest glide g-scores in molecular docking studies and validated the biocidal property.Graphical abstractGraphical abstract for this article
       
  • Thiazolo[3,2-a]pyrimidin-5-one derivatives as a novel class of
           11β-hydroxysteroid dehydrogenase inhibitors
    • Abstract: Publication date: December 2018Source: Bioorganic Chemistry, Volume 81Author(s): Renata Studzińska, Daria Kupczyk, Anita Płazińska, Renata Kołodziejska, Tomasz Kosmalski, Bożena Modzelewska-Banachiewicz11β-hydroxysteroid type 1 dehydrogenase (11β-HSD1) is an enzyme that increases tissue concentrations of cortisol. Selective inhibitors of this enzyme regulate the level of cortisol and thus play a key role in the treatment of Cushing's syndrome, metabolic syndrome and type 2 diabetes.In this study the inhibitory activity of 29 thiazolo[3,2-a]pyrimidin-5-one derivatives on 11β-HSD1 were investigated. Studies were carried out with pooled human liver microsomes. A lot of analyzed compounds show activity for inhibiting 11β-HSD1 (up to 59.15% at concentration 10 µmol/l). Molecular docking simulation show that the molecule of the most active compound: 7-(cyclohexylmethyl)-2-iodomethyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-one forms hydrogen bonds with Ala172, Leu171, Leu215 or Tyr177. In addition, the cycloalkane moiety can create the hydrophobic contacts with NADP+. For this compound also the most favourable Docking Score value was obtained.The most active compound only in the slight degree inhibits 11β-HSD2 activity and is a selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1. Consequently it can have a real effect on the regulation of the cortisol level in the body.Graphical abstractGraphical abstract for this article
       
  • 1,2,3-triazole tethered Indole-3-glyoxamide derivatives as multiple
           inhibitors of 5-LOX, COX-2 & tubulin: Their anti-proliferative &
           anti-inflammatory activity
    • Abstract: Publication date: December 2018Source: Bioorganic Chemistry, Volume 81Author(s): Fatima Naaz, M.C. Preeti Pallavi, Syed Shafi, Naveen Mulakayala, M. Shahar Yar, H.M. Sampath KumarTo evaluate the role of COX-2 and 5-LOX as dual inhibitors in controlling the cancer cell proliferation, a set of two series having 42 compounds of 1, 2, 3-Tethered Indole-3-glyoxamide derivatives were synthesized by employing click chemistry approach and were also evaluated for their in vitro cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) inhibitory activities with in vivo anti-inflammatory and in vitro anti-proliferative potencies. Among the compounds tested, compounds 11q and 13s displayed excellent inhibition of COX-2 (IC50 0.12 µM) with good COX-2 selectivity index (COX-2/COX-1) of 0.058 and 0.046 respectively. Compounds 11q and 13s also demonstrated comparable 5-LOX inhibitory activity with IC50 7.73 and 7.43 µM respectively to that of standard Norhihydroguaiaretic acid (NDGA: IC50 7.31 µM). Among all the selected cell lines, prostate cancer cell line DU145 was found to be susceptible to this class of compounds. Among all the tested compounds, compounds 11g, 11i, 11k, 11q, 13r, 13s and 13u demonstrated excellent to moderate anti-proliferative activity with IC50s ranging between 6.29 and 18.53 µM. Compounds 11q and 11g demonstrated better anti-proliferative activities against DU145 cancer cell line with IC50 values 8.17 and 8.69 µM respectively when compared to the standard drug etoposide (VP16; IC50 9.80 µM). Compounds 11g, 11k, 11q, 13s and 13u showed good dual COX-2/5-LOX inhibitory potentials with excellent anti-proliferative activity. Results from carrageenan-induced hind paw edema demonstrated that compounds 11b, 11l, 11q and 13q exhibited significant anti-inflammatory activity with 69–77% inhibition at 3 h, 75–82% inhibition at 5 h when compared to the standard drug indomethacin (66.6% at 3 h and 77.94% at 5 h). Ulcerogenic study revealed that compounds 11q and 13q did not cause any gastric ulceration. In vitro tubulin assay resuted that compound 11q interfered with microtubulin dynamic and act as tubulin polymerization inhibitor. In silico molecular docking studies demonstrated that compounds 11q and 13s are occupying the colchicines binding site of tubulin polymer and 11q illustrated very good binding affinities towards COX-2 and 5-LOX.Graphical abstract1,2,3-triazole tethered Indole-3-glyoxamide derivatives demonstrated excellent anti-proliferative activities through COX-2/5-LOX dual inhibition.Graphical abstract for this article
       
  • Dicoumarol derivatives: Green synthesis and molecular modelling studies of
           their anti-LOX activity
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Dušica Simijonović, Evangelia-Eirini Vlachou, Zorica D. Petrović, Dimitra J. Hadjipavlou-Litina, Κonstantinos E. Litinas, Nevena Stanković, Nezrina Mihović, Milan P. MladenovićDicoumarol derivatives were synthesized in the InCl3 catalyzed pseudo three-component reactions of 4-hydroxycoumarin with aromatic aldehydes in excellent yields. The reactions were performed in water under microwave irradiation. All synthesized compounds were characterized using NMR, IR, and UV–Vis spectroscopy, as well as with TD-DFT. Obtained dicoumarols were subjected to evaluation of their in vitro lipid peroxidation and soybean lipoxygenase inhibition activities. It was shown that five of ten examined compounds (3e, 3h, 3b, 3d, 3f) possess significant potential of antilipid peroxidation (84–97%), and that compounds 3b, 3e, 3h provided the highest soybean lipoxygenase (LOX-Ib) inhibition (IC50 = 52.5 µM) and 3i somewhat lower activity (IC50 = 55.5 µM). The bioactive conformations of the best LOX-Ib inhibitors were obtained by means of molecular docking and molecular dynamics. It was shown that, within the bioactive conformations interior to LOX-Ib active site, the most active compounds form the pyramidal structure made of two 4-hydroxycoumarin cores and a central phenyl substituent. This form serves as a spatial barrier which prevents LOX-Ib Fe2+/Fe3+ ion activity to generate the coordinative bond with the C13 hydroxyl group of the α-linoleate. It is worth pointing out that the most active compounds 3b, 3e, 3h and 3i can be candidates for further examination of their in vitro and in vivo anti-inflammatory activity and that molecular modeling study results provide possibility to screen bioactive conformations and elucidate the mechanism of dicoumarols anti-LOX activity.Graphical abstractGraphical abstract for this article
       
  • Improvement of carbonyl reductase activity for the bioproduction of
           tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Zhi-Qiang Liu, Huan-Huan Yin, Xiao-Jian Zhang, Rong Zhou, Yan-Mei Wang, Yu-Guo Zhengtert-Butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate ((3R,5S)-CDHH) is a key chiral intermediate for the side chain synthesis of rosuvastatin. In this study, random mutagenesis, site-saturation mutagenesis and combinatorial mutagenesis methods were applied to improve the activity of a synthesized stereoselective short chain carbonyl reductase (SCR) to prepare (3R,5S)-CDHH. After screened by high-throughput screening method and high-performance liquid chromatography, mut-Phe145Met/Thr152Ser and mut-Phe145Tyr/Thr152Ser, were obtained, and the enzyme activities of mutants were improved by 1.60- and 1.91-fold compared with parent enzyme, respectively. The catalytically efficiencies (kcat/Km) of mut-Phe145Met/Thr152Ser and mut-Phe145Tyr/Thr152Ser exhibited 5.11- and 8.07-fold improvements in initial activity toward (S)-6-chloro-5-hydroxy-3-oxohexanoate ((S)-CHOH), respectively. In the asymmetric reduction, mut-Phe145Tyr/Thr152Ser catalyzed 500 g L−1 of (S)-CHOH to produce (3R,5S)-CDHH with>99% yield and>99% e.e., and the highest space-time yield achieved at 752.76 mmol L−1 h−1 g−1 wet cell weight within 8 h bioconversion. This study provides a foundation for the preparation of (3R,5S)-CDHH by carbonyl reductase.Graphical abstractGraphical abstract for this article
       
  • DNA-binding, enzyme inhibition, and photochemical properties of
           chalcone-containing metallophthalocyanine compounds
    • Abstract: Publication date: Available online 4 August 2018Source: Bioorganic ChemistryAuthor(s): Furkan Özen, Aslıhan Günel, Arif BaranIn this study, two novel phthalocyanine complexes were synthesized using their corresponding metal salts and 4-(4-(3-(2,4,5-trimethoxyphenyl)acryloyl)phenoxy)phthalo-nitrile as chalcone ligand (4), which was prepared from the reaction of 4-nitrophthalonitrile with 4-hydroxyphenyl-3-(2,4,5-trimethoxyphenyl)prop-2-en-1-one (3). These metallophthalocyanines showed good solubility in organic solvents such as CDCl3, DCM, THF, DMF, and DMSO. The novel phthalocyanine compounds 4a (Pc-Zn) and 4b (Pc-Co) were characterized using their UV-vis, FT-IR, 1H NMR, 13C NMR, and MALDI-TOF mass spectra and elemental analysis. Then the DNA-binding and xanthine oxidase and carbonic anhydrase-I inhibition properties of compounds 4a and 4b were investigated. Photochemical properties (such as singlet oxygen generation and photodegradation) of this novel chalcone phthalocyanine (4a) were determined in dimethyl sulfoxide (DMSO).Graphical abstractIn the study, two novel phthalocyanine complexes were synthesized using their corresponding metal salts, showed good solubility in organic solvents such as CDCl3, DCM, THF, DMF, and DMSO. This compounds 4a (Pc-Zn) and 4b (Pc-Co) were characterized using their UV-vis, FT-IR, 1H NMR, 13C NMR, and MALDI-TOF mass spectra. Then the DNA-binding and xanthine oxidase and carbonic anhydrase-inhibition properties were investigated. Photochemical properties (such as singlet oxygen generation and photodegradation) of this novel chalcone phthalocyanine (4a) were determined in dimethyl sulfoxide (DMSO).Graphical abstract for this article
       
  • Cytotoxic ent-Abietane-type Diterpenoids from the Roots of
           Euphorbia ebracteolata
    • Abstract: Publication date: Available online 2 August 2018Source: Bioorganic ChemistryAuthor(s): Chunhui Han, Yulin Peng, Yifei Wang, Xiaokui Huo, Baojing Zhang, Dawei Li, Aijing Leng, Houli Zhang, Xiaochi Ma, Chao WangEuphoroids A−C (1−3), three new ent-abietane-type diterpenoids, together with ten known analogues (4−13) were obtained from the roots of Euphorbia ebracteolata. The structures of these compounds were determined by extensive spectroscopic data analysis, including UV, HRESIMS, 1D-, and 2D-NMR data. The inhibitory effects of compounds 1−13 on human cancer cells were determined using the MTT assay. The results revealed that new compounds 2 and 3 showed moderate cytotoxic activities against human cancer cell lines. Especially, compound 3 displayed selective cytotoxic effect agains cancer cell lines.Graphical abstractGraphical abstract for this article
       
  • Six kanshone C-derived sesquiterpenoid hybrids nardochalaristolones A–D,
           nardoflavaristolone A and dinardokanshone F from Nardostachys jatamansi DC
           
    • Abstract: Publication date: Available online 2 August 2018Source: Bioorganic ChemistryAuthor(s): Xu Deng, Yan Wang, Hong-Hua Wu, Weize Zhang, Xueqi Dong, Zhimei Wang, Yan Zhu, Xiu-Mei Gao, Li Li, Ya-Nan Wang, Yan-Tong XuFour sesquiterpenoid-chalcone hybrids (nardochalaristolones A–D, 1–4), a pair of epimeric sesquiterpenoid-flavonone hybrids ((2'S)- and (2'R)-nardoflavaristolone A, 5 and 6), and a sesquiterpenoid dimer (dinardokanshone F, 7), all sharing a kanshone C-derived sesquiterpenoid unit, were isolated from the underground parts of Nardostachys jatamansi (D.Don) DC. Their structures were elucidated by analysis of the extensive spectroscopic data, and the absolute configurations were established by analysis of 2D NMR spectroscopic data including NOESY data, combined with comparisons of experimental and calculated electronic circular dichroism spectra. Further, the plausible biosynthetic pathways for these compounds were proposed. And the results of SERT activity assay revealed that nardochalaristolones C–D (3 and 4) significantly enhanced SERT activity, while other compounds didn't show any SERT regulatory activities.Graphical abstractPreviously undescribed kanshone C-derived sesquiterpenoid hybrids nardochalaristolones A–D, nardoflavaristolone A and dinardokanshone F, were isolated from the underground parts of Nardostachys jatamansi DC., and their SERT activities were evaluated.Graphical abstract for this article
       
  • Synthesis, Biological Activity and Structure Activity Relationship studies
           of Novel Conazole Analogues via Conventional, Microwave and Ultrasound
           Mediated Techniques
    • Abstract: Publication date: Available online 1 August 2018Source: Bioorganic ChemistryAuthor(s): Arif Mermer, Neslihan Demirbas, Ahmet Demirbas, Nesrin Colak, Faik Ahmet Ayaz, Manikandan Alagumuthu, Sivakumar Arumugam1,2,4-Triazole derivatives containing a piperazine nucleus (4a-d and 10) were prepared starting from 1-(2-methoxyphenyl)piperazine or ethyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate via several steps. The synthesis of fifteen compounds (7a-l and 13a-c), which can be considered as new analogues of azole class antifungals was performed starting from 1,2,4-triazoles (4a-d and 10) via three steps containing the condensation with 2-bromo-1-(4-chlorophenyl)ethanone, reduction of carbonyl group to alcohol and alkylation of OH group,repectively. All the reactions were examined under conventional, ultrasound and microwave irradiation conditions as green chemistry techniques, and optimum conditions were defined. The newly synthesized compounds were screened for their biological potentials including antimicrobial, antioxidant, antiurease and anti α-glucosidase activities and promising results were obtained. The enzyme inhibitory potentials of these compounds were further validated through molecular docking.Graphical abstractGraphical abstract for this article
       
  • Bioactive compounds from sclerotia extract of Poria cocos that control
           adipocyte and osteoblast differentiation
    • Abstract: Publication date: Available online 31 July 2018Source: Bioorganic ChemistryAuthor(s): Seulah Lee, Eunyong Choi, Su-Man Yang, Rhim Ryoo, Eunjung Moon, Seon-Hee Kim, Ki Hyun KimPoria cocos Wolf confers edible sclerotia also known as ‘Indian bread’ in North America, that have been used for the treatment of various diseases in Asian countries. As part of our ongoing aim to identify biologically new metabolites from Korean edible mushrooms, we investigated the ethanol (EtOH) extract of the sclerotia of P. cocos by applying a comparative LC/MS- and bioassay-based analysis approach, since the EtOH extract reciprocally regulated adipocyte and osteoblast differentiation in mouse mesenchymal stem cells (MSCs). Bioassay-based analysis of the EtOH extract led to the successful isolation of two sterols, ergosterol peroxide (1) and 9,11-dehydroergosterol peroxide (2); three diterpenes, dehydroabietic acid (3), 7-oxocallitrisic acid, (4) and pimaric acid (5); and two triterpenes, dehydroeburicoic acid monoacetate (6) and eburicoic acid acetate (7) from the active hexane-soluble fraction. The isolated compounds (1–7) were examined for their effects on the regulation of MSC differentiation. The two sterols (1 and 2) were able to suppress MSC differentiation toward adipocytes. In contrast, the three diterpenes (3–5) showed activity to promote osteogenic differentiation of MSC. These findings demonstrate that the EtOH extract of P. cocos sclerotia is worth consideration as a new potential source of bioactive compounds effective in the treatment of osteoporosis in the elderly, since the extract contains sterols that inhibit adipogenic differentiation as well as diterpenes that promote osteogenic differentiation from MSCs.Graphical abstractGraphical abstract for this article
       
  • Imidazopyridine linked triazoles as tubulin inhibitors, effectively
           triggering apoptosis in lung cancer cell line
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Ibrahim Bin Sayeed, M.V.P.S. Vishnuvardhan, Apoorva Nagarajan, Srinivas Kantevari, Ahmed KamalA library of new imidazopyridine linked triazole hybrid conjugates (8a-r) were designed, synthesized and evaluated for their cytotoxicity against four cancer cell lines namely, human lung (A549), human prostate (DU-145), human colon (HCT-116) and breast (MDA-MB 231) cancer. These conjugates exhibited good to moderate activity against the tested human cancer cell lines. Two of the conjugates (8g and 8j) showed significant antitumor activity against human lung cancer cell line (A549) with IC50 values of 0.51 µM and 0.63 µM respectively. Flow cytometry analysis revealed that these conjugates arrested the cell cycle at G2/M phase in human lung cancer cell line (A549). Immune-histochemistry and tubulin polymerization assay suggest inhibition of tubulin. Hoechst staining, annexin V and DNA fragmentation by tunnel assay suggested that these compounds induce cell death by apoptosis. Overall, the current study demonstrates that the synthesis of imidazopyridine linked triazole conjugates as promising anticancer agents causing G2/M arrest and apoptotic-inducing ability.Graphical abstractGraphical abstract for this article
       
  • Synthesis of novel isoindoline-1,3-dione-based oximes and
           benzenesulfonamide hydrazones as selective inhibitors of the
           tumor-associated carbonic anhydrase IX
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Alaa A.-M. Abdel-Aziz, Adel S. El-Azab, Mohamed A. Abu El-Enin, Abdulrahman A. Almehizia, Claudiu T. Supuran, Alessio NocentiniThe synthesis, characterization and biological evaluation of a library of isoindoline-1,3-dione-based oximes and benzenesulfonamide hydrazones is disclosed. The set of hydroxyiminoethyl aromatic derivatives 10–18 was designed to assess the potentiality as zinc-binder for a feebly studied functional group in the field of carbonic anhydrase (CA, EC 4.2.1.1) inhibition. Analogue phenylphthalimmides were linked to benzenesulfonamide scaffold by hydrazone spacers in the second subset of derivatives 20–28 to further investigate the application of the “tail approach” as tool to afford CA selective inhibition profiles. The compounds were assayed for the inhibition of physiologically relevant isoforms of human carbonic anhydrases (hCA, EC 4.2.1.1), the cytosolic CA I and II, and the membrane-bound CA IV and tumor-associated CA IX. The new zinc-binders, both of the oxime and sulfonamide types, showed a striking selective activity against the target hCA IX over ubiquitous hCA I and II, with diverse inhibitory ranges and ratio differing the two subsets. With CA IX being a strongly current antitumor/antimetastatic drug target, these series of compounds may be of interest for the development of new, both conventional and unconventional anticancer drugs targeting hypoxia-induced CA isoforms such as CA IX with minimum ubiquitous CAs-related side effects.Graphical abstractGraphical abstract for this article
       
  • Synthesis and DNase I inhibitory properties of some
           5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Anelia Ts. Mavrova, Stefan Dimov, Denitsa Yancheva, Ana Kolarević, Budimir S. Ilić, Gordana Kocić, Andrija ŠmelcerovićA series of six novel and six known thieno[2,3-d]pyrimidin-4-amines 2–13 were synthesized, and further were used as a starting material for preparation of a small series of eight novel thieno[2,3-d]pyrimidin-4-phthalimides 14–21. Eight compounds, five amine and three phthalimide derivatives, inhibited bovine pancreatic DNase I with an IC50 below 200 µM, being more effective than referent inhibitor crystal violet. Phthalimide derivatives 16, 18 and 19 exhibited higher DNase I inhibitory activity compared to their amine precursors 7, 10 and 11. Compound 19, as the most potent (IC50 = 106 ± 16 µM), offers a good starting point for a design of new DNase I inhibitors. The Pharma RQSAR model showed a significant enhancement of thieno[2,3-d]pyrimidines activity using aryl substituents at R1 position. The E-State RQSAR model clarified the most important structural fragments relevant for DNase I inhibition. Molecular docking and Site Finder module defined the thieno[2,3-d]pyrimidines interactions with the most important catalytic residues of DNase I, including Glu 39, His 134, Asp 168 and His 252. We also found that steric effects and increase of molecular volume play a vital role in DNase I inhibition.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and docking study of pyridine and thieno[2,3-b] pyridine
           derivatives as anticancer PIM-1 kinase inhibitors
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Marwa E. Abdelaziz, Mostafa M.M. El-Miligy, Salwa M. Fahmy, Mona A. Mahran, Aly A. HazzaaA series of pyridine and thieno[2,3-b]pyridine derivatives have been designed and synthesized as anticancer PIM-1 kinase inhibitors. Thirty-seven compounds were selected by NCI to be tested initially at a single dose (10 µM) in the full NCI 60 cell line panel. Compound 5b showed potent anticancer activity and was tested twice in the five-dose assay which confirmed its potent antitumor activity (GI50 values 0.302–3.57 µM) against all tested tumor cell lines except six cell lines where they showed moderate sensitivity. This compound was sent to NCI biological evaluation committee and still under consideration for further testing. In addition, the most active anticancer compounds in each series, 5b, 8d, 10c, 13h, and 15e, were evaluated for their PIM-1 kinase inhibitory activity. Compound 8d was the most potent one with IC50 = 0.019 µM followed by 5b, 15e, 10c and 13h with IC50 values 0.044, 0.083, 0.128 and 0.479 µM respectively. Moreover, docking study of the most active compounds in PIM-1 kinase active site was consistent with the in vitro activity.Graphical abstractGraphical abstract for this article
       
  • Discovery of polar spirocyclic orally bioavailable urea inhibitors of
           soluble epoxide hydrolase
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Alexey Lukin, Jan Kramer, Markus Hartmann, Lilia Weizel, Victor Hernandez-Olmos, Konstantin Falahati, Irene Burghardt, Natalia Kalinchenkova, Darya Bagnyukova, Nikolay Zhurilo, Jarkko Rautio, Markus Forsberg, Jouni Ihalainen, Seppo Auriola, Jukka Leppänen, Igor Konstantinov, Denys Pogoryelov, Ewgenij Proschak, Dmitry Dar'in, Mikhail KrasavinSpirocyclic 1-oxa-9-azaspiro[5.5]undecan-4-amine scaffold was explored as a basis for the design of potential inhibitors of soluble epoxide hydrolase (sEH). Synthesis and testing of the initial SAR-probing library followed by biochemical testing against sEH allowed nominating a racemic lead compound (±)-22. The latter showed remarkable (> 0.5 mM) solubility in aqueous phosphate buffer solution, unusually low (for sEH inhibitors) lipophilicity as confirmed by experimentally determined logD7.4 of 0.99, and an excellent oral bioavailability in mice (as well as other pharmacokinetic characteristics). Individual enantiomer profiling revealed that the inhibitory potency primarily resided with the dextrorotatory eutomer (+)-22 (IC50 4.99 ± 0.18 nM). For the latter, a crystal structure of its complex with a C-terminal domain of sEH was obtained and resolved. These data fully validate (+)-22 as a new non-racemic advanced lead compound for further development as a potential therapeutic agent for use in such areas as cardiovascular disease, inflammation and pain.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and anti leukemia cells proliferation activities of
           pyrimidylaminoquinoline derivatives as DOT1L inhibitors
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Li Zhang, Yantao Chen, Na Liu, Linjuan Li, Senhao Xiao, Xiaoliu Li, Kaixian Chen, Cheng Luo, Shijie Chen, Hua ChenA series of novel pyrimidylaminoquinoline derivatives 8(a-i) and 9(a-i) containing amino side chain, and the bisaminoquinoline analogs 3(b-e) have been designed and synthesized by structural modifications on a lead DOT1L inhibitor, 3a. All the compounds have been evaluated for their DOT1L inhibitory activities. The results showed that most of the compounds have strong anti DOT1L activities. Compounds 3e, 8h and 9e are the most potential ones from each category with the IC50 values of 1.06 ± 0.35 μM, 5.72 ± 1.56 μM and 3.55 ± 1.28 μM, respectively. Such inhibitors expressed significant binding interactions with DOT1L by surface plasmon resonance (SPR)-based binding assay. The results of molecular docking experiments suggested that they could occupy the SAM binding pocket of DOT1L. Compounds 8h and 9e exhibited better inhibitory activities but poor selectivities against the both MLL-rearranged MV4-11 cells and the non MLL-rearranged Kasumi-1 cells than those of 3a and 3e, which suggested that the introduction of the amino side chain would be beneficial for their anti leukemia cells proliferation activities, possibly due to the improvement of the fat solubility. Additionally, the direct cellular inhibition activities were found that compound 9e could effectively down-regulate both the level of H3k79 methylation and MLL-rearranged leukemia gene expression of Hoxa9 and Meis1 in MV4-11 in the qRT-PCR and western blot studies. These observations suggested DOT1L was one of the potential targets but perhaps not the most pivotal one for these compounds, which made their poor selectivities against leukemia cells proliferation.Graphical abstractGraphical abstract for this article
       
  • Investigation of salicylanilide and 4-chlorophenol-based N-monosubstituted
           carbamates as potential inhibitors of acetyl- and butyrylcholinesterase
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Martin Krátký, Šárka Štěpánková, Katarína Vorčáková, Jarmila VinšováBased on the presence of carbamate moiety, twenty salicylanilide N-monosubstituted carbamates concomitantly with their parent salicylanilides and five newly prepared 4-chlorophenyl carbamates obtained from isocyanates were investigated using Ellman’s method for their in vitro inhibitory activity against acetylcholinesterase (AChE) from electric eel and butyrylcholinesterase (BChE) from equine serum. The carbamates and salicylanilides exhibited mostly a moderate inhibition of both cholinesterase enzymes with IC50 values ranging from 5 to 235 µM. IC50 values for AChE were in a narrower concentration range when compared to BChE, but many of the compounds produced a balanced inhibition of both cholinesterases. The derivatives were comparable or superior to rivastigmine for AChE inhibition, but only a few of carbamates also for BChE. Several structure-activity relationships were identified, e.g., N-phenethylcarbamates produce clearly favourable BChE inhibition. The compounds also share convenient physicochemical properties for CNS penetration.Graphical abstractGraphical abstract for this article
       
  • Development of dilipid polymyxins: Investigation on the effect of
           hydrophobicity through its fatty acyl component
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Ronald Domalaon, Liam Berry, Quinn Tays, George G. Zhanel, Frank SchweizerContinuous development of new antibacterial agents is necessary to counter the problem of antimicrobial resistance. Polymyxins are considered as drugs of last resort to combat multidrug-resistant Gram-negative pathogens. Structural optimization of polymyxins requires an in-depth understanding of its structure and how it relates to its antibacterial activity. Herein, the effect of hydrophobicity was explored by adding a secondary fatty acyl component of varying length onto the polymyxin structure at the amine side-chain of l-diaminobutyric acid at position 1, resulting to the development of dilipid polymyxins. The incorporation of an additional lipid was found to confer polymyxin activity against Gram-positive bacteria, to which polymyxins are inherently inactive against. The dilipid polymyxins showed selective antibacterial activity against Pseudomonas aeruginosa. Moreover, dilipid polymyxin 1 that consists of four carbon-long aliphatic lipids displayed the ability to enhance the antibacterial potency of other antibiotics in combination against P. aeruginosa, resembling the adjuvant activity of the well-known outer membrane permeabilizer polymyxin B nonapeptide (PMBN). Interestingly, our data revealed that dilipid polymyxin 1 and PMBN are substrates for the MexAB-OprM efflux system, and therefore are affected by efflux. In contrast, dilipid polymyxin analogs that consist of longer lipids and colistin were not affected by efflux, suggesting that the lipid component of polymyxin plays an important role in resisting active efflux. Our work described herein provides an understanding to the polymyxin structure that may be used to usher the development of enhanced polymyxin analogs.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of
           benzo[b]furo[3,4-e][1,4]diazepin-1-one derivatives as anti-cancer agents
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Sina Omid Malayeri, Zahra Tayarani-Najaran, Fatemeh Shaebani Behbahani, Roghayeh Rashidi, Saeedeh Delpazir, Razieh GhodsiA new series of novel Podophyllotoxin-like benzo[b]furo[3,4-e][1,4]diazepin-1-ones possessing structural elements of 4-aza-2,3-didehydropodophyllotoxins with central diazepine ring was designed and synthesized as anti-cancer agents. In initial assessment, the cytotoxic activity of the synthesized compounds was evaluated against three cancer cell lines including MCF-7, PC3 and B16-F10 employing the MTT assay. Some of compounds (12h, 13a, 13c and 14b) showed significant cytotoxic activity. So, we investigated the cytotoxicity of compounds 12h, 13a, 13c and 14b, along with podophyllotoxin as the reference drug in different cancer cell lines including A549, A2780, DU145, HeLa, and normal Huvec cell line. Among these four compounds, 13c showed promising antiproliferative activity against all cancer cells stronger than the other compounds and comparable to reference drug podophyllotoxin in some cancer cells. All these four compounds did not show significant cytotoxicity on normal Huvec cell line. The flow cytometry analysis of the MCF-7, PC3 and A2780 human cancer cell lines treated with 13c showed that 13c, induced apoptosis in the MCF-7, PC3 and A2780 human cancer cell lines, which is in good agreement to its cytotoxic activity as well. Compound 13c did not show significant influence on tubulin assembly and exert its cytotoxic effects via induction of apoptosis and has potent and selective cytotoxic effects in cancer cells.Graphical abstractThe in vitro anti-proliferative activities (IC50 (µM)) of 13c, and podophyllotoxin against human cancer cell lines and normal Huvec cell line.Graphical abstract for this article
       
  • Albumin coated copper-cysteine nanozyme for reducing oxidative stress
           induced during sperm cryopreservation
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Fariba Dashtestani, Hedayatollah Ghourchian, Atefeh NajafiIn the present work, SOD mimetic nanozyme (NACu-Cys) consisting of Cu-Cys complex and nano-albumin (NA) were synthesized. After characterizing the nanozyme, its superoxide dismutase (SOD) behavior was evaluated by inhibition of the pyrogallol autoxidation method. The results revealed that NACu-Cys exhibited SOD mimetic activity with a half inhibition concentration (IC50) value of 7.0 × 10−3 µM and a turnover number (kcat) of 5.4 × 107 s−1. In the next step, this nanozyme was applied as a protective agent against oxidative stress induced by sperm cryopreservation. Increasing the motility, raising the viability and reducing the apoptosis occurred as a result of NACu-Cys additions to human sperm freezing medium. Comparison between the natural SOD and SOD mimic behavior of NACu-Cys revealed that this nanoparticle has the ability to be used as oxidative stress decrescent during cryopreservation process.Graphical abstractGraphical abstract for this article
       
  • Dual EGFR/HER2 inhibitors and apoptosis inducers: New benzo[g]quinazoline
           
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Mostafa M. Ghorab, Mansour S. Alsaid, Aiten M. SolimanDual targeting of EGFR and HER2 is a proven anticancer strategy for the treatment of solid tumors. An array of new N-substituted-2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio) acetamides 5–18 were designed and synthesized from the starting compound 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4. The targeted compounds were screened for their cytotoxic activity against MDA-MB-231 breast cancer cell line. The IC50 of all the compounds were in the range of 0.36–40.90 µM. The percentage inhibition towards EGFR was measured and found to be in the range of 63.00–16.90 %. The most potent compounds 5, 9, 15, 17 and 18 were further screened for their activity against both EGFR and HER2 receptors. The compounds showed IC50 in the range of 0.64–1.81 µM for EGFR and 1.13–2.21 µM for HER2, in comparison to erlotinib, the reference drug. Compound 17, the most potent towards EGFR in this series, undergoes cell cycle analysis and was found to arrest the cycle at the G2/M phase. Measurement of the cytotoxicity of compound 17 against normal breast cell line showed mild cytotoxic activity. The most potent compounds were subjected to a single dose of 8 Gy of γ-radiation and the cytotoxicity of the tested compounds was found to increase after irradiation, thus proving the synergistic effect of γ-irradiation. Molecular docking was adopted for all the synthesized compounds to confirm their mechanism of action.Graphical abstractGraphical abstract for this article
       
  • 11a-N-tosyl-5-carbapterocarpans: Synthesis, antineoplastic evaluation and
           in silico prediction of ADMETox properties
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Joseane A. Mendes, Eduardo J. Salustiano, Carulini de S. Pires, Thaís Oliveira, Julio C.F. Barcellos, Jhonny M.C. Cifuentes, Paulo R.R. Costa, Magdalena N. Rennó, Camilla D. Buarque11a-N-tosyl-5-carbapterocarpans (5a–c and 6a–c), 9-N-tosyl-4,4a,9,9a-tetrahydro-3H-carbazole (7), 11a-N-tosyl-5-carbapterocarpen (8) analogues of LQB-223 (4a), were synthesized through palladium catalyzed azaarylation of substituted dihydronaphtalenes (14a–c) and cyclohexadiene (15), respectively, with N-tosyl-o-iodoaniline (11). In order to understand the role of the N-tosyl moiety for the pharmacological activity, the azacarbapterocarpen (9) was also synthesized by Fischer indol reaction. The structural requirements at the A and D-rings for the antineoplastic activity toward human leukemias and breast cancer cells were evaluated as well. Substitutions on the A-ring of 4a and analogues alter the effect on different breast cancer subtypes. On the other hand, A-ring is not essential for antileukemic activity since compound 7, which does not contain the A-ring, showed efficacy with high selectivity indices for drug-resistant leukemias. On the other hand, substitutions on the D-ring of 4a for fluorine or iodine did not improve the antileukemic activity. In silico studies concerning Lipinskís rule of five, ADMET properties and drug scores of those compounds were performed, indicating good physicochemical properties for all compounds, in special for compound 7.Graphical abstractGraphical abstract for this article
       
  • Sam domain-based stapled peptides: Structural analysis and interaction
           studies with the Sam domains from the EphA2 receptor and the lipid
           phosphatase Ship2
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Flavia Anna Mercurio, Luciano Pirone, Concetta Di Natale, Daniela Marasco, Emilia Maria Pedone, Marilisa LeoneSam (Sterile alpha motif) domains represent small helical protein-protein interaction modules which play versatile functions in different cellular processes. The Sam domain from the EphA2 receptor binds the Sam domain of the lipid phosphatase Ship2 and this interaction modulates receptor endocytosis and degradation primarily generating pro-oncogenic effects in cell. To identify molecule antagonists of the EphA2-Sam/Ship2-Sam complex with anti-cancer activity, we focused on hydrocarbon helical stapled peptides. EphA2-Sam and one of its interactors (i.e., the first Sam domain of the adaptor protein Odin) were used as model systems for peptide design. Increase in helicity in the stapled peptides, with respect to the corresponding linear/native-like regions, was proved by structural studies conducted through CD (Circular Dichroism) and NMR (Nuclear Magnetic Resonance). Interestingly, interaction assays by means of NMR, SPR (Surface Plasmon Resonance) and MST (MicroScale Thermophoresis) techniques led to the discovery of a novel ligand of Ship2-Sam.Graphical abstractGraphical abstract for this article
       
  • Synthesis of C-2 and C-3 substituted quinolines and their evaluation as
           anti-HIV-1 agents
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Purvi Shah, Dharav Naik, Nisha Jariwala, Deepali Bhadane, Sanjay Kumar, Smita Kulkarni, Kamlesh Kumar Bhutani, Inder Pal SinghA plenty of natural products and synthetic derivatives containing quinoline moiety have been reported to possess various pharmacological activities. Quinolines such as 2-styrylquinolines and 8-hydroxyquinolines are extensively studied for their anti-HIV-1 activity and found to act mainly through HIV-1 integrase enzyme inhibition. In continuation of our efforts to search for newer anti-HIV-1 molecules, thirty-one quinoline derivatives with different linkers to ancillary phenyl ring were synthesized and evaluated for in vitro anti-HIV-1 activity using TZM-bl assays. Compound 31 showed higher activity in TZM-bl cell line against HIV-1VB59 and HIV-1UG070 cell associated virus (IC50 3.35 ± 0.87 and 2.57 ± 0.71 μM) as compared to other derivatives. Compound 31 was further tested against cell free virus HIV-1VB59 and HIV-1UG070 (IC50 1.27 ± 0.31 and 2.88 ± 1.79 μM, TI 42.20 and 18.61, respectively). This lead molecule also showed good activity in viral entry inhibition assay and cell fusion assay defining its mode of action. The activity of compound 31 was confirmed by testing against HIV-1VB51 in activated peripheral blood mononuclear cells (PBMCs). Binding interactions of 31 were compared with known entry inhibitors.Graphical abstractGraphical abstract for this article
       
  • Natural constituents from Cortex Mori Radicis as new pancreatic lipase
           inhibitors
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Xu-Dong Hou, Guang-Bo Ge, Zi-Miao Weng, Zi-Ru Dai, Yue-Hong Leng, Le-Le Ding, Ling-Ling Jin, Yang Yu, Yun-Feng Cao, Jie HouPancreatic lipase (PL), a key enzyme responsible for the hydrolysis of triacylglycerides in the gastrointestinal tract, has been identified as the therapeutic target for the regulation of lipid absorption. In the present study, six major constituents from a famous Chinese herbal medicine Cortex Mori Radicis (also named sangbaipi in Chinese), have been collected and their inhibitory effects on PL have been carefully investigated and well characterized by a fluorescence-based assay. The results clearly demonstrated that all tested bioactive constituents from Cortex Mori Radicis including sanggenone C (SC), sanggenone D (SD), kuwanon C (KC), kuwanon G (KG), morin and morusin displayed strong to moderate inhibitory effects towards PL with the IC50 values ranging from 0.77 μM to 20.56 μM. Further investigations on inhibition kinetics demonstrated that SC, SD, KC and KG functioned as potent and mixed inhibitors against PL-mediated 4-MU oleate hydrolysis, with the Ki values less than 5.0 μM. Furthermore, molecular docking simulations demonstrated that SD (the most potent PL inhibitor from Cortex Mori Radicis) could create strong interaction with Ser152 (the key amino acid in the catalytic triad) of PL via hydrogen bonding. All these findings provided a new powerful evidence for explaining the hypolipidemic effect of Cortex Mori Radicis, also suggested that some abundant natural compounds in this herbal medicine could be served as lead compounds for the development of new PL inhibitors.Graphical abstractGraphical abstract for this article
       
  • Efficient synthesis of the ketone body ester
           (R)-3-hydroxybutyryl-(R)-3-hydroxybutyrate and its (S,S) enantiomer
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Noah Budin, Erin Higgins, Anthony DiBernardo, Cassidy Raab, Chun Li, Scott UlrichThe ketone body ester (R)-3-hydroxybutyryl-(R)-3-hydroxybutyrate and its (S,S) enantiomer were prepared in a short, operationally simple synthetic sequence from racemic β-butyrolactone. Enantioselective hydrolysis of β-butyrolactone with immobilized Candida antarctica lipase-B (CAL-B) results in (R)-β-butyrolactone and (S)-β-hydroxybutyric acid, which are easily converted to (R) or (S)-ethyl-3-hydroxybutyrate and reduced to (R) or (S)-1,3 butanediol. Either enantiomer of ethyl-3-hydroxybutyrate and 1,3 butanediol are then coupled, again using CAL-B, to produce the ketone body ester product. This is an efficient, scalable, atom-economic, chromatography-free, and low cost synthetic method to produce the ketone body esters.Graphical abstractGraphical abstract for this article
       
  • Synthesis, characterization, monoamine oxidase inhibition, molecular
           docking and dynamic simulations of novel 2,1-benzothiazine-2,2-dioxide
           derivatives
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Shakeel Ahmad, Sumera Zaib, Saquib Jalil, Muhammad Shafiq, Matloob Ahmad, Sadia Sultan, Mazhar Iqbal, Sana Aslam, Jamshed IqbalIn this research work, we report the synthesis and biological evaluation of two new series of 1-benzyl-4-(benzylidenehydrazono)-3,4-dihydro-1H-benzo[c] [1,2]thiazine 2,2-dioxides and 1-benzyl-4-((1-phenylethylidene)hydrazono)-3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxides. The synthetic plan involves the mesylation of methyl anthranilate with subsequent N-benzylation of the product. The methyl 2-(N-benzylmethylsulfonamido)benzoate was subjected to cyclization reaction in the presence of sodium hydride to obtain 1-benzyl-1H-benzo[c][1,2]thiazin-4(3H)-one 2,2-dioxide which was treated with hydrazine hydrate to get corresponding hydrazone precursor. Finally, the titled compounds were obtained by reaction of hydrazone with various substituted aldehydes and ketones. The synthesized derivatives were subjected to carry out their inhibition activities against monoamine oxidases along with modelling investigations to evaluate their binding interactions and dynamic stability during the docking studies. The inhibition profile of potent compounds was found as competitive for both the isozymes. The compounds were more selective inhibitors of MAO-A as compared to MAO-B. Moreover, drug likeness profile of the derivatives was evaluated to have an additional insight into the physicochemical properties. The molecular dynamic simulations predicted the behaviour of amino acids with the active site residues.Graphical abstractMolecular docking and dynamic simulations of novel 2,1-benzothiazine-2,2-dioxide derivative as potent and selective monoamine oxidase A inhibitor.Graphical abstract for this article
       
  • QM/MM study of the reaction mechanism of Cl-cis,cis-muconate with muconate
           lactonizing enzyme
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Ledong Zhu, Xiaowen Tang, Yanwei Li, Ruiming Zhang, Junjie Wang, Qingzhu Zhang, Wenxing WangThe lactonization process of Cl-cis,cis-muconate catalyzed by anti-muconate lactonizing enzyme (anti-MLE) was studied theoretically with the aid of a combined quantum mechanics/molecular mechanics (QM/MM) approach. Two elementary processes steps involved in the lactanization process were investigated. The calculated energy barriers agree well with the experimental values. The present work provided the explicit structures of the enolate anion intermediates. The electrostatic influence analysis highlighted residues Arg51, Gln294 and TIP383 for the MLE-Cl-2 system and the residue Asn193 for the MLE-Cl-4 system as the possible mutation targets for rational design of anti-MLE in future enzyme modification.Graphical abstractGraphical abstract for this article
       
  • Structural comparison of Mtb-DHFR and h-DHFR for design, synthesis and
           evaluation of selective non-pteridine analogues as antitubercular agents
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Kalicharan Sharma, Omprakash Tanwar, Shweta Sharma, Shakir Ali, M.M. Alam, M.S. Zaman, Mymoona AkhterTuberculosis is an infectious disease that affects millions of population every year. Mtb-DHFR is a validated target that is vital for nucleic acids biosynthesis and therefore DNA formation and cell replication. This paper report identification and synthesis of novel compounds for selective inhibition of Mtb-DHFR and unleash the selective structural features necessary to inhibit the same. Virtual screening of databases was carried out to identify novel compounds on the basis of difference between the binding pockets of the two proteins. Consensus docking was performed to improve upon the results and best ten hits were selected. Hit 1 was subjected to analogues design and the analogues were docked against Mtb-DHFR. From the docking results 11 compounds were selected for synthesis and biological assay against H37Rv. Most potent compound (IND-07) was tested for selectivity using enzymatic assay against Mtb-DHFR and h-DHFR. The compounds were found to have good inhibitory activity (25–200 µM) against H37Rv and in enzyme assay against Mtb-DHFR and h-DHFR the compound was found selective towards Mtb-DHFR with selectivity index of 6.53. This work helped to identify indole moiety as novel scaffold for development of novel selective Mtb-DHFR inhibitors as antimycobacterial agents.Graphical abstractA series of indole based compounds showed excellent antitubercular activity against H37RV. The compounds were found to have good inhibitory activity (25–200) µM against H37Rv and in enzyme assay against Mtb-DHFR and h-DHFR the compound was found selective towards Mtb-DHFR with selectivity index of 6.53. The antitubercular potential of indole based compounds was validated by molecular modelling studies. The synthesised drug-like compounds were also found non-toxic and can be optimized to get more potent antitubercular agents for future use.Graphical abstract for this article
       
  • Synthesis of Bis-indolylmethane sulfonohydrazides derivatives as potent
           α-Glucosidase inhibitors
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Mohammed Gollapalli, Muhammad Taha, Hayat Ullah, Muhammad Nawaz, Laode Muhammad Ramadhan AlMuqarrabun, Fazal Rahim, Faiza Qureshi, Ashik Mosaddik, Norizan Ahmat, Khalid Mohammed KhanIn search of better α-glucosidase inhibitors, a series of bis-indolylmethane sulfonohydrazides derivatives (1-14) were synthesized and evaluated for their α-glucosidase inhibitory potential. All derivatives exhibited outstanding α-glucosidase inhibition with IC50 values ranging between 0.10 ± 0.05 to 5.1 ± 0.05 μM when compared with standard drug acarbose having IC50 value 856.28 ± 3.15 μM. Among the series, analog 7 (0.10 ± 0.05 μM) with tri-chloro substitution on phenyl ring was identified as the most potent inhibitor of α-glucosidase (∼ 8500 times). The structure activity relationship has been also established. Molecular docking studies were also performed to help understand the binding interaction of the most active analogs with receptors. From the docking studies, it was observed that all the active bis-indolylmethane sulfonohydrazides derivatives showed considerable binding interactions within the active site (acarbose inhibition site) of α-glucosidase. We also evaluated toxicity of all derivatives and found none of them are toxic.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of some N-(3-(1H-tetrazol-5-yl)
           phenyl)acetamide derivatives as novel non-carboxylic PTP1B inhibitors
           designed through bioisosteric modulation
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Neelesh Maheshwari, Chandrabose Karthikeyan, Shraddha V. Bhadada, Chandan Sahi, Amit K. Verma, N.S. Hari Narayana Moorthy, Piyush TrivediDescribed herein is the synthesis and biological evaluation of a series of non-carboxylic inhibitors of Protein Tyrosine Phosphatase 1B designed using bioisosteric replacement strategy. Six N-(3-(1H-tetrazol-5-yl)phenyl)acetamide derivatives designed employing the aforementioned strategy were synthesized and screened for PTP1B inhibitory activity. Among the synthesized compounds, compound NM-03 exhibited the most potent inhibitory activity with IC50 value of 4.48 µM. Docking studies with NM-03 revealed the key interactions with desired amino acids in the binding site of PTP1B. Furthermore, compound NM-03 also elicited good in vivo activity. Taken together, the results of this study establish N-(3-(1H-tetrazole-5-yl)phenyl)-2-(benzo[d]oxazol-2-ylthio)acetamide (NM-03) as a valuable lead molecule with great potential for PTP1B inhibitor development targeting diabetes.Graphical abstractSix N-(3-(1H-tetrazol-5-yl)phenyl)acetamide derivatives designed by using ‘bioisosteric replacement strategy’. Compound NM-03 exhibited the most potent inhibitory activity with IC50 value of 4.48 µM.Graphical abstract for this article
       
  • Discovery of dihydrobenzofuran neolignans from Rubus ideaus L. with
           enantioselective anti-Aβ 1–42 aggregation activity
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Le Zhou, Jie Wang, Rui Guo, Bin Lin, Xiao-Bo Wang, Xiao-Xiao Huang, Shao-Jiang SongFour new dihydrobenzofuran neolignans 1a/1b and 2a/2b were isolated from the fruit of Rubus ideaus. 1a/1b and 2a/2b as two pairs of enantiomers were separated on a chiral chromatographic column. Their structures were determined using a suite of techniques including 1D and 2D NMR, HRESIMS, together with theoretical electronic circular dichroism (ECD) calculation. All compounds were evaluated for their inhibition of self-induced Aβ1–42 aggregation. Compounds 1b and 2a exhibited optimal Aβ1–42 aggregation inhibition capability, with an inhibition potency of 81.6% and 83.4% at 20 μM, respectively. Additionally, molecular docking was performed to identify the possible factor responsible for the enantioselectivity in the anti-Aβ1–42 aggregation activity.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and antiplasmodial activity of novel imidazole
           derivatives based on 7-chloro-4-aminoquinoline
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Srinivasarao Kondaparla, Ashan Manhas, Vasantha Rao Dola, Kumkum Srivastava, Sunil K. Puri, S.B. KattiA series of short chain 4-aminoquinoline-imidazole derivatives have been synthesized in one pot two step multicomponent reaction using van leusen standard protocol. The diethylamine function of chloroquine is replaced by substituted imidazole derivatives containing tertiary terminal nitrogen. All the synthesized compounds were screened against the chloroquine sensitive (3D7) and chloroquine resistant (K1) strains of Plasmodium falciparum. Some of the compounds (6, 8, 9 and 17) in the series exhibited comparable activity to CQ against K1 strain of P. falciparum. All the compounds displayed resistance factor between 0.09 and 4.57 as against 51 for CQ. Further, these analogues were found to form a strong complex with hematin and inhibit the β-hematin formation, therefore these compounds act via heme polymerization target.Graphical abstractGraphical abstract for this article
       
  • Synthesis and cholinesterase inhibitory activity of new 2-benzofuran
           carboxamide-benzylpyridinum salts
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Fahimeh Abedinifar, S. Morteza F. Farnia, Mohammad Mahdavi, Hamid Nadri, Alireza Moradi, Jahan B. Ghasemi, Tuba Tüylü Küçükkılınç, Loghman Firoozpour, Alireza ForoumadiA series of benzofuran-2-carboxamide-N-benzyl pyridinium halide derivatives (6a-o) are synthesized as new cholinesterase inhibitors. The synthetic pathway involves the reaction of salicylaldehyde derivatives and ethyl bromoacetate, followed by hydrolysis and amidation with 3- and 4-picolyl amine. Subsequently, N-((pyridin-4-yl) methyl) benzofuran-2-carboxamide and substituted N-((pyridin-3-yl) methyl) benzofuran-2-carboxamides reacts with benzyl halides to afford target compounds (6a-o). The chemical structures of all derivatives were confirmed by spectroscopic methods. The studies reveal that some of the synthesized compounds are potent butyrylcholinesterase inhibitors with IC50 values in the range of 0.054–2.7 µM. In addition, good inhibitory effects on Aβ self-aggregation are observed for 6h and 6k (33.1 and 46.4% at 100 µM, respectively).Graphical abstractGraphical abstract for this article
       
  • Efficient chemoenzymatic synthesis of (S)-α-amino-4-fluorobenzeneacetic
           acid using immobilized penicillin amidase
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Chao-Ping Lin, Xiao-Ling Tang, Ren-Chao Zheng, Yu-Guo ZhengAn efficient chemoenzymatic route was developed for synthesis of (S)-α-amino-4-fluorobenzeneacetic acid, a valuable chiral intermediate of Aprepitant, using immobilized penicillin amidase catalyzed kinetic resolution of racemic N-phenylacetyl-4-fluorophenylglycine. The optimum temperature, pH and agitation rate of the reaction were determined to be 40 °C, 9.5 and 300 rpm, respectively. Kinetic resolution of 80 g L−1N-phenylacetyl-4-fluorophenylglycine by immobilized amidase 20 g L−1 resulted in 49.9% conversion and>99.9% e.e. within 3 h. The unreacted N-phenylacetyl-4-fluorophenylglycine can be easily racemized and then recycled as substrate. The production of (S)-α-amino-4-fluorobenzeneacetic acid was further amplified in 1 L reaction system, affording excellent conversion (49.9%) and enantioselectivity (99.9%). This chemoenzymatic approach was demonstrated to be promising for industrial production of (S)-α-amino-4-fluorobenzeneacetic acid.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and evaluation of some pyrazolo[3,4-d]pyrimidine
           derivatives bearing thiazolidinone moiety as anti-inflammatory agents
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Gina N. Tageldin, Salwa M. Fahmy, Hayam M. Ashour, Mounir A. Khalil, Rasha A. Nassra, Ibrahim M. LaboutaTwo new series of pyrazolo[3,4-d]pyrimidine bearing thiazolidinone moiety were designed and synthesized. The newly synthesized compounds were evaluated for their in vitro (COX-1 and COX-2) inhibitory assay. Compounds that showed promising COX-2 selectivity were further subjected to in vivo anti-inflammatory screening applying formalin induced paw edema (acute model) and cotton-pellet induced granuloma (chronic model) assays using celecoxib and diclofenac sodium as reference drugs. The histopathological and ulcerogenic potential were also determined. In vivo anti-inflammatory data showed that compounds 2, 6, 7d displayed anti-inflammatory activity higher than both references in the formalin induced paw edema model. On the other hand, compounds 2, 3d, 3e, 7b and 7d displayed anti-inflammatory activity greater than or nearly equivalent to diclofenac sodium in the cotton pellet-induced granuloma assay. Moreover, most of the tested compounds revealed good gastrointestinal safety profile. Collectively, compounds 2 and 7d were considered as promising candidates in managing both acute and chronic inflammation with safe gastrointestinal margin.Graphical abstractThese compounds showed promising anti-inflammatory activity with COX-2 selectivity comparable to celecoxib.Graphical abstract for this article
       
  • Novel pyrrol-2(3H)-ones and pyridazin-3(2H)-ones carrying quinoline
           scaffold as anti-proliferative tubulin polymerization inhibitors
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Mahmoud S. Abdelbaset, Gamal El-Din A. Abuo-Rahma, Mostafa H. Abdelrahman, Mohamed Ramadan, Bahaa G.M. Youssif, Syed Nasir Abbas Bukhari, Mamdouh F.A. Mohamed, Mohamed Abdel-AzizA novel quinolinyl pyrrolone and quinolinyl pyridazinone derivatives has been synthesized and characterized using different spectroscopic and elemental analysis techniques. Most of the target compounds displayed promising antiproliferative activity; In general, the pyrrolone derivatives 4a-f exhibited higher antiproliferative activity than their corresponding pyridazinone. The pyrrolone 4f showed outstanding antiproliferative activity with moderate selectivity against CNS and renal cancer with selectivity ratio of 3.49 and 3.56, respectively. Compound 4e and 5d experienced tubulin polymerization inhibitory activity comparable to that of vincristine while 4c, 4e and 4d showed good BRAF kinase inhibition compared to Erlotinib. Docking of compound 4e into colchicine binding site and biological assay results revealed that these compounds act mainly through tubulin polymerization inhibitory mechanism and can exhibit pre G1 apoptosis and cell cycle arrest at G2/M phase.Graphical abstractGraphical abstract for this article
       
  • Synthesis, in vitro urease inhibitory activity, and molecular docking
           studies of thiourea and urea derivatives
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Bilquees Bano, Kanwal, Khalid Mohammed Khan, Arif Lodhi, Uzma Salar, Farida Begum, Muhammad Ali, Muhammad Taha, Shahnaz PerveenThe current study deals with the synthesis of urea and thiourea derivatives 1–37 which were characterized by various spectroscopic techniques including FAB-MS, 1H-, and 13C NMR. The synthetic compounds were subjected to urease inhibitory activity and compounds exhibited good to moderate urease inhibitory activity having IC50 values in range of 10.11–69.80 µM. Compound 1 (IC50 = 10.11 ± 0.11 µM) was found to be most active and even better as compared to the standard acetohydroxamic acid (IC50 = 27.0 ± 0.5 µM). A limited structure–activity relationship (SAR) was established and the compounds were also subjected to docking studies to confirm the binding interactions of ligands (compounds) with the active site of enzyme.Graphical abstractGraphical abstract for this article
       
  • Synthesis and molecular docking study of some novel 2,3-disubstituted
           quinazolin-4(3H)-one derivatives as potent inhibitors of urease
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Gülay Akyüz, Emre Menteşe, Mustafa Emirik, Nimet BaltaşA new series of 2,3-disubstituted quinazolin-4(3H)-one compounds including oxadiazole and furan rings was synthesized. Their inhibitory activities on urease were assessed in vitro. All newly synthesized compounds exhibited potent urease inhibitory activity in the range of IC50 = 1.55 ± 0.07–2.65 ± 0.08 µg/mL, when compared with the standard urease inhibitors such as thiourea (IC50 = 15.08 ± 0.71 µg/mL) and acetohydroxamic acid (IC50 = 21.05 ± 0.96 µg/mL). 2,3-Disubstituted quinazolin-4(3H)-one derivatives containing furan ring (3a-e) were found to be the most active inhibitors when compared with the compounds 2a-e bearing oxadiazole ring. Compound 3a, bearing 4-chloro group on phenyl ring, was found as the most effective inhibitor of urease with the IC50 value of 1.55 ± 0.11 µg/mL. The molecular docking studies of the newly synthesized compounds were performed to identify the probable binding modes in the active site of the Jack bean urease (JBU) enzymes.Graphical abstractGraphical abstract for this article
       
  • Nitric oxide inhibitory constituents from Siegesbeckia pubescens
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Hari Jang, Jin Woo Lee, Jun Gu Kim, Hye Ryoung Hong, Thi Phoung Linh Le, Jin Tae Hong, Youngsoo Kim, Mi Kyeong Lee, Bang Yeon HwangTwo new sesquiterpenoids (1 and 2) and a new ent-pimarane type diterpenoid (3), together with eighteen known compounds (4–21), were isolated from the whole plants of Siegesbeckia pubescens. The structures of the new compounds were determined on the basis of 1D-, 2D NMR and HRESIMS data. All compounds were evaluated for their inhibitory effects on LPS-induced nitric oxide production in RAW 264.7 macrophages. Of these, highly oxygenated germacrane type sesquiterpenoids (1–2 and 13–14) showed significant inhibitory effects with IC50 values ranging from 3.9 to 16.8 μM.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, in-vitro thymidine phosphorylase inhibition, in-vivo
           antiangiogenic and in-silico studies of C-6 substituted dihydropyrimidines
           
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Fatima Iftikhar, Farhana Yaqoob, Nida Tabassum, Muhammad Saeed Jan, Abdul Sadiq, Saba Tahir, Tahira Batool, Basit Niaz, Farzana Latif Ansari, Muhammad Iqbal Choudhary, Umer RashidThymidine phosphorylase (TP) is an angiogenic enzyme. It plays an important role in angiogenesis, tumour growth, invasion and metastasis. In current research work, we study the effect of structural modification of dihydropyrimidine-2-ones (DHPM-2-ones) on TP inhibition. A series of eighteen new derivatives of 3,4-dihydropyrimidone-2-one were designed and synthesized through the structural modification at C-6 position. All these new derivatives were then assessed for in-vitro inhibition of thymidine phosphorylase (TP) from E. coli. Oxadiazole derivatives 4a-e exhibited excellent TP-inhibition at low micromolar concentration levels better than standard drug 7-deazaxanthine (7-DX). Among all these compounds, 4b was found to be the most potent with IC50 = 1.09 ± 0.004 μM. Anti-angiogenesis potential of representative compounds were also studied in a chorioallantoic membrane (CAM) assay. Here again, compound 4b was found to be the potent anti-angiogenesis compound in a CAM assay. Docking studies were also performed with Molecular Operating Environment (MOE) to further analyse the mode of inhibition of these compounds. Binding mode analysis of the most active inhibitors showed that these are well accommodated into the binding site of enzyme though stable hydrogen bonding and hydrophobic interactions.Graphical abstractGraphical abstract for this article
       
  • The first activation studies of the η-carbonic anhydrase from the malaria
           parasite Plasmodium falciparum with amines and amino acids
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Andrea Angeli, Sonia Del Prete, Fatmah A.S. Alasmary, Linah S. Alqahtani, Zeid AlOthman, William A. Donald, Clemente Capasso, Claudiu T. SupuranThe first activation study of a η-class carbonic anhydrase (CAs, EC 4.2.1.1) is reported. A panel of 24 natural and non-natural amino acids and amines was used to explore the activation profile of Plasmodium falciparum CA (PfACA). The most effective activators belonged to the amino acid chemotype, with d-Glu, l-Asp, l-/d-Phe and l-/d-DOPA possessing activation constant in the range of 82 nM–0.75 µM, whereas l-/d-His, l-Tyr, 4-amino-l-Phe and l-Gln were slightly less effective (KA in the range of 1.00–2.51 µM. The only amine with submicromolar activating properties was 1-(2-aminoethyl-piperazine) with a KA of 0.71 µM, whereas histamine, dopamine and serotonin showed KA ranging between 7.18 and 9.97 µM. As CA activators have scarcely been investigated for their interaction with protozoan CAs, this study may be relevant for an improved understanding of the role of this enzyme in the life cycle of the malaria producing organisms belonging to the genus Plasmodium.Graphical abstractGraphical abstract for this article
       
  • Characterization of inhibitory constituents of NO production from Catalpa
           ovata using LC-MS coupled with a cell-based assay
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Sangmin Park, Hyeji Shin, Yeeun Park, Ilgyu Choi, Byoungduck Park, Ki Yong LeeAn effective screening method for inhibitors of NO production in natural products using LC-QTOF MS/MS coupled with a cell-based assay was proposed. The ethyl acetate fraction of Catalpa ovata exhibited a strong inhibitory effect on NO production in lipopolysaccharide-induced BV2 microglia cells. We attempted to identify the active constituents of C. ovata by using LC-QTOF MS/MS coupled with a cell-based assay. Peaks at approximately 14–15 min on the MS chromatogram were estimated to be the bioactive constituents. A new iridoid compound, 6-O-trans-feruloyl-3β-hydroxy-7-deoxyrehamaglutin A (4), and nine known compounds (1–3, 5–10) were isolated from the ethyl acetate fraction of C. ovata by repeated column chromatography. Compounds 3, 4, 5, 7, and 8 significantly attenuated lipopolysaccharide-stimulated NO production in BV2 cells. Our results indicate that LC-QTOF MS/MS coupled with a cell-based NO production inhibitory assay successfully predicted active compounds without a time-consuming isolation process.Graphical abstractGraphical abstract for this article
       
  • Cytoprotective and antioxidant properties of organic selenides for the
           myelin-forming cells, oligodendrocytes
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Saad Shaaban, Dominique Vervandier-Fasseur, Pierre Andreoletti, Amira Zarrouk, Philippe Richard, Amr Negm, Georg Manolikakes, Claus Jacob, Mustapha Cherkaoui-MalkiHere a new series of twenty-one organoselenides, of potential protective activity, were synthesized and tested for their intrinsic cytotoxicity, anti-apoptotic and antioxidant capacities in oligodendrocytes. Most of the organoselenides were able to decrease the ROS levels, revealing antioxidant properties. Compounds 5b and 7b showed a high glutathione peroxidase (GPx)-like activities, which were 1.5 folds more active than ebselen. Remarkably, compound 5a diminished the formation of the oligodendrocytes SubG1 peak in a concentration-dependent manner, indicating its anti-apoptotic properties. Furthermore, based on the SwissADME web interface, we performed an in-silico structure-activity relationship to explore the drug-likeness of these organoselenides, predicting the pharmacokinetic parameters for compounds of interest that could cross the blood-brain barrier. Collectively, we present new organoselenide compounds with cytoprotective and antioxidant properties that can be considered as promising drug candidates for myelin diseases.Graphical abstractTwenty-one organoselenides were synthesized and tested for their intrinsic cytotoxicity, anti-apoptotic and antioxidant capacities in oligodendrocytes. In-silico structure-activity relationship were performed to explore the drug-likeness of these organoselenides, predicting the pharmacokinetic parameters for compounds of interest that could cross the blood-brain barrier.Graphical abstract for this article
       
  • Synthesis, α-amylase inhibitory potential and molecular docking study of
           indole derivatives
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Muhammad Taha, Mohd Syukri Baharudin, Nor Hadiani Ismail, Syahrul Imran, Muhammad Naseem Khan, Fazal Rahim, Manikandan Selvaraj, Sridevi Chigurupati, Muhammad Nawaz, Faiza Qureshi, Shantini VijayabalanIn search of potent α-amylase inhibitor we have synthesized eighteen indole analogs (1–18), characterized by NMR and HR-EIMS and screened for α-amylase inhibitory activity. All analogs exhibited a variable degree of α-amylase inhibition with IC50 values ranging between 2.031 ± 0.11 and 2.633 ± 0.05 μM when compared with standard acarbose having IC50 values 1.927 ± 0.17 μM. All compounds showed good α-amylase inhibition. Compound 14 was found to be the most potent analog among the series. Structure-activity relationship has been established for all compounds mainly based on bringing about the difference of substituents on phenyl ring. To understand the binding interaction of the most active analogs molecular docking study was performed.Graphical abstractGraphical abstract for this article
       
  • Benzimidazole scaffold based hybrid molecules for various inflammatory
           targets: Synthesis and evaluation
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Gaganpreet Kaur, Om SilakariDesigning of hybrid drugs with specific multitarget profile is a promising line of attack against inflammation. In light of this, a series of benzimidazole scaffold based hybrid molecules were designed by integrating benzimidazoles (containing pharmacophoric elements for COXs and LOXs inhibitors) with phthalimide subunit of thalidomide (pharmacophore element for TNF-α inhibitor) under one construct via molecular hybridization strategy. The designed molecules were synthesized and evaluated for their inhibitory activity against COXs (COX-1, COX-2), LOXs (5-LOX, 15-LOX) enzymes as well as TNF-α inhibitory effect. The results revealed that, compounds (3a–l) obtained showed inhibition in submicromolar range against COXs and LOXs targets whereas milder inhibitory activity was obtained against lipopolysaccharides (LPS)-induced TNF-α secretion by murine macrophage-like cells (RAW264.7). Within this class of compounds, 3j emerged as having alluring multiple inhibitory effects on set of COX-1/2 and 5-/15-LOX enzymes (COX-1 IC50 = 9.85 µM; COX-2 IC50 = 1.00 µM; SI = 9.85; 5-LOX IC50 = 0.32 µM; 15-LOX IC50 = 1.02 µM) in conjunction with a good anti-inflammatory and analgesic activities. Additionally, compound 3j showed gastrointestinal safety with reduced lipid peroxidation. Docking results of compound 3j with COX-2 and 5-LOX were also consistent with the in vivo anti-inflammatory results.Graphical abstractGraphical abstract for this article
       
  • Imidazo[2′,1′:2,3]thiazolo[4,5-d]pyridazinone as a new scaffold of
           DHFR inhibitors: Synthesis, biological evaluation and molecular modeling
           study
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Menna A. Ewida, Dalal A. Abou El Ella, Deena S. Lasheen, Heba A. Ewida, Yomna I. El-Gazzar, Hussein I. El-SubbaghNew series of thiazolo[4,5-d]pyridazin and imidazo[2′,1′:2,3]thiazolo[4,5-d]pyridazin analogues were designed, synthesized and evaluated for their in vitro DHFR inhibition and antitumor activity. Compounds 13 and 43 proved to be DHFR inhibitors with IC50 0.05 and 0.06 μM, respectively. 43 proved lethal to OVCAR-3 Ovarian cancer and MDA-MB-435 Melanoma at IC50 0.32 and 0.46 μM, respectively. The active compounds formed hydrogen bond at DHFR binding site between N1-nitrogen of the pyridazine ring with Glu30; the carbonyl group with Trp24, Arg70 or Lys64; π-cation interaction with Arg22 and π-π interaction with Phe31 residues. Ring annexation of the active 1,3-thiazole ring analogue 13 into the bicyclic thiazolo[4,5-d]pyridazine (18,19) or imidazo[2,1-b]thiazoles (23–25) decreased the DHFR inhibition activity; while the formation of the tricyclic imidazo[2′,1′:2,3]-thiazolo[4,5-d]pyridazine (43–54) increased potency. The obtained model could be useful for the development of new class of DHFR inhibitors.Graphical abstractGraphical abstract for this article
       
  • Targeting oncogenic transcriptional corepressor Nac1 POZ domain with
           conformationally constrained peptides by cyclization and stapling
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Tao Wu, Ping He, Wei Wu, Yingli Chen, Fenglin LvThe oncogenic transcriptional corepressor Nac1 contains a conserved POZ protein–protein interaction module that mediates homodimerization or heterodimerization with itself or other POZ proteins. The dimerization has been recognized as an attractive target for cancer therapy. Here, we attempted to (i) discover those potential binding partners of Nac1 in the human genome, (ii) derive key peptide segments from the complex interface of Nac1 with its putative partners, and (iii) improve the peptide binding affinity to Nac1 POZ domain. In the procedure, Nac1 POZ dimerization with 136 human POZ domains was modeled, simulated and analyzed at atomic level to elucidate structural basis, energetic property and dynamics behavior. Two hotspot regions, namely α1-helix and α2/α3-hairpin, at the dimerization interface were identified that are responsible for stabilizing the formed POZ–POZ dimer complexes. The α1-helix and α2/α3-hairpin were stripped from the interface to derive their respective isolated SIP peptides, which, however, exhibited a large flexibility and intrinsic disorder in free state, and thus would incur a considerable penalty upon rebinding to Nac1 POZ domain. By carefully examining the natively folded structures of α1-helix and α2/α3-hairpin in protein context and their interaction modes with the domain, we rationally designed a hydrocarbon bridge and a disulfide bond separately for the two peptides in order to constrain their conformational flexibility in free state, thus largely minimizing the flexibility penalty. Consequently, three α1-helix peptides derived from Nac1, Miz1 and Slx4 were stapled by all-hydrocarbon bridge, while four α2/α3-hairpin peptides derived from Nac1, Bacd1, Klh28 and Mynn were cyclized by disulfide bond. Binding affinity analysis revealed that, as designed, these peptides were converted from non- or weak binders to moderate or good binders of Nac1 POZ domain upon the stapling and cyclization.Graphical abstractGraphical abstract for this article
       
  • Multi-targetable chalcone analogs to treat deadly Alzheimer’s disease:
           Current view and upcoming advice
    • Abstract: Publication date: October 2018Source: Bioorganic Chemistry, Volume 80Author(s): Xu Zhang, K.P. Rakesh, S.N.A. Bukhari, Moku Balakrishna, H.M. Manukumar, Hua-Li QinThe complications of Alzheimer’s disease AD were deadly dangerous cause of neurodegenerative disorders connected with the decline of the cognitive functions and loss of memory. The common form of dementia is accounted as the sixth leading cause of the death affecting any stage of people in a lifetime. Synthetic natural chalcone analogs were currently a hot research topic for the treatment of (AD) which has affected millions of peoples throughout the world. The present aim was set to understand the important problems of the AD and its treatment based on natural derivatives of novel chalcones. One interesting strategy currently of searching for the treatment of AD is to find inhibitors for acetylcholinesterase (AChE) and using metal chelators to target amyloid-β (Aβ) peptides, and then metal-Aβ complexes for the AD pathogenesis. The present compressed review focuses and highlights the design and synthesis of new approaches for the construction of important chalcones playing multiple beneficiary roles in the AD treatments. These hallmarks of concurred research represent the immediate needs of development of novel therapeutic drugs for effective treatment of ADs by understanding the specific pharmacology targets.Graphical abstractGraphical abstract for this article
       
  • Promiscuous Enzyme-catalyzed Cascade Reaction: Synthesis of Xanthone
           Derivatives
    • Abstract: Publication date: Available online 11 July 2018Source: Bioorganic ChemistryAuthor(s): Yajie Fu, Bingbing Fan, Hongyue Chen, He Huang, Yi HuBased on the screening of biocatalysts and reaction conditions including organic solvent, water content, lipase loading, reaction temperature and time, lipase TLIM exhibited the prominent promiscuity for the Knoevenagel-Michael cascade reactions of 1, 3-diketones with aromatic aldehydes to synthesize xanthone derivatives. This procedure provides satisfactory advantages such as environmental begin, simple work-up, generality, obtaining in excellent yields (80-97%), and potential for recycling of biocatalyst.Graphical abstractGraphical abstract for this article
       
  • Novel benzotriazole N-acylarylhydrazone hybrids: Design, synthesis,
           anticancer activity, effects on cell cycle profile, caspase-3 mediated
           apoptosis and FAK inhibition
    • Abstract: Publication date: Available online 10 July 2018Source: Bioorganic ChemistryAuthor(s): Asmaa E. Kassab, Rasha A. HassanA series of novel benzotriazole N-acylarylhydrazone hybrids was synthesized according fragment-based design strategy. All the synthesized compounds were evaluated for their anticancer activity against 60 human tumor cell lines by NCI (USA). Five compounds: 3d, 3e, 3f, 3o and 3q exhibited significant to potent anticancer activity at low concentrations. Compound 3q showed the most prominent broad-spectrum anticancer activity against 34 tumor cell lines, with mean growth inhibition percent of 45.80%. It exerted the highest potency against colon HT-29 cell line, with cell growth inhibition 86.86%. All leukemia cell lines were highly sensitive to compound 3q. Additionally, compound 3q demonstrated lethal activity to MDA-MB-435 belonging melanoma. Compound 3e exhibited the highest anticancer activity against leukemic CCRF-CEM and HL-60(TB) cell lines, with cell growth inhibition 86.69% and 86.42%, respectively. Moreover, it exerted marked potency against ovarian OVCAR-3 cancer cell line, with cell growth inhibition 78.24%. Four compounds: 3d, 3e, 3f and 3q were further studied through determination of IC50 values against the most sensitive cancer cell lines. The four compounds exhibited highly potent anticancer activity against ovarian cancer OVCAR-3 and leukemia HL-60 (TB) cell lines, with IC50 values in nano-molar range between 25 and 130 nM. They showed 18 to 2.3 folds more potent anticancer activity than doxorubicin. The most prominent compound was 3e, (IC50 values 29 and 25 nM against OVCAR-3 and HL-60 (TB) cell lines, respectively), representing 10 and 18 folds more potency than doxorubicin. The anti-proliferative activity of these four compounds appeared to correlate well with their ability to inhibit FAK at nano-molar range between 44.6 and 80.75 nM. Compound 3e was a potent, inhibitor of FAK and Pyk2 activity with IC50 values of 44.6 and 70.19 nM, respectively. It was 1.6 fold less potent for Pyk2 than FAK. Additionally, it displayed inhibition in cell based assay measuring phosphorylated-FAK (IC50 =32.72 nM). Inhibition of FAK enzyme led to a significant increase in the level of active caspase-3, compared to control (11.35 folds), accumulation of cells in pre-G1 phase and annexin-V and propidium iodide staining in addition to cell cycle arrest at G2/M phase indicating that cell death proceeded through an apoptotic mechanism.Graphical abstractGraphical abstract for this article
       
  • Design and synthesis of novel imidazo[4,5-b]pyridine based compounds as
           potent anticancer agents with CDK9 inhibitory activity
    • Abstract: Publication date: Available online 6 July 2018Source: Bioorganic ChemistryAuthor(s): Nada M. Ghanem, Faten Farouk, Riham F. George, Safinaz E.S. Abbas, Ossama M. El-BadryNew imidazo[4,5-b]pyridine derivatives were designed, synthesized and screened for their anticancer activity against breast (MCF-7) and colon (HCT116) cancer cell lines. Nine compounds (I, II, IIIa, IIIb, IV, VI, VIIa, VIII, IX) showed significant activity against MCF-7, while six compounds (I, VIIc, VIIe, VIIf, VIII, IX) elicited a remarkable activity against HCT116. Compounds showing significant anticancer activity revealed remarkable CDK9 inhibitory potential (IC50= 0.63-1.32 μM) relative to sorafenib (IC50= 0.76μM). Moreover, a molecular docking study was performed to illustrate the binding mode of the most active compounds in the active site of CDK9 and revealed superior binding affinity relative to the natural ligand (T3C).Graphical abstractGraphical abstract for this article
       
  • Lipid reducing activity of novel cholic acid (CA) analogs: Design,
           Synthesis and Preliminary mechanism study
    • Abstract: Publication date: Available online 5 July 2018Source: Bioorganic ChemistryAuthor(s): Guoshun Luo, Zhouyang Qian, Rongmao Qiu, Qidong You, Hua XiangBile acids, initially discovered as endogenous ligands of farnesoid X receptor (FXR), play a central role in the regulation of triglyceride and cholesterol metabolism and have recently emerged as a privileged structure for interacting with nuclear receptors relevant to a large array of metabolic processes. In this paper, phenoxy containing cholic acid derivatives with excellent drug-likeness have been designed, synthesized, and assayed as agents against cholesterol accumulation in Raw264.7 macrophages. The most active compound 14b reduced total cholesterol accumulation in Raw264.7 cells up to 30.5% at non-toxic 10 μM and dosage-dependently attenuated oxLDL-induced foam cell formation. Western blotting and qPCR results demonstrate that 14b reduced both cholesterol and lipid in Raw264.7 cells through (1) increasing the expression of cholesterol transporters ABCA1 and ABCG1, (2) accelerating ApoA1-mediated cholesterol efflux. Through a cell-based luciferase reporter assay and molecular docking analysis, LXR was identified as the potential target for 14b. Interestingly, unlike conventional LXR agonist, 14b did not increase lipogenesis gene SREBP-1c expression. Overall, these diverse properties disclosed herein highlight the potential of 14b as a promising lead for further development of multifunctional agents in the therapy of cardiovascular disease.Graphical abstractGraphical abstract for this article
       
  • Synthesis and dopaminergic activity of a series of new 1-aryl
           
    • Abstract: Publication date: Available online 5 July 2018Source: Bioorganic ChemistryAuthor(s): Cristina Lucena-Serrano, Ana Lucena-Serrano, Alicia Rivera, Juan Manuel López-Romero, María Valpuesta, Amelia DíazA series of new 1-aryl-6,7-dihydroxy tetrahydroisoquinolines with several substitution patterns in the 1-aryl group at C-1 were prepared in good yields. The influence of each substituent on the affinity and selectivity for D1 and D2 dopaminergic receptors was studied. Moreover, N-alkyl salts of these tetrahydroisoquinolines were used as starting material to synthesize a series of new 1-aryl-7,8-dihydroxy 3-tetrahydrobenzazepines derivatives with electron-withdrawing substituents at C-2 position by the diastereoselective Stevens rearrangement. The structure-activity relationship of these compounds was explored to evaluate the effect of the functional group at C-2 in benzazepines and the modification in the aryl group at the isoquinoline C-1 position towards the affinity and selectivity for the mentioned receptors. The 1-aryl-6,7-dihydroxy tetrahydroisoquinoline 4c shows significant affinity towards D2 receptor, with Ki value of 31 nM. This significant affinity can be attributed to the presence of a thiomethyl group, and it is the most active 1-aryl-6,7-dihydroxy tetrahydroisoquinoline derivative reported to date.Graphical abstractGraphical abstract for this article
       
  • Synthesis of spherical Fe3O4 nanoparticles from the thermal decomposition
           of iron (III) nano-structure complex: DFT studies and evaluation of the
           biological activity
    • Abstract: Publication date: Available online 3 July 2018Source: Bioorganic ChemistryAuthor(s): Nahid Zare, Abedien Zabardasti, Abdelnasser Mohammadi, Farideh AzarbaniA novel Fe(III) Schiff base complex of the [FeL2(NO3)2]NO3 type where L= 2-((pyridin-4-yl)methyleneamino)-3-aminomaleonitrile was synthesized using the reflux and sonochemical methods and their antibacterial and antifungal activity were evaluated. The nanoparticles of iron oxide (Fe2O3) were obtained from the iron nano-structure complex as a precursor after calcination at 600 ˚C for 3 h. All the synthesized compounds were characterized by various spectroscopic techniques. The results of SEM showed that the morphology of iron nano-structure complex was rod-like while the morphology of the Fe2O3 nano powder was spherical. The results of the biological studies indicated that the iron nano-structure complex showed a stronger antibacterial and antifungal efficiency than its bulk complex. Finally, the empirical geometrical parameters of complexes revealed a good agreement with calculated ones at DFT-B3LYP level.Graphical abstractGraphical abstract for this article
       
  • Synthesis, biological evaluation and docking study of
           1,3,4-thiadiazole-thiazolidinone hybrids as anti-inflammatory agents with
           dual inhibition of COX-2 and 15-LOX
    • Abstract: Publication date: Available online 3 July 2018Source: Bioorganic ChemistryAuthor(s): Yasser M. Omar, Hajjaj H.M. Abdu-Allah, Samia G. Abdel-MotySelective inhibition of both cyclooxygenase-2 (COX-2) and 15-lipooxygenase (15-LOX) may provide good strategy for alleviation of inflammatory disorders while minimizing side effects associated with current anti-inflammatory drugs. The present study describes the synthesis, full characterization and biological evaluation of a series of thiadiazole-thiazolidinone hybrids bearing 5-alk/arylidene as dual inhibitors of these enzymes. Our design was based on merging pharmacophores that exhibit portent anti-inflammatory activities in one molecular frame. 5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-amine (3) was efficiently synthesized, chloroacetylated and cyclized to give the key 4-thiazolidinone (5). Knovenagel condensation of 5 with different aldehydes afforded the final compounds 6a-m, 7, 8 and 9. These compounds were subjected to in vitro COX-1/COX-2, 15-LOX inhibition assays. Compounds (6a, 6f, 6i, 6l, 6m and 9) with promising potency (IC50 = 70-100 nM) and selectivity index (SI = 220-55) were further tested for in vivo anti-inflammatory activity and effect on gastric mucosa. The most promising compound (6l) inhibits COX-2 enzyme at a nanomolar concentration (IC50 = 70 nM, SI = 220) with simultaneous inhibition of 15-LOX (IC50 = 11 µM). These results are comparable to the potency and selectivity of the standard drugs of both enzymes; celecoxib (COX-2 IC50 = 49 nM, SI = 308) and zileuton (15-LOX IC50 = 15 µM) in one construct. Interestingly three compounds (6a, 6l and 9) exhibited equivalent to or even higher than that of celecoxib in vivo anti-inflammatory activity at 3 h interval with good GIT safety profile. Molecular docking study conferred binding sites of these compounds on COX-2 and 15-LOX. Such type of compounds would represent valuable leads for further investigation and derivatization.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and activity of light deactivatable microRNA inhibitor
    • Abstract: Publication date: Available online 2 July 2018Source: Bioorganic ChemistryAuthor(s): Hao Yan, Umesh Bhattarai, Yabin Song, Fu-Sen LiangmiRNAs are key cellular regulators and their dysregulation is associated with many human diseases. They are usually produced locally in a spatiotemporally controlled manner to target mRNAs and regulate gene expression. Thus, developing chemical tools for manipulating miRNA with spatiotemporal precise is critical for studying miRNA. Herein, we designed a strategy to control miRNA biogenesis with light controllable inhibitor targeting the pre-miRNA processing by Dicer. By conjugating two non-inhibiting units, a low affinity Dicer inhibitor and a pre-miRNA binder, through a photocleavable linker, the bifunctional molecule obtained could inhibit miRNA production. Taking advantage of the photocleavable property of the linker, the bifunctional inhibitor can be fragmented into separate non-inhibiting units and therefore be deactivated by light. We expect that this strategy could be applied to generate chemical biological tools that allow light-mediated spatiotemporal control of miRNA maturation and contribute to the study of miRNA function.Graphical abstractGraphical abstract for this article
       
  • Studies on the Lipid-regulating Mechanism of Alisol-Based Compounds on
           Lipoprotein Lipase
    • Abstract: Publication date: Available online 2 July 2018Source: Bioorganic ChemistryAuthor(s): Fei Xu, Cai Lu, Qinan Wu, Wei Gu, Jun Chen, Fang Fang, Bo Zhao, Wenjia Du, Min YouStudies on the lipid-regulating effects of alisol compounds are reported that include alisol B, alisol A 24-acetate (24A), alisol A and an alisol B - 24A - alisol A mixture (content ratio = 1:1:1). The effects on the activity of lipoprotein lipase (LPL), a key lipid-modulating enzyme, were studied to investigate the molecular mechanism of lipid-regulating activity of alisols. The effects of alisols on regulating blood lipids and the activities of LPL were determined using a reagent kit method. The structure of LPL was obtained by homology modeling and the interactive mechanism of alisol monomers and the mixture with LPL was investigated by molecular simulation. The alisol monomer and mixture were shown to regulate blood lipids, suggesting that alisols may decrease the level of triglyceride (TG) by improving the activity of LPL. The order of intensity was: mixture> alisol A> alisol B> 24A, indicating that alisols of alismatis rhizoma feature a synergistic effect on LPL. The N- and C-terminus of LPL both represented the catalytic active domains of this lipid-regulating effect. Cys306, Gln129 and Ser166 were the key amino acid residues resulting in the lipid-regulating effect of the alisol monomer while Ser166 and Arg18 were found to be responsible for the lipid-regulating effect of the mixture. The C-terminus of LPL was indirectly involved in the enzymatic process. A folded side chain of alisols or the parent ring was found to bind somewhat weaker to LPL than an open side chain or parent ring. The hydroxyl groups on the C14-, C22-, C28-, C30- and C31-terminus in the side chain, the ring ether structure in C23-position, and the acetyl group in C29-position represented the key sites for the lipid-regulating action of alisols. Meanwhile, the C30-site hydroxyl group played an important role in the synergistic effect of the alisol mixture.Graphical abstractThe Alisol monomer and mixture decreased the TG content by enhancing LPL activity. The mixture exhibited the strongest effect on the activity of LPL, indicating that there was a synergistic effect on LPL. The N- and C-terminus of LPL represented lipid catalytic active regions in which Cys306, Gln129 and Ser166 were the key amino acid residues of the Alisol monomer and Ser166 as well as Arg18 represented important amino acid residues of Alisol during this synergistic lipid-regulation. The C-terminus of LPL was indirectly involved in the enzymatic hydrolysis. The hydroxyl groups on C14-, C22-, C28-, C30- and C31-groups in the side chain, the ring ether structure in C23-position, and the acetyl group in C29-position represent the key sites for the lipid-regulating action of Alisols. Meanwhile, the C30-site hydroxyl group played an important role in the synergistic effect of the Alisol mixture.Graphical abstract for this article
       

  •        3-Aryl/Heteroaryl-5-Amino-1-(3’,4’,5’-Trimethoxybenzoyl)-1,2,4-Triazoles
           as Antimicrotubule Agents. Design, Synthesis, Antiproliferative Activity
           and Inhibition of Tubulin Polymerization
    • Abstract: Publication date: Available online 30 June 2018Source: Bioorganic ChemistryAuthor(s): Romeo Romagnoli, Filippo Prencipe, Paola Oliva, Stefania Baraldi, Pier Giovanni Baraldi, Andrea Brancale, Salvatore Ferla, Ernest Hamel, Roberta Bortolozzi, Giampietro ViolaMany natural and synthetic substances are known to interfere with the dynamic assembly of tubulin, preventing the formation of microtubules. In our search for potent and selective antitumor agents, a novel series of 1-(3’,4’,5’-trimethoxybenzoyl)-5-amino-1,2,4-triazoles were synthesized. The compounds had different heterocycles, including thiophene, furan or the three isomeric pyridines, and they possessed a phenyl ring bearing electron-releasing or electron-withdrawing substituents at the 3-position of the 5-amino-1,2,4-triazole system. Most of the twenty-two tested compounds showed moderate to potent antiproliferative activities against a panel of solid tumor and leukemic cell lines, with four (5j, 5k, 5o and 5p) showing strong antiproliferative activity (IC50
       
  • Tetrahydroindolocarbazoles (THICZs) as New Class of Urokinase (uPA)
           Inhibitors: Synthesis, Anticancer Evaluation, DNA-Damage Determination,
           and Molecular Modelling Study
    • Abstract: Publication date: Available online 30 June 2018Source: Bioorganic ChemistryAuthor(s): Marwa A.M.Sh. El-Sharief, Mohamed H. El-Naggar, Entesar M. Ahmed, Shahenda M. El-Messery, Abeer E. Mahmoud, Mamdouh M. Ali, Lamiaa M. Salem, Karima F. Mahrous, Mardia T. El SayedTetrahydroindolocarbazoles (THICZs) with versatile substituents, have been designed, synthesized, structure characterized, then investigated for their in-vitro anticancer screening, urokinase inhibition (uPA) evaluated, DNA-damage determination was further explored. Compounds 5, 8, 10 and 17 displayed the most promising antitumor activities against the breast cancer cell line as compared to the standard drug, doxorubicin with IC50 = 5.24±0.37, 4.00±0.52, 7.20±0.90 and 9.60±1.10 µg/ml (versus 3.30±0.48 µg/ml for doxorubicin). Compounds 5, 8, 10 and 17 represents the most significant uPA inhibitors of our study with IC50 of 3.80, 2.70. 4.75, 10.80 (ng/ml) respectively. The expression levels of CDKN2A gene were decreased in 8, 10 and 17 cell lines as compared to those in positive control samples. Cell lines treated with 5, 8, 10 and 17 clearly observed a high score of damaged DNA cells. A deeper examination revealed that our hetroaromatics showed an extensive hydrogen bonding interactions that is required in the S pocket which is important for activity Arg 217, Gly 219, Gly 216 , Lys 143 and Ser 190. So we present THICZs as promising uPA inhibitors expected as significant promise for further development as anti-invasiveness drugs.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, docking study, α-glucosidase inhibition, and cytotoxic
           activities of acridine linked to thioacetamides as novel agents in
           treatment of type 2 diabetes
    • Abstract: Publication date: Available online 30 June 2018Source: Bioorganic ChemistryAuthor(s): Maryam Mohammadi-Khanaposhtani, Sepideh Rezaei, Reza Khalifeh, Somaye Imanparast, Mohammad Ali Faramarzi, Saeed Bahadorikhalili, Malihe Safavi, Fatemeh Bandarian, Ensieh Nasli Esfahani, Mohammad Mahdavi, Bagher LarijaniA novel series of acridine linked to thioacetamides 9a–o were synthesized and evaluated for their α-glucosidase inhibitory and cytotoxic activities. All the synthesized compounds exhibited excellent α-glucosidase inhibitory activity in the range of IC50 = 80.0 ± 2.0–383.1 ± 2.0 µM against yeast α-glucosidase, when compared to the standard drug acarbose (IC50 = 750.0 ± 1.5 µM). Among the synthesized compounds, 2-((6-chloro-2-methoxyacridin-9-yl)thio)-N-(p-tolyl) acetamide 9b displayed the highest α-glucosidase inhibitory activity (IC50 = 80.0 ± 2.0 μM). The in vitro cytotoxic assay of compounds 9a–o against MCF-7 cell line revealed that only the compounds 9d, 9c, and 9n exhibited cytotoxic activity. Cytotoxic compounds 9d, 9c, and 9n did not show cytotoxic activity against the normal human cell lines HDF. Kinetic study revealed that the most potent compound 9b is a competitive inhibitor with a Ki of 85 μM. Furthermore, the interaction modes of the most potent compounds 9b and 9f with α-glucosidase were evaluated through the molecular docking studies.Graphical abstractA new series of acridine linked to thioacetamides 9a-o were synthesized and evaluated as novel inhibitors for α-glucosidase. All the compounds showed more inhibitory activity of than standard drug acarbose, and also with exception the compounds 9d, 9c, and 9n found to be non-cytotoxic. The compound 9b showed the most potent anti-α-glucosidase activity (IC50 value = 80.0 ± 2.0 μM). Furthermore, the interaction modes of the most potent compounds 9b and 9f with α-glucosidase was evaluated through molecular docking studies.Graphical abstract for this article
       
  • Structure-Based Design of Free Fatty Acid Receptor 1 Agonists Bearing
           Non-biphenyl Scaffold
    • Abstract: Publication date: Available online 30 June 2018Source: Bioorganic ChemistryAuthor(s): Zheng Li, Yueming Chen, Yuhan Zhang, Hongwei Jiang, Yanzhi Liu, Yufang Chen, Luyong Zhang, Hai QianThe free fatty acid receptor 1 (FFA1) enhances the glucose-stimulated insulin secretion without the risk of hypoglycemia. However, most of FFA1 agonists have a common biphenyl moiety, leading to a relative deprivation in structure types. Herein, we describe the exploration of non-biphenyl scaffold based on the co-crystal structure of FFA1 to increase additional interactions with the lateral residues, which led to the identification of lead compounds 3 and 9. In induced-fit docking study, compound 3 forms an edge-on interaction with Trp150 by slightly rotating the indole ring of Trp150, and compound 9 has additional hydrogen bond and δ-π interactions with Leu135, which demonstrated the feasibility of our design strategy. Moreover, lead compounds 3 and 9 revealed improved polar surface area compared to GW9508, and have considerable hypoglycemic effects in mice. This structure-based study might inspire us to design more promising FFA1 agonists by increasing additional interactions with the residues outside of binding pocket.Graphical abstractAiming to further increasing the interactions with the lateral residues at the outside of binding pocket, the design strategy of incorporating series non-biphenyl scaffolds was developed, exemplified by the potent and orally bioavailable FFA1 agonists 3 and 9.Graphical abstract for this article
       
  • New C-2 diastereomers of flavanone glycosides conjugated with
           3-hydroxy-3-methylglutaric acid from the pericarp of Citrus grandis (L.)
           Osbeck
    • Abstract: Publication date: Available online 27 June 2018Source: Bioorganic ChemistryAuthor(s): Shuang-Gang Ma, Ru-Bing Wang, Wen-Rui Li, Yun-Bao Liu, Jing Qu, Yong Li, Xiao-Jing Wang, Song Xu, Shi-Shan YuTwo new 3-​hydroxy-​3-​methylglutaryl (HMG) flavanone 7-​O-diglycosides, cigranosides A and B (1 and 2), the known naringenin 7-(2′′-α-rhamnosyl-6′′-(3′′′′-hydroxy-3′′′′-methylglutaryl)-glucoside (melitidin, 3), their common biosynthetic precursor flavanone 7-​O-diglycoside (naringin, 4), and one known flavone 7-​O-diglycoside (rhoifolin, 5) were isolated from the pericarp of Citrus grandis (L.) Osbeck. The structures of these compounds were elucidated by spectroscopic and chemical techniques. The relative ratios and absolute configurations of the C-2 diastereomers of compounds 1, 2 and 4 were determined by online normal-phase HPLC-CD using a Chiralcel column. The absolute configuration of the HMG fragment in compounds 1−3 was assigned to be S through spectroscopic analysis of the mevalonamide obtained by amidation and reduction of the HMG moiety. The NO inhibitory activities of compounds 1−5 were evaluated using lipopolysaccharide-induced RAW264.7 cells. Compounds 1-5 were not cytotoxic to RAW264.7 cells at 10 μM.Graphical abstractGraphical abstract for this article
       
  • Lambertellin from Pycnoporus sanguineus MUCL 51321 and its
           anti-inflammatory effect via modulation of MAPK and NF-κB signaling
           pathways
    • Abstract: Publication date: Available online 27 June 2018Source: Bioorganic ChemistryAuthor(s): Jean-Bosco Jouda, Emmanuel Mfotie Njoya, Céline Djama Mbazoa, ZongYuan Zhou, Alain Meli Lannang, Jean Wandji, Yoshihito Shiono, Fei WangLambertellin (1) and ergosta-5,7,22-trien-3-ol (2) were isolated from the solid rice fermentation of the plant pathogenic fungus Pycnoporus sanguineus MUCL 51321. Their structures were elucidated using comprehensive spectroscopic methods. The isolated compounds were tested on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. Lambertellin (1) exhibited promising inhibitory activity against nitric oxide (NO) production with IC50 value of 3.19 µM, and it significantly inhibited the expression of inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2). Lambertellin (1) also decreased the expression of pro-inflammatory cytokines IL-6 and IL-1β. The study of the mechanistic pathways revealed that lambertellin (1) exerts its anti-inflammatory effect in LPS-stimulated RAW 264.7 macrophage cells by modulating the activation of the mitogen activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways. Therefore, lambertellin (1) could be a promising lead compound for the development of new anti-inflammatory drugs.Graphical abstractGraphical abstract for this article
       
  • Bioactive secondary metabolites from the marine-associated fungus
           Aspergillus terreus
    • Abstract: Publication date: Available online 27 June 2018Source: Bioorganic ChemistryAuthor(s): Mengting Liu, Weiguang Sun, Jianping Wang, Yan He, Jinwen Zhang, Fengli Li, Changxing Qi, Hucheng Zhu, Yongbo Xue, Zhengxi Hu, Yonghui ZhangThree new compounds, including a prenylated tryptophan derivative, luteoride E (1), a butenolide derivative, versicolactone G (2), and a linear aliphatic alcohol, (3E,7E)-4,8-dimethyl-undecane-3,7-diene-1,11-diol (3), together with nine known compounds (4–12), were isolated and identified from a coral-associated fungus Aspergillus terreus. Their structures were elucidated by HRESIMS, one- and two-dimensional NMR analysis, and the absolute configuration of 2 was determined by comparison of its electronic circular dichroism (ECD) spectrum with the literature. Structurally, compound 1 featured an unusual (E)-oxime group, which occurred rarely in natural products. Compounds 1–3 were evaluated for the α-glucosidase inhibitory activity, and compound 2 showed potent inhibitory potency with IC50 value of 104.8 ± 9.5 μM, which was lower than the positive control acarbose (IC50 = 154.7 ± 8.1 µM). Additionally, all the isolated compounds were evaluated for the anti-inflammatory activity against NO production, and compounds 1–3, 5–7, and 10 showed significant inhibitory potency with IC50 values ranging from 5.48 to 29.34 μM.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, biological activities and DFT calculation of novel
           1,2,4-triazole Schiff base derivatives
    • Abstract: Publication date: Available online 25 June 2018Source: Bioorganic ChemistryAuthor(s): Ru-Yi Jin, Chu-Yue Zeng, Xu-Hua Liang, Xiao-Hong Sun, Yuan-Fa Liu, Yan-Yan Wang, Sha ZhouSeries of 1,2,4-triazole Schiff bases (2a-h and 3a-h) have been designed and synthesized. The structure of title compounds was confirmed on the basis of their spectral data and elemental analysis. All the target compounds were screened for their in vitro antifungal activity and antibacterial activity. Two of the tested compounds (2a and 2b) exhibited significant antifungal activity against most fungi, especially compound 2a showed better antifungal activity than triadimefon. Meanwhile, the antibacterial activity assay also indicated compound 2a exhibited excellent antibacterial activities comparable to chloramphenicol. The SAR manifested no substitution at position 5 of the triazole ring caused an increase in activity, and 3-phenoxy phenyl group introduced in 1,2,4-triazole scaffold can enhance the antibacterial activity. The DFT calculation indicated triazole ring, S atom and benzene ring in both of the 2a and 3a make a major contribution to the activity.Graphical abstractSeries of novel 1,2,4-triazole Schiff bases were synthesized and evaluated for antifungal and antibacterial activities. The bioassay showed compound 2a has potential to developing candidate compound. The DFT calculation indicated triazole ring, S atom and benzene ring in both of the 2a and 3a make a major contribution to the activity.Graphical abstract for this article
       
  • Design and Synthesis of Donepezil Analogues as Dual AChE and BACE-1
           inhibitors
    • Abstract: Publication date: Available online 25 June 2018Source: Bioorganic ChemistryAuthor(s): Moustafa T. Gabr, Mohammed S. Abdel-RaziqMulti-target-directed ligands (MTDLs) centered on β-secretase 1 (BACE-1) inhibition are emerging as innovative therapeutics in addressing the complexity of neurodegenerative diseases. A new series of donepezil analogues was designed, synthesized and evaluated as MTDLs against neurodegenerative diseases. Profiling of donepezil, a potent acetylcholinesterase (hAChE) inhibitor, into BACE-1 inhibition was achieved through introduction of backbone amide linkers to the designed compounds which are capable of hydrogen-bonding with BACE-1 catalytic site. In vitro assays and molecular modeling studies revealed the dual mode of action of compounds 4-6 against hAChE and BACE-1. Notably, compound 4 displayed potent hAChE inhibition (IC50 value of 4.11 nM) and BACE-1 inhibition (IC50 value of 18.3 nM) in comparison to donepezil (IC50 values of 6.21 and 194 nM against hAChE and BACE-1, respectively). Moreover, 4 revealed potential metal chelating property, low toxicity on SH-SY5Y neuroblastoma cells and ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay which renders 4 a potential lead for further optimization of novel small ligands for the treatment of Alzheimer's disease.Graphical abstractProfiling donepezil template to dual AChE and BACE-1 inhibitionGraphical abstract for this article
       
  • Biological properties and structural study of new aminoalkyl derivatives
           of benzimidazole and benzotriazole, dual inhibitors of CK2 and PIM1
           kinases
    • Abstract: Publication date: Available online 22 June 2018Source: Bioorganic ChemistryAuthor(s): K. Chojnacki, P. Wińska, M. Wielechowska, E. Łukowska-Chojnacka, C. Tölzer, K. Niefind, M. BretnerThe new aminoalkyl- substituted derivatives of known CK2 inhibitors 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi) and 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) were synthesized, and their influence on the activity of recombinant human CK2 α, CK2 holoenzyme and PIM1 kinases was evaluated. All derivatives inhibited the activity of studied kinases and the most efficient were aminopropyl- derivatives 8b and 14b. These compounds also exerted inhibition of cancer cell lines - CCRF-CEM (acute lymphoblastoid leukemia), MCF-7 (human breast cancer), and PC-3 (prostate cancer) proliferation and their EC50 is comparable with the value for clinically studied CK2 inhibitor CX-4945. Preliminary structure activity relationship analysis indicated that the spacer length affected antitumor potency, and two to three methylene units were more favorable. The complex of CK2 α1-335/8b was crystallized, both under high-salt conditions and under low-salt conditions giving crystals which diffracted X-rays to about 2.4 Å resolution, what enabled the determination of the corresponding 3D-structures.Graphical abstractGraphical abstract for this article
       
  • 2-S-cysteinylhydroquinone is an intermediate for the firefly luciferin
           biosynthesis that occurs in the pupal stage of the Japanese firefly,
           Luciola lateralis
    • Abstract: Publication date: Available online 21 June 2018Source: Bioorganic ChemistryAuthor(s): Shusei Kanie, Ryosuke Nakai, Makoto Ojika, Yuichi ObaFirefly luciferin is a natural product that is well-known to function as the substrate of the bioluminescence reaction in luminous beetles. However, the details of the biosynthetic system are still unclear. In this study, we showed by LC-MS/MS analysis that stable isotope-labeled 2-S-cysteinylhydroquinone was incorporated into firefly luciferin in living firefly specimens. Comparison of the incorporation efficiency among the developmental stages suggested that firefly luciferin is biosynthesized predominantly in the pupal stage. We also accomplished the in vitro biosynthesis of firefly luciferin using 2-S-cysteinylhydroquinone and the crude buffer extract of firefly pupae, suggesting the presence of a biosynthetic enzyme in the pupal extract.Graphical abstractGraphical abstract for this article
       
  • Cytotoxic Macrocyclic Diterpenoids from Jatropha multifida
    • Abstract: Publication date: Available online 20 June 2018Source: Bioorganic ChemistryAuthor(s): Jun-Sheng Zhang, Yao Zhang, Shen Li, Abrar Ahmed, Gui-Hua Tang, Sheng YinNine new macrocyclic diterpenoids (1-9), jatromultones A-I, along with eight known analogues (10-17) were isolated from the trunks of Jatropha multifida. The structures of the new compounds, including their absolute configurations, were elucidated by combination of spectroscopic analysis, single crystal X-ray diffraction, Rh2(OCOCF3)4-induced CD method, and chemical correlations. All compounds were screened for the cytotoxicity against five cancer cell lines, including one drug-resistant cell line, and seven compounds exhibited significant activity with IC50 values less than 10 μM. Compound 4 with IC50 values ranging from 2.69 to 6.44 μM toward all cell lines was selected for further mechanistic study, which showed that 4 could arrest cell cycle at G2/M phase and induce apoptosis. The brief structure-activity relationships (SARs) of these macrocyclic diterpenoids were also discussed.Graphical abstractGraphical abstract for this article
       
  • Syntheses, antiviral activities and induced resistance mechanisms of novel
           quinazoline derivatives containing a dithioacetal moiety
    • Abstract: Publication date: Available online 20 June 2018Source: Bioorganic ChemistryAuthor(s): Dandan Xie, Jing Shi, Awei Zhang, Zhiwei Lei, Guangcheng Zu, Yun Fu, Xiuhai Gan, Limin Yin, Baoan Song, Deyu HuA series of novel quinazoline derivatives containing a dithioacetal moiety were designed and synthesized, and their structures were characterized by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and high-resolution mass spectrometry. Bioassay results indicated that compound 4b exhibited remarkable protective activity against cucumber mosaic virus (CMV, EC50 = 248.6 μg/mL) and curative activity against potato virus Y (EC50 = 350.5 μg/mL), which were better than those of ningnanmycin (357.7 μg/mL and 493.7 μg/mL, respectively). Moreover, compound 4b could increase the chlorophyll content in plants, improve photosynthesis, and effectively induce tobacco anti-CMV activity.Graphical abstractGraphical abstract for this article
       
  • Enhancement in anti-tubercular activity of indole based thiosemicarbazones
           on complexation with copper(I) and silver(I) halides: Structure
           elucidation, evaluation and molecular modelling
    • Abstract: Publication date: Available online 20 June 2018Source: Bioorganic ChemistryAuthor(s): Ashiq Khan, Jerry P. Jasinski, Victoria A. Smolenski, Ethan P. Hotchkiss, Patrick T. Kelley, Zachary A. Shalit, Manpreet Kaur, Kamaldeep Paul, Rekha SharmaA series of monomeric tetrahedral complexes of stoichiometry, [MX(HL)(Ph3P)2] (In case of M = Cu, H1L, X = I, 1; Br, 2; Cl, 3; H3L, X = I, 4; Br, 5; Cl, 6; H4L, X = I, 7; Br, 8; Cl, 9 and in case of M = Ag, H1L, X = Cl, 13; Br, 14; H2L, X = Cl, 15, Br 16; H3L, X = Cl, 17, Br, 18) were synthesized by the reaction of copper (I) or silver (I) halides with indole-3-thiosemicarbazone (H1L) or 5-methoxy indole-3-thiosemicarbazone (H2L) or 5-methoxy indole-N1-methyl-3-thiosemicarbazone (H3L), whereas dimers of stoichiometry, [Cu2(μ-X)2(η1-S-H2L)2(Ph3P)2] (X = I, 10; Br, 11; Cl, 12) were obtained by the reaction of copper (I) halides with indole-N1-methyl-3-thiosemicarbazone (HIntsc-N1-Me, H2L). The synthesized complexes were characterized using NMR (1H and 13C) and single crystal X-ray diffraction (H2L, 3, 7, 8, 10, 11 and 13) as well as elemental analysis. Anti- M. tuberculosis activity of ligands (H1L-H4L) and their metal complexes (1-18) were evaluated against M. tuberculosis H37RV strain ATCC 27294. It has been observed that there is unusual enhancement in anti TB activity of these ligands on complexation with copper (I) and silver (I). Molecular modelling studies in the active binding site are also giving complementary theoretical support for the experimental biological data acquired.Graphical abstractEnhancement in anti-tubercular activity of indole based thiosemicarbazones on complexation with copper(I) and silver(I) has been observed. Molecular modelling studies in the active binding site is also giving complementary theoretical support for the experimental biological data acquiredGraphical abstract for this article
       
  • Design and Amberlyst-15 mediated synthesis of novel thienyl-pyrazole
           carboxamides that potently inhibit Phospholipase A2 by binding to an
           allosteric site on the enzyme
    • Abstract: Publication date: Available online 19 June 2018Source: Bioorganic ChemistryAuthor(s): Achutha Dileep Kumar, Malledevarapura Gurumurthy Prabhudeva, Srinivasan Bharath, Karthik Kumara, Neratur Krishnappagowda Lokanath, Kariyappa Ajay KumarInflammation-mediated disorders are on the rise and hence, there is an urgent need for the design and synthesis of new anti-inflammatory drugs with higher affinity and specificity for their potential targets. The current study presents an effective and new protocol for the synthesis of thienyl-pyrazoles through 3+2 annulations using a recyclable heterogeneous catalyst Amberlyst-15. Chalcones 3(a-g) prepared from 3-methylthiophene-2-carbaldehyde and acetophenones by Claisen-Schmidt approach reacted with semicarbazide hydrochloride 4 in the presence of Amberlyst-15 in acetonitrile at room temperature producing thienyl-pyrazole carboxamides 5(a-h) in good yields. Alternatively, the compounds 5(a-h) were prepared by conventional method using acetic acid (30%) medium. Structures of synthesized new pyrazoles were confirmed by spectral and crystallographic studies. All the new compounds were evaluated for their in vitro inhibition of Phospholipase A2 from Vipera russelli and preliminary studies revealed that, amongst the designed series, compounds 5b, 5c and 5h showed promising inhibition. Further, the compounds exhibited linear mixed-type inhibition behavior for the sPLA2 enzyme indicating that they bind to an allosteric site distinct from either the calcium or substrate binding site on the enzyme. These kinetic conclusions were further validated by macromolecular rigid-body docking whereby compounds 5c and 5h showed binding to distinct pockets on the protein. These findings present a promising series of lead molecules that can serve as prototypes for the treatment of inflammatory related disorders.Graphical abstractGraphical abstract for this article
       
  • New monoterpenoid by biotransformation of thymoquinone using
           Aspergillus niger
    • Abstract: Publication date: Available online 12 June 2018Source: Bioorganic ChemistryAuthor(s): Mohammad Yasin Mohammad, Ashok Shakya, Ramia Al-Bakain, M.H. Haroon, M. Iqbal ChoudharyMicrobial transformation of thymoquinone (1) by suspended cell-cultures of the plant pathogenic fungus Aspergillus niger resulted in the production of three metabolites. These metabolites were identified as 5-isopropyl-2-methyl-2,4-cyclohexenone lactone (2), hydroxythymoquinone (3), and 4-hydroxy-2-isopropyl-5-methylphenol (4) by different spectroscopic methods. Metabolite 2 was found to be a new compound. Compound 4 showed potent antioxidant activity.Graphical abstractTransformation of thymoquinone (1) by Aspergillus niger produced three metabolites 2-4. Metabolite 2 was found to be new.Graphical abstract for this article
       
  • Design, synthesis and anticancer evaluation of
           1H-pyrazolo[3,4-d]pyrimidine derivatives as potent EGFRWT and EGFRT790M
           inhibitors and apoptosis inducers
    • Abstract: Publication date: Available online 12 June 2018Source: Bioorganic ChemistryAuthor(s): Ahmed A. Gaber, Ashraf H. Bayoumi, Ahmed M. El-morsy, Farag F. Sherbiny, Ahmed B.M. Mehany, Ibrahim H. EissaIn our attempt to develop effective EGFR-TKIs, two series of 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesized. All the newly synthesized compounds were evaluated in vitro for their inhibitory activities against EGFRWT. Compounds 15b, 15j, and 18d potently inhibited EGFRWT at sub-micro molar IC50 values comparable to that of erlotinib. Moreover, thirteen compounds that showed promising IC50 values against EGFRWT were tested in vitro for their inhibitory activities against mutant EGFRT790M. Compounds 17d and 17f exhibited potent inhibitory activities towards EGFRT790M comparable to osimertinib. Compounds that showed promising IC50 values against EGFRWT were further tested for their anti-proliferative activities against three cancer cell lines bearing EGFRWT (MCF-7, HepG2, A549), and two cancer cell lines bearing EGFRT790M (H1975 and HCC827). Compounds 15g, 15j, 15n, 18d and 18e were the most potent anticancer agents against the EGFRWT containing cells, while compounds15e, 17d and 17f showed promising anti-proliferative activities against EGFRT790M containing cells. Furthermore, the most active compound 18d was selected for further studies regarding to its effects on cell cycle progression and induction of apoptosis in the HepG2 cell line. The results indicated that this compound is good apoptotic agent and arrests G0/ G1and G2/M phases of cell cycle. Finally, molecular docking studies were performed to investigate binding pattern of the synthesized compounds with the prospective targets, EGFRWT (PDB: 4HJO) and EGFRT790M (PDB: 3W2O).Graphical abstractGraphical abstract for this article
       
  • Design and Synthesis of Gallocyanine Inhibitors of DKK1/LRP6 Interactions
           for Treatment of Alzheimer ’s Disease
    • Abstract: Publication date: Available online 12 June 2018Source: Bioorganic ChemistryAuthor(s): Savvas Thysiadis, Sotirios Katsamakas, Spyros Mpousis, Nicolaos Avramidis, Spiros Efthimiopoulos, Vasiliki SarliBased on NCI8642, a series of gallocyanine derivatives was synthesized with modifications of the substituent groups in position 1, 2 and 4 of the phenoxazinone scaffold. The effectiveness of gallocyanines to inhibit DKK1/LRP6 interactions and Tau phosphorylation induced by prostaglandin J2 and DKK1 was elucidated by both experimental data and molecular docking simulations. Bis-alkylated with flexible alkyl ester groups on C1 and bis-benzyl gallocyanines provided the most active inhibitors, while amino derivatives on C2 of NCI8642 that have alkoxy or benzyloxy substituents on C4, were less active. Furthermore, it is shown that treating of SHSY5Y cells with NCI8642 derivatives activates Wnt signaling and increases the levels of pGSK3β kinase and β-catenin.Graphical abstractGraphical abstract for this article
       
  • Synthesis, in vitro and in silico Evaluation of Diaryl Heptanones as
           Potential 5LOX Enzyme Inhibitors
    • Abstract: Publication date: Available online 8 June 2018Source: Bioorganic ChemistryAuthor(s): Bharani Meka, Suryachandra Rao Ravada, Muthyala Murali Krishna Kumar, Kurre Purna Nagasree, Trimurtulu GolakotiA new series of diaryl heptanones (12a-q) were synthesized and their structures were confirmed by its 1H, 13C NMR and Mass spectral data. These analogs were evaluated for their anti-oxidant activity and potential to inhibit 5-lipoxygenase. Compounds 12k and 12o showed potent in vitro 5-lipoxygenase enzyme inhibitory activity with IC50 values of 22.2, 21.5 μM, which are comparable to curcumin (24.4 μM). Further they also have shown significant antioxidant activity. Molecular docking studies clearly showed correlation between binding energy and potency of these compounds.Graphical abstractDocking poses of the compound 12k and Curcumin at the receptor pocket. Ligand (salmon red), Fe (magenta) and active site residues making polar contacts (light yellow orange).Graphical abstract for this article
       
  • Design, Synthesis of Novel Azolyl Flavonoids and Their Protein Tyrosine
           Phosphatase-1B Inhibitory Activities
    • Abstract: Publication date: Available online 5 June 2018Source: Bioorganic ChemistryAuthor(s): Ling Zhang, Yu Ge, Hao Ming Song, Qing Ming Wang, Cheng-He ZhouA series of azolyl flavonoids were synthesized and characterized by NMR, IR, MS and HRMS spectra. All the newly prepared compounds were screened for their potential protein tyrosine phosphatase inhibitory activities. Bioactive assay manifested that most of the azolyl flavonoids exhibited good protein phosphatase 1B (PTP1B) inhibitory activities. Especially, triazolyl flavonoid 6a displayed the best inhibitory activity (IC50 = 1.6 μM) with 9.9-fold selectivity for PTP1B over the closely related T-cell protein tyrosine phosphatase (TCPTP). Cell viability assays indicated 6a has lower cytotoxicity. Molecular modeling and dynamics studies revealed the reason of selectivity for PTP1B over TCPTP. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity.Graphical abstractGraphical abstract for this article
       
  • Design, Synthesis and Molecular Modeling Study of certain
           4-Methylbenzenesulfonamides with CDK2 inhibitory Activity as Anticancer
           and Radio-sensitizing agents
    • Abstract: Publication date: Available online 5 June 2018Source: Bioorganic ChemistryAuthor(s): Mostafa M. Ghorab, Fatma A. Ragab, Helmy I. Heiba, Mohamed S.A. Elsayed, Walid M. GhorabTwo series of 2-aminopyridine derivatives 6-17 and tyrphostin AG17 analogs 18-22 bearing 4-methylbenzenesulfonamide moiety were designed and synthesized as anticancer compounds. The synthesized compounds were biologically evaluated for their cytotoxic activity against human breast cancer cell line MCF-7. From 2-aminopyridine and tyrphostin AG17 series, compounds 14, 16 and 20 showed the best activities with IC50 values of 20.4, 18.3 and 26.3 µM, respectively compared to E7070 IC50 36.3 µM. Further biological evaluation of 14, 16 and 20 against cyclin dependent kinase-2 (CDK2) revealed good inhibitory activity with IC50 of 2.53, 1.79 and 2.92 µM, respectively compared to roscovitine IC50 0.43 µM. Additionally, capability of γ-radiation to augment the cytotoxic activity of 14, 16 and 20 was studied and showed a dramatic increase in the cell killing effect at lower concentrations after irradiation. Docking was used to investigate the possible binding modes of compounds 14, 16 and 20 inside the active site of CDK2 enzyme.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of novel pyrrole derivatives
           as potential ClpP1P2 inhibitor against Mycobacterium tuberculosis
    • Abstract: Publication date: Available online 4 June 2018Source: Bioorganic ChemistryAuthor(s): Pingxian Liu, Yang Yang, Yuan Ju, Yunxiang Tang, Zitai Sang, Lijuan Chen, Tao Yang, Qi An, Tianyu Zhang, Youfu LuoIn an effort to discover novel inhibitors of M. tuberculosis Caseinolytic proteases (ClpP1P2), a combination strategy of virtual high-throughput screening and in vitro assay was employed and a new pyrrole compound, 1-(2-chloro-6-fluorobenzyl)-2, 5-dimethyl-4-((phenethylamino)methyl)-1H-pyrrole-3-carboxylate was found to display inhibitory effects against H37Ra with an MIC value of 77 µM. In order for discovery of more potent anti-tubercular agents that inhibit ClpP1P2 peptidase in M. tuberculosis, a series of pyrrole derivatives were designed and synthesized based on this hit compound. The synthesized compounds were evaluated for in vitro studies against ClpP1P2 peptidase and anti-tubercular activities were also evaluated. The most promising compounds 2-(4-bromophenyl)-N-((1-(2-chloro-6-fluorophenyl)-2, 5-dimethyl-1H- pyrrolyl)methyl)ethan-1-aminehydrochloride 7d, ethyl 4-(((4-bromophenethyl) amino) methyl)-2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13i, ethyl 1- (4-chlorophenyl)-4-(((2-fluorophenethyl)amino)methyl)-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13n exhibited favorable anti-mycobacterial activity with MIC value at 5 µM against Mtb H37Ra, respectively.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of novel 1,2,3-triazole linked
           coumarinopyrazole conjugates as potent anticholinesterase,
           anti-5-lipoxygenase, anti-tyrosinase and anti-cancer agents
    • Abstract: Publication date: Available online 4 June 2018Source: Bioorganic ChemistryAuthor(s): Samia Chekir, Meriem Debbabi, Anne Regazzetti, Delphine Dargère, Olivier Laprévote, Hichem Ben Jannet, Rafik GharbiA series of new 1,2,3-triazole linked coumarinopyrazole conjugates 4a-e and 5a-e have been synthesized via the Copper(I)-catalysed Alkyne-Azide Cycloaddition (CuAAC). Going through the reaction of compound 2 with the 3-propargyl bromide gave a mixture of propargylated regioisomers 3+3’ used as a dipolarophile to access to triazoles 4a-e and 5a-e. The structures of the prepared cycloadducts were determined by 1H, 13C and 2D-NMR techniques and by HRMS analysis. All the synthesized derivatives have been evaluated for their anticholinesterase, anti-5-lipoxygenase, anti-tyrosinase, and cytotoxic activities.Graphical abstractGraphical abstract for this article
       
  • The zinc- but not cadmium – containing ζ-carbonic from the diatom
           
    • Abstract: Publication date: Available online 26 May 2018Source: Bioorganic ChemistryAuthor(s): Andrea Angeli, Martina Buonanno, William A. Donald, Simona Maria Monti, Claudiu T. SupuranThe activation of the ζ-class carbonic anhydrase (CAs, EC 4.2.1.1) from the diatom Thalassiosira weissflogii (TweCAζ) incorporating both Zn(II) and Cd(II) at the active site, was investigated for the first time, using a panel of natural and non-natural amino acids and amines. CdTweCAζ was completely insensitive to activation, whereas all these compounds were effective activators of the zinc-containing enzyme ZnTweCAζ, with activation constants ranging between 92 nM and 37.9 µM. The most effective ZnTweCAζ activators were L-adrenaline, 1-(2-aminoethyl)-piperazine and 4-(2-aminoethyl)-morpholine, with KAs in the range of 92 – 150 nM. L-His, L- and D-Tyr and some pyridyl-alkylamines, had KAs in the range of 0.62 – 0.98 µM, whereas L-/D-DOPA, D-Trp, histamine, serotonin and L-Asn were the next most efficient activators, with KAs in the range of 1.27 – 3.19 µM. The least effective activators were L-Phe (KA of 15.4 µM) and L-Asp (KA of 37.9 µM). This in vitro study may be useful for a more complete understanding of the activation processes of various CA enzyme families, of which the ζ-class was scarcely investigatedGraphical abstractGraphical abstract for this article
       
  • Design, synthesis of novel isoindoline hybrids as COX-2 inhibitors:
           anti-inflammatory, analgesic activities and docking study
    • Abstract: Publication date: Available online 21 May 2018Source: Bioorganic ChemistryAuthor(s): Madlen B. Labib, Souty M.Z. Sharkawi, Mahmoud El-DalyA group of novel isoindoline hybrids incorporating oxime, hydrazone, pyrazole, chalcone or aminosulfonyl pharmacophores (9-14) was designed and characterized by spectral data and elemental analyses results. All newly synthesized compounds were evaluated as COX-2 inhibitors, anti-inflammatory and analgesic agents. Six hybrid derivatives (10b, 10c, 11a, 11d, 13, 14) were moderate COX-2 inhibitors (IC50 = 0.11-0.18 µM) close to standard celecoxib (IC50 = 0.09 µM). The most active compounds showed outstanding in vivo anti-inflammatory activity (% edema inhibition = 41.7-50, 1h; 40.7-67.4, 3h; 20-46.7, 6h) better than reference drug diclofenac (% edema inhibition = 29.2, 1h; 22.2, 3h; 20, 6h). Most compounds showed significant peripheral and/or central analgesic activity. The moderate selective COX-2 inhibitor; dimethoxychalcone 11d (SI = 103) displayed excellent anti-inflammatory activity (% edema inhibition = 45.8-59.3) and increased thermal pain threshold (50-92.85%) comparable to piroxicam (75%). Molecular docking studies have been established.Graphical abstractGraphical abstract for this article
       
 
 
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