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  Subjects -> CHEMISTRY (Total: 908 journals)
    - ANALYTICAL CHEMISTRY (56 journals)
    - CHEMISTRY (642 journals)
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CHEMISTRY (642 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: 30)
ACS Catalysis     Hybrid Journal   (Followers: 53)
ACS Chemical Neuroscience     Hybrid Journal   (Followers: 23)
ACS Combinatorial Science     Hybrid Journal   (Followers: 23)
ACS Macro Letters     Hybrid Journal   (Followers: 27)
ACS Medicinal Chemistry Letters     Hybrid Journal   (Followers: 44)
ACS Nano     Hybrid Journal   (Followers: 328)
ACS Photonics     Hybrid Journal   (Followers: 15)
ACS Symposium Series     Full-text available via subscription  
ACS Synthetic Biology     Hybrid Journal   (Followers: 25)
Acta Chemica Iasi     Open Access   (Followers: 6)
Acta Chimica Slovaca     Open Access   (Followers: 2)
Acta Chimica Slovenica     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 8)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 7)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 8)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 9)
Adsorption Science & Technology     Open Access   (Followers: 7)
Advanced Functional Materials     Hybrid Journal   (Followers: 62)
Advanced Science Focus     Free   (Followers: 5)
Advances in Chemical Engineering and Science     Open Access   (Followers: 77)
Advances in Chemical Science     Open Access   (Followers: 21)
Advances in Chemistry     Open Access   (Followers: 27)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 20)
Advances in Drug Research     Full-text available via subscription   (Followers: 26)
Advances in Environmental Chemistry     Open Access   (Followers: 7)
Advances in Enzyme Research     Open Access   (Followers: 11)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 12)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 27)
Advances in Nanoparticles     Open Access   (Followers: 17)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Polymer Science     Hybrid Journal   (Followers: 45)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 4)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 8)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Al-Kimia : Jurnal Penelitian Sains Kimia     Open Access  
Alchemy : Journal of Chemistry     Open Access   (Followers: 3)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 68)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 22)
American Journal of Chemistry     Open Access   (Followers: 34)
American Journal of Plant Physiology     Open Access   (Followers: 13)
American Mineralogist     Hybrid Journal   (Followers: 15)
Anadolu University Journal of Science and Technology A : Applied Sciences and Engineering     Open Access  
Analyst     Full-text available via subscription   (Followers: 37)
Angewandte Chemie     Hybrid Journal   (Followers: 187)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 273)
Annales Universitatis Mariae Curie-Sklodowska, sectio AA – Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 4)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 9)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 15)
Antiviral Chemistry and Chemotherapy     Open Access   (Followers: 2)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 9)
Applied Spectroscopy     Full-text available via subscription   (Followers: 26)
Applied Surface Science     Hybrid Journal   (Followers: 34)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 3)
Asian Journal of Chemistry and Pharmaceutical Sciences     Open Access  
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 4)
Avances en Quimica     Open Access  
Biochemical Pharmacology     Hybrid Journal   (Followers: 11)
Biochemistry     Hybrid Journal   (Followers: 382)
Biochemistry Insights     Open Access   (Followers: 7)
Biochemistry Research International     Open Access   (Followers: 7)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 11)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 2)
Biomacromolecules     Hybrid Journal   (Followers: 24)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 143)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 93)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 20)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 1)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 25)
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: 12)
Canadian Mineralogist     Full-text available via subscription   (Followers: 7)
Carbohydrate Research     Hybrid Journal   (Followers: 25)
Carbon     Hybrid Journal   (Followers: 70)
Catalysis for Sustainable Energy     Open Access   (Followers: 10)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 10)
Catalysis Science and Technology     Hybrid Journal   (Followers: 10)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 14)
Cellulose     Hybrid Journal   (Followers: 13)
Cereal Chemistry     Full-text available via subscription   (Followers: 5)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 2)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 23)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 75)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 28)
Chemical Physics Letters : X     Open Access  
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 22)
Chemical Reviews     Hybrid Journal   (Followers: 218)
Chemical Science     Open Access   (Followers: 29)
Chemical Technology     Open Access   (Followers: 36)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 57)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 21)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry     Open Access  
Chemistry & Biodiversity     Hybrid Journal   (Followers: 7)
Chemistry & Biology     Full-text available via subscription   (Followers: 33)
Chemistry & Industry     Full-text available via subscription   (Followers: 9)
Chemistry - A European Journal     Hybrid Journal   (Followers: 183)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 16)
Chemistry and Materials Research     Open Access   (Followers: 21)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Open Access   (Followers: 3)
Chemistry Letters     Full-text available via subscription   (Followers: 46)
Chemistry of Materials     Hybrid Journal   (Followers: 281)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 10)
Chemistry World     Full-text available via subscription   (Followers: 21)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 1)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 3)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 12)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 11)
Chromatographia     Hybrid Journal   (Followers: 22)
Chromatography     Open Access   (Followers: 3)
Chromatography Research International     Open Access   (Followers: 5)
Cogent Chemistry     Open Access   (Followers: 2)
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 11)
Colloids and Interfaces     Open Access  
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 7)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 23)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Communications Chemistry     Open Access   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 7)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 1)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 13)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 10)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 4)
Copernican Letters     Open Access   (Followers: 1)
Corrosion Series     Full-text available via subscription   (Followers: 7)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 8)
Croatica Chemica Acta     Open Access  
Crystal Structure Theory and Applications     Open Access   (Followers: 4)
CrystEngComm     Full-text available via subscription   (Followers: 13)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Chromatography     Hybrid Journal  
Current Green Chemistry     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 6)
Current Microwave Chemistry     Hybrid Journal  
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 14)
Current Research in Chemistry     Open Access   (Followers: 9)
Current Science     Open Access   (Followers: 77)
Current Topics in Medicinal Chemistry     Hybrid Journal   (Followers: 9)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 2)
Dalton Transactions     Full-text available via subscription   (Followers: 26)

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Similar Journals
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  [3161 journals]
  • Targeting Malaria and Leishmaniasis: Synthesis and Pharmacological
           Evaluation of Novel Pyrazole-1,3,4-Oxadiazole Hybrids. Part II
    • Abstract: Publication date: Available online 17 May 2019Source: Bioorganic ChemistryAuthor(s): Garima Verma, Mohemmed Faraz Khan, Lalit Mohan Nainwal, Mohd Ishaq, Mymoona Akhter, Afroz Bakht, Tariq Anwer, Farhat Afrin, Mohammad Islamuddin, Ibraheem Husain, Mohammad Mumtaz Alam, Mohammad Shaquiquzzaman In continuance with earlier reported work, an extension has been carried out by the same research group. Mulling over the ongoing condition of resistance to existing antimalarial agents, we had reported synthesis and antimalarial activity of certain pyrazole-1,3,4-oxadiazole hybrid compounds. Bearing previous results in mind, our research group ideated to design and synthesize some more derivatives with varied substitutions of acetophenone and hydrazide. Following this, derivatives 5a-r were synthesized and tested for antimalarial efficacy by schizont maturation inhibition assay. Further, depending on the literature support and results of our previous series, certain potent compounds (5f, 5n and 5r) were subjected to Falcipain-2 inhibitory assay. Results obtained for these particular compounds further strengthened our hypothesis. Here, in this series, compound 5f having unsubstituted acetophenone part and a furan moiety linked to oxadiazole ring emerged as the most potent compound and results were found to be comparable to that of the most potent compound (indole bearing) of previous series. Additionally, depending on the available literature, compounds (5a-r) were tested for their antileishmanial potential. Compounds 5a, 5c and 5r demonstrated dose-dependent killing of the promastigotes. Their IC50 values were found to be 33.3±1.68, 40.1±1.0 and 19.0±1.47μg/mL respectively. These compounds (5a, 5c and 5r) also had effects on amastigote infectivity with IC50 of 44.2±2.72, 66.8±2.05 and 73.1±1.69 μg/mL respectively. Further target validation was done using molecular docking studies. Acute oral toxicity studies for most active compounds were also performed.Graphical abstractGraphical abstract for this article
  • An efficient one-pot synthesis of polyphenolic amino acids and evaluation
           of their radical-scavenging activity
    • Abstract: Publication date: August 2019Source: Bioorganic Chemistry, Volume 89Author(s): Luís S. Monteiro, Fátima Paiva-Martins, Sandra Oliveira, Inês Machado, Marlene Costa A simple and efficient procedure for the synthesis of N-acyl 4-hydroxy, 4-hydroxy-3-methoxy and 3,4-dihydroxy phenylglycine amides by a strategy based on the multicomponent Ugi reaction is proposed. Hydroxybenzaldehyde derivatives were reacted with 4-methoxybenzylamine, cyclohexyl isocyanide and benzoic acid or 2-naphthylacetic acid to give Ugi adducts that were treated with trifluoroacetic acid yielding N-acyl hydroxyphenylglycine amides in good yields. The same procedure using as acid component protocatechuic acid or hydrocaffeic acid gave N-catechoyl 3,4-dihydroxyphenylglycine amides. The use of N-benzyloxycarbonylglycine as acid component allowed the preparation of a 3,4-dihydroxyphenylglycyl dipeptide derivative. Radical-scavenging activity studies of the polyphenolic amino acid derivatives showed a sharp increase in activity with the increase in number of hydroxyl or catechol groups present. Cyclic voltammetry experiments established a correlation between oxidation peak potentials and the radical-scavenging activity.Graphical abstractGraphical abstract for this article
  • Naphthalimides in fluorescent imaging of tumor hypoxia – An
           up-to-date review
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Rashmi Kumari, Dhanya Sunil, Raghumani S. Ningthoujam Hypoxia is a distinctive characteristic of advanced solid malignancies that results from a disparity between oxygen supply and its consumption. The degree of hypoxia is believed to have adverse prognostic significance. Therefore detecting cellular hypoxia can potentially offer insights into the grade of tumour as well as its evolution towards a progressive malignant phenotype, which clinically translates to greater metastatic potential and treatment resistance. Fluorescence imaging to visualize hypoxia in biological systems is a minimally-invasive method. Recently there are several reports on interdisciplinary research that aims at developing functional probes that can be efficiently used for non-invasive imaging of hypoxic tumours. Upregulated levels of nitroreductase (NTR) is detected in hypoxic solid malignancies, and this characteristic feature is increasingly utilized in the development of NTR-targeted fluorescent molecules to selectively sense hypoxia in vivo. The present review summarizes various reports published on the design concepts of nitro naphthalimide-based bio-reductive fluorescent sensors that can be applied noninvasively to image hypoxia in cancer.Graphical abstractGraphical abstract for this article
  • Identification of 10-dehydrooxyglycyuralin E as a selective human estrogen
           receptor alpha partial agonist
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Nao Saito, Keiko Kawase, Naoya Yamashita, Yingzhan Tang, Ying Wang, Jian Wang, Yongxiang Liu, Ning Li, Wei Li, Mao-Sheng Cheng, Kazuo Koike, Yuichiro Kanno, Kiyomitsu Nemoto Selective estrogen receptor modulators (SERMs) act as either agonist or antagonist of estrogen receptor (ER) in a tissue selective manner and have been used in several diseases such as breast cancer, postmenopausal syndrome, osteoporosis, and cardiovascular diseases. However, current SERMs may also increase the risk of serious side effects and trigger drug resistance. Herein, a screening program, that was designed to search for novel SERMs, resulted in the identification of a series of 2-arylbenzofuran-containing compounds that are ligands for ERα, when applying the Gaussia-luciferase reporter assay. One of these compounds, 10-dehydrooxyglycyuralin E (T9) was chemically synthesized. T9 showed anti-estrogenic/proliferative activity in ERα-positive breast cancer cells. Pretreatment of T9 prevented the mRNA expression of GREB1, which is an estrogen response gene. Furthermore, by an in silico docking simulation study we demonstrated that T9 showed interactions directly to ERα. Taken together, these results demonstrated that T9 is a candidate of SERMs and a useful seed compound for the foundation of the selective activity of SERMs.Graphical abstractGraphical abstract for this article
  • Synthesis and biological evaluation of flavone-8-acrylamide derivatives as
           potential multi-target-directed anti Alzheimer agents and investigation of
           binding mechanism with acetylcholinesterase
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Jeelan Basha Shaik, Daniel Pushparaju Yeggoni, Yelamanda Rao Kandrakonda, Mohan Penumala, Raveendra Babu Zinka, Kasi Viswanath Kotapati, Mark Manidhar Darla, Dinakara Rao Ampasala, Rajagopal Subramanyam, Damu Gangaiah Amooru In a search for novel multifunctional anti-Alzheimer agents, a congeneric set of seventeen flavone-8-acrylamide derivatives (8a─q) were synthesized and evaluated for their cholinesterase inhibitory, antioxidant, neuroprotective and modulation of Aβ aggregation activities. The target compounds showed effective and selective inhibitory activity against the AChE over BuChE. In addition, the target compounds also showed moderate anti-oxidant activity and strong neuroprotective capacities, and accelerated dosage-dependently the Aβ aggregation. Also, we presented here a complete study on the interaction of 8a, 8d, 8e, 8h and 8i with AChE. Through fluorescence emission studies, the binding sites number found to be 1, binding constants were calculated as 2.04 × 104, 2.22 × 104, 1.18 × 104, 9.8 × 103 and 3.2 × 104 M−1 and free energy change as −5.83, −5.91, −5.51, −5.41 and −6.12 kcal M−1 at 25 °C which were well agreed with the computational calculations indicating a strong binding affinity of flavones and AChE. Furthermore, the CD studies revealed that the secondary structure of AChE became partly unfolded upon binding with 8a, 8d, 8e, 8h and 8i.Graphical abstractGraphical abstract for this article
  • Excavating precursors from the traditional Chinese herb Polygala
           tenuifolia and Gastrodia elata: Synthesis, anticonvulsant activity
           evaluation of 3,4,5-trimethoxycinnamic acid (TMCA) ester derivatives
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Zefeng Zhao, Yajun Bai, Jing Xie, Xufei Chen, Xirui He, Ying Sun, Yujun Bai, Yangyang Zhang, Shaoping Wu, Xiaohui Zheng Epilepsy is a group of neurological disorders characterized by recurrent seizures that disturbs about 60 million people worldwide. In this article, a novel series of 3,4,5-trimethoxycinnamic acid (TMCA) ester derivatives 1–35 were designed inspired from the traditional Chinese herb pair drugs Polygala tenuifolia and Gastrodia elata and synthesized followed by in vivo and in silico evaluation of their anticonvulsant potential. All the synthesized derivatives were biologically evaluated for their anticonvulsant potential using two acute model of seizures induced in mice, the maximal electroshock (MES) and sc-pentylenetetrazole (PTZ) models. Simultaneously, the motor impairment as a surrogate of acute neurotoxicity and in vitro screening of cytotoxicity against HepG-2 cells line were assessed through the rotarod performance test and CCK-8 assay, respectively. In addition, the physicochemical and pharmacokinetic parameters of the active compounds were determined. Our results showed that compounds 5, 7, 8, 13, 20, 25, 28, 30 and 32 exhibited preferable anticonvulsant activity in primary evaluation, with compounds 28 and 32 being the most promising anticonvulsant agents in according to results of subsequent pharmacology and toxicity evaluation. Additionally, the molecular modeling experiments predicted good binding interactions of part of the obtained active molecules with the gamma-aminobutyric acid (GABA) transferas. Therefore, it could be concluded that the synthesized derivatives 28 and 32 would represent useful lead compounds for further investigation in the development of anticonvulsant agents.Graphical abstractGraphical abstract for this article
  • Tetrahydro-1H,5H-pyrazolo[1,2-a]pyrazole-1-carboxylates as inhibitors of
           Plasmodium falciparum dihydroorotate dehydrogenase
    • Abstract: Publication date: Available online 15 May 2019Source: Bioorganic ChemistryAuthor(s): Nika Strašek, Lara Lavrenčič, Andraž Oštrek, Dejan Slapšak, Uroš Grošelj, Marina Klemenčič, Helena Brodnik Žugelj, Jernej Wagger, Marko Novinec, Jurij Svete The reactions between 5-substituted pyrazolidine-3-ones, aldehydes, and methyl methacrylate provided tetrahydropyrazolo[1,2-a]pyrazole-1-carboxylates as mixtures of syn- and anti-diastereomers. Testing for inhibition of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH) revealed high activity of some anti-isomers of the methyl esters, while the corresponding carboxylic acids and carboxamides were not active. The most active representative, methyl (1S*,3S*,5R*)-1,5-dimethyl-7-oxo-3-phenyltetrahydro-1H,5H-pyrazolo[1,2-a]pyrazole-1-carboxylate (IC50 = 2.9 ± 0.3 μM), also exhibited very high selectivity of the parasite enzyme vs. the human enzyme, PfDHODH/HsDHODH> 350. According to the molecular docking score, this high activity is explainable by synergic interactions of the methyl, phenyl and the CO2Me substituent with the hydrophobic pockets in the active site of the enzyme. The carboxylic acid and carboxamides derived from this compound did not inhibit PfDHODH.Graphical abstractGraphical abstract for this article
  • Syntesis of thio- and seleno-acetamides bearing benzenesulfonamide as
           potent inhibitors of human carbonic anhydrase II and XII
    • Abstract: Publication date: Available online 15 May 2019Source: Bioorganic ChemistryAuthor(s): Damiano Tanini, Antonella Capperucci, Martina Scopelliti, Andrea Milaneschi, Andrea Angeli, Claudiu T. Supuran A novel series of thio- and seleno-acetamides bearing benzenesulfonamide were synthetized and tested as human carbonic anhydrase inhibitors. These compounds were tested for the inhibition of four human (h) isoforms, hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX/XII). Several derivatives showed potent inhibition activity in low nanomolar range such as 3a, 4a, 7a and 8a. Furthermore, based on the tail approach we explain the interesting and selective inhibition profile of compound such as 5a and 9a, which were more selective for hCA I, 9b which was selective for hCA II, 3f selective for hCA IX and finally, 3e and 4b selective for hCA XII, over the other three isoforms. They are interesting leads for the development of more effective and isoform-selective inhibitors.Graphical abstractGraphical abstract for this article
  • Synthesis and In Vitro Anticancer Evaluation of Some Fused Indazoles,
           Quinazolines and Quinolines as Potential EGFR Inhibitors
    • Abstract: Publication date: Available online 15 May 2019Source: Bioorganic ChemistryAuthor(s): Esraa A. Abdelsalam, Wafaa A. Zaghary, Kamilia M. Amin, Nageh A. Abou Taleb, Amal A.I. Mekawey, Wagdy M. Eldehna, Hatem A. Abdel-Aziz, Sherif F. Hammad derivatives of benzo[g]indazole 5a, b, benzo[h]quinazoline 7, 12a-c, 13a-c and 15a-c and benzo[h]quinoline 17a-c and 19a-c were synthesized from 6-methoxy-3,4-dihydronaphthalen-1(2H)-one (1). Anticancer activity of all the synthesized compounds was evaluated against four cancerous cell lines; HepG2, MCF-7, HCT116 and Caco-2. MCF-7 cells emerged as the most sensitive cell line against the target compounds. All the examined compounds, except 5a and 5b, displayed potent to moderate anticancer activity against MCF-7 cells with an IC50 values ranging from 7.21 to 21.55 µM. In particular, compounds 15c and 19b emerged as the most potent derivatives against EGFR-expressing MCF-7 cells with IC50 values = 7.70 ± 0.39 and 7.21 ± 0.43 μM, respectively. Additionally, both compounds did not display any significant cytotoxicity towards normal BHK-21 fibroblast cells (IC50 value>200 µM), thereby providing a good safety profile as anticancer agents. Furthermore, compounds 15c and 19b displayed potent inhibitory activity towards EGFR in the sub-micromolar range (IC50 = 0.13 ± 0.01 and 0.14 ± 0.01 μM, respectively), compared to that of Erlotinib (IC50 = 0.11 ± 0.01 μM). Docking studies for 15c and 19b into EGFR active site was carried out to explore their potential binding modes. Therefore, compounds 15c and 19b can be considered as interesting candidates for further development of more potent anticancer agents.Graphical abstractGraphical abstract for this article
  • Design and synthesis of new benzoxazole/benzothiazole-phthalimide hybrids
           as antitumor-apoptotic agents
    • Abstract: Publication date: Available online 10 May 2019Source: Bioorganic ChemistryAuthor(s): John N. Philoppes, Phoebe F. Lamie Herein, we synthesized a series of twelve benzoxazole and benzothiazole derivatives incorporated with phthalimide core as anticancer agents. The most active compounds were 5a and 5g against HepG2 and MCF7 cell lines with IC50 = 0.011 and 0.006 μM, respectively.They evaluated against EGFR and HER2 enzymes. From cell cycle analysis, it was observed that test compounds exerted pre G1 apoptosis and cell cycle arrest at G2/M phase. The achieved results suggested that apoptosis was due to activation of caspase-7 and caspase-9. EGFR was chosen as a biological target for carrying molecular modeling study for the newly synthesized compounds.Graphical abstractGraphical abstract for this article
  • Chiral β-lactam-based integrin ligands through Lipase-catalysed kinetic
           resolution and their enantioselective receptor response
    • Abstract: Publication date: Available online 9 May 2019Source: Bioorganic ChemistryAuthor(s): Giulia Martelli, Paola Galletti, Monica Baiula, Luca Calcinari, Giacomo Boschi, Daria Giacomini Obtainment and testing of pure enantiomers are of great importance for bioactive compounds, because of the assessed implications of enantioselectivity in receptor-mediated responses. Herein we evaluated the use of biocatalysis to obtain enantiomerically pure β-lactam intermediates further exploited in the synthesis of novel integrin ligands as single enantiomers. From a preliminary screening on a set of commercially available hydrolases, Burkholderia Cepacia Lipase (BCL) emerged as a suitable and highly performing enzyme for the kinetic resolution of a racemic azetidinone, key intermediate for the synthesis of novel agonists of integrins. Upon optimization of the biocatalytic protocol in terms of enzymes, acylating agents and procedures, the two β-lactam enantiomers were obtained in excellent enantiomeric excesses (94% and 98% ee). Synthetic elaborations on the separated enantiomers allowed the synthesis of four chiral β-lactams which were evaluated in cell adhesion assays on Jurkat cell line expressing α4β1 integrin, and K562 cell line expressing α5β1 integrin. Biological tests revealed that only (S)-enantiomers maintained the agonist activity of racemates with a nanomolar potency, and a specific enantio-recognition by integrin receptors was demonstrated.Graphical abstractGraphical abstract for this article
  • Synthesis of Oxazolidinone from Enantiomerically Enriched Allylic Alcohols
           and Determination of Their Molecular Docking and Biologic Activities
    • Abstract: Publication date: Available online 9 May 2019Source: Bioorganic ChemistryAuthor(s): Ufuk Atmaca, Rüya Kaya, Halide Sedef Karaman, Murat Çelik, İlhami Gülçin Enantioselective synthesis of functionalized cyclic allylic alcohols via kinetic resolution in transesterifcation with different lipase enzymes has been developed. The influence of the enzymes and temperature activity was studied. By determination of ideal reaction conditions, byproduct formation is minimized; this made it possible to prepare enantiomerically enriched allylic alcohols in high ee's and good yields. Enantiomerically enriched allylic alcohols were used for enantiomerically enriched oxazolidinone synthesis. Using benzoate as a leaving group means that 1 mol % of potassium osmate is necessary and can be obtained high yields 98%. Inhibitory activities of enantiomerically enriched oxazolidinones (8, 10 and 12) were tested against human carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE), and α-glycosidase (α-Gly) enzymes. These enantiomerically enriched oxazolidinones derivatives had Ki values in the range of 11.6±2.1-66.4±22.7 nM for hCA I, 34.1±6.7-45.2±12.9 nM for hCA II, 16.5±2.9 to 35.6±13.9 for AChE, and 22.3±6.0-70.9±9.9 nM for α-glycosidase enzyme. Moreover, they had high binding affinity with -5.767, -6.568, -9.014, and -8.563 kcal/mol for hCA I, hCA II, AChE and α-glycosidase enzyme, respectively. These results strongly supported the promising nature of the enantiomerically enriched oxazolidinones as selective hCA, AChE, and α-glycosidase inhibitors. Overall, due to these derivatives’ inhibitory potential on the tested enzymes, they are promising drug candidates for the treatment of diseases like glaucoma, leukemia, epilepsy; Alzheimer’s disease; type-2 diabetes mellitus that are associated with high enzymatic activity of CA, AChE, and α-glycosidase.Graphical abstractIn this study, synthesis, characterization, molecular docking and biological activivtes of some enantiomerically enriched oxazolidinones were achieved. Also, inhibition effects of novel copounds were inwestigated against the carbonic anhydrase I, and II isoenzymes, acetylcholinesterase and α-glycosidase enzymes.Graphical abstract for this article
  • Synthesis, molecular modeling and biological evaluation of new
           pyrazolo[3,4-b]pyridine analogs as potential antimicrobial,
           antiquorum-sensing and anticancer agents
    • Abstract: Publication date: Available online 8 May 2019Source: Bioorganic ChemistryAuthor(s): N.S. El-Gohary, M.T. Gabr, M.I. Shaaban New pyrazolo[3,4-b]pyridine analogs 2-9 were synthesized and subjected to antimicrobial testing toward chosen Gram-negative bacteria, Gram-positive bacteria and fungi. Compound 2 exhibited potent and extended-spectrum antimicrobial activity. Further, 6 and 9c demonstrated remarkable and extended-spectrum antibacterial activity. Antiquorum-sensing activity of the new members was tested over C. violaceum, whereas 9c demonstrated strong efficacy, while 2, 8b and 9b displayed moderate efficacy. In vitro anticancer assay toward HepG2, MCF-7 and Hela cancer cells manifested that 2 and 9c are powerful and extended-spectrum anticancer agents. Additionally, 8a, 8b and 9b showed excellent activity toward the three cancer cells. In vivo anticancer assay over EAC in mice indicated that 2 and 9c have the greatest activity. Moreover, cytotoxicity assay over WISH and W138 normal cells clarified that the checked analogs possess weak cytotoxicity toward the two normal cells. DNA-binding affinity was also tested, whereas 2, 3, 8b, 9b and 9c demonstrated great affinity. Molecular modeling studies revealed that the investigated compounds bind to DNA through intercalation similarly to doxorubicin. In silico studies revealed that the new members are anticipated to show excellent intestinal absorption.Graphical abstractGraphical abstract for this article
  • Follow on-based optimization of the biphenyl-DAPYs as HIV-1 nonnucleoside
    • Abstract: Publication date: Available online 4 May 2019Source: Bioorganic ChemistryAuthor(s): Yali Sang, Sheng Han, Shuwen Han, Christophe Pannecouque, Erik De Clercq, Chunlin Zhuang, Fener Chen The present work follows our preliminary discovery of biphenyl diarylpyrimidines (DAPYs) as HIV-1 nonnucleoside reverse transcriptase inhibitors. Further structural optimization of biphenyl-DAPYs led to the identification of a new series of biphenyl-substituted thiophene[3,2-d]pyrimidine analogues by a scaffold-hopping strategy. Biological evaluation of this series showed that these compounds possessed up to single-digit nanomolar potency (EC50 = 7.8∼526.2 nM) and prominently low toxicity (CC50 = 18.5∼280.8 μM) against wild-type (WT) HIV-1-infected cells. Furthermore, the results also demonstrated that compounds 29-32 exhibited high, broad-spectrum antiviral effects against clinically observed HIV-1 mutants. Specifically, compound 30, which had the highest selectivity index (SI = 16094) and the best anti-reverse transcriptase ability (IC50 = 39 nM), displayed marked inhibitory activity (EC50 = 13.5, 9.4, 17.0, 52.0, and 58.2 nM) against WT, K103N, E138K, L100I, Y181C mutants and moderate activity against double mutants. This study provides important avenues for the further design of HIV-1 inhibitors.Graphical abstractGraphical abstract for this article
  • Discovery of novel (+)-Usnic acid derivatives as potential anti-leukemia
           agents with pan-Pim kinases inhibitory activity
    • Abstract: Publication date: Available online 2 May 2019Source: Bioorganic ChemistryAuthor(s): Shuxiang Wang, Jie Zang, Min Huang, Lihong Guan, Kun Xing, Jian Zhang, Dan Liu, Linxiang Zhao Usnic acid (UA) is the main secondary metabolite isolated from lichens, with moderate anticancer activity. A small group of (+)-UA derivatives characterized with flavanone moiety was designed and synthesized, and their anticancer activities were evaluated in leukemia cells. It was demonstrated that (+)-UA derivatives 6a-6g inhibited the proliferation of leukemia cells HL-60 and K562 with low micromolar IC50 values. Mechanisms of action were investigated to find that 6g induced apoptosis in HL-60 and K562 cell lines, and affected the expression of MNK/eIF4E axis-related proteins, such as Mcl-1, p-eIF4E, p-4E-BP1. Finally, kinase inhibition assay suggested 6g was a potential inhibitor of pan-Pim kinases. Meanwhile, the blocking of phosphorylation of BAD and 4E-BP1 by 6g, together with the proposed binding mode of 6g with Pim-1 further confirmed its Pim inhibition effects. Our finding provides the sight towards the potential mechanism of (+)-UA derivatives 6g as anti-leukemia agents.Graphical abstractGraphical abstract for this article
  • Phytosynthesis of silver nanoparticles using Mangifera indica flower
           extract as bioreductant and its broad-spectrum antibacterial activity
    • Abstract: Publication date: Available online 2 May 2019Source: Bioorganic ChemistryAuthor(s): Fuad Ameen, P. Srinivasan, T. Selvankumar, S. Kamala-Kannan, S. Al Nadhari, A. Almansob, T. Dawoud, M. Govarthanan The present study focused on the evaluation of antibacterial property of silver nanoparticles (AgNPs) synthesized using mango flower extract. The morphology of the synthesized AgNPs was observed under transmission electron microscopy and the particles have shown spherical shape in the range of 10-20 nm. X-ray powder diffraction analysis confirmed the crystalline nature of the AgNPs. The atomic percentage of the Ag element in the nanoparticles was about 7.58% which is greater than the other elements present in the sample. The AgNPs showed extensive lethal effect on both Gram-positive (Staphylococcus sp.) and Gram negative (Klebsiella sp., Pantoea agglomerans, and Rahnella sp.) bacteria. The extensive lethal effect of AgNPs against clinically important pathogens demonstrated that the mango flower mediated AgNPs could be applied as potential antibacterial agent to control the bacterial population in the respective industries.Graphical abstractGraphical abstract for this article
  • Discovery of pyrazolopyrimidine derivatives as potent BTK inhibitors with
           effective anticancer activity in MCL
    • Abstract: Publication date: Available online 25 April 2019Source: Bioorganic ChemistryAuthor(s): Fansheng Ran, Yang Liu, Meixia Liu, Daoguang Zhang, Peng Wang, Junze Dong, Wendi Tang, Guisen Zhao Bruton’s tyrosine kinase (BTK) is a key regulator of B-cell receptor (BCR) signaling pathway and takes effect in the regulation of B-cell activation, survival, proliferation and differentiation. It has been proved that BTK is commonly overexpressed in mantle cell lymphoma (MCL), which makes it a focus of targeted therapy for MCL. Our studies yielded a novel series of pyrazolopyrimidine derivatives capable of potent inhibition of BTK. Notably, 12a showed higher selectivity against BTK and exhibited robust antiproliferative effects in both mantle cell lymphoma cell lines and primary patient tumor cells. Low micromolar doses of 12a induced strong cell apoptosis in Jeko-1 and Z138 cells.Graphical abstractGraphical abstract for this article
  • Three New Methylated Δ8-pregnene Steroids from the Polyalthia
           laui-Derived Fungus Stemphylium sp. AZGP4-2
    • Abstract: Publication date: Available online 16 April 2019Source: Bioorganic ChemistryAuthor(s): Rong-Li Huang, Cai-Juan Zheng, Xue-Ming Zhou, Xin-Ming Song, Ping-Ping Wu, Yi-Fang Zhao, Guang-Ying Chen, Xiao-Ping Song, Chang-Ri Han Three new methylated Δ8-pregnene steroids, stemphylisteroids A–C (1–3) were isolated from the medicinal plant Polyalthia laui-derived fungus Stemphylium sp. AZGP4-2. Their structures were elucidated by the detailed analysis of comprehensive spectroscopic data. The absolute configuration of 1 was determined by X-ray crystallographic analysis. Compound 1 show antibacterial activity against Escherichia coli with the MIC value of 6.25 μg/mL, and 2 exhibited a broad spectrum of antibacterial activities against six pathogenic bacteria with the MIC values ranging from 12.5 to 50 μg/mL. The discovery of three methylated Δ8-pregnene steroids 1–3 are a further addition to diverse and complex array of methylated steroids.Graphical abstractGraphical abstract for this article
  • Hydrolysis of surfactin over activated carbon
    • Abstract: Publication date: Available online 3 April 2019Source: Bioorganic ChemistryAuthor(s): Hanna Fałtynowicz, Paweł Hodurek, Jan Kaczmarczyk, Marek Kułażyński, Marcin Łukaszewicz Surfactin is obtained through biocatalysis by microorganisms. In our biorefinery concept, it is purified on activated carbon (AC) during downstream processing. Besides cyclic surfactin, it is possible to obtain linear surfactin analogues, when AC with specific properties is used. In the present article, the hydrolysis of various cyclic surfactin analogues mediated by activated carbon is described. Hydrolysis products were identified using HPLC/UV/MS and (Q-TOF)MS/MS. Hydrolytic activity of six commercial and three modified activated carbons was evaluated. The porous texture of ACs was determined by sorption measurements and elemental composition of ACs surface – by SEM-EDS analysis. Their pHPZC value and moisture, ash, and volatile matter content using proximate analysis were also determined. Properties of ACs were correlated with their hydrolytic activity, and the crucial role of alkaline pHPZC was found. The beneficial effect of alkaline pHPZC was further confirmed by acid modification of AC that had previously shown hydrolytic activity and lost this ability after the pHPZC decrease.Graphical abstractGraphical abstract for this article
  • Rational design, synthesis and biological evaluation of ubiquinone
           derivatives as IDO1 inhibitors
    • Abstract: Publication date: Available online 20 March 2019Source: Bioorganic ChemistryAuthor(s): Yuyang Ding, Fei Tang, Xiaoqian Xue, Jinfeng Luo, Muzammal Hussain, Yanhui Huang, Zhen Wang, Hao Jiang, Zhengchao Tu, Jiancun Zhang Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive therapeutic target for the treatment of cancer, chronic viral infections and neurological disorders characterized by pathological immune stimulation. Herein, a series of known metal-chelating ubiquinone derivatives were designed, synthesized and evaluated for the IDO1 inhibiting activities. The docking studies showed that the compounds 11, 16, 18 and coenzyme-Q1 exhibited different binding modes to IDO1 protein. Among these compounds, the most active compound is 16d with an IC50 of 0.13 μM in enzymatic assay. The results reveal that a possible halogen bonding interaction between the bromine atom (3-Br) and Cys129 significantly enhances the inhibition activity against IDO1. This study provides structural insights of the interactions between ubiquinone analogues and IDO1 protein for the further modification and optimization.Graphical abstractGraphical abstract for this article
  • N-phosphonomethylglycine utilization by the psychrotolerant yeast
           Solicoccozyma terricola M 3.1.4.
    • Abstract: Publication date: Available online 20 March 2019Source: Bioorganic ChemistryAuthor(s): Natalia Stosiek, Agata Terebieniec, Adam Ząbek, Piotr Młynarz, Hubert Cieśliński, Magdalena Klimek-Ochab Solicoccozyma terricola M 3.1.4., the yeast strain isolated from soil sample from blueberry cultivation in Miedzyrzec Podlaski in Poland, is capable to split of phosphorus to nitrogen and nitrogen to carbon bonds in N-phosphonomethylglycine (PMG, glyphosate). The biodegradation process proceeds in the phosphate-independent manner. It is the first example of a psychrotolerant yeast strain able to degrade PMG via CN bond cleavage accompanied by AMPA formation and not like in most microorganisms via CP bond disruption followed by the sarcosine pathway. Glyphosate oxidoreductase (GOX) type activity was detected in cell-free extracts prepared from S. terricola M 3.1.4. pregrown on 4 mM PMG as a sole phosphorus and nitrogen source in cultivation medium.Graphical abstractGraphical abstract for this article
  • Biotransformation of rapeseed meal leading to production of polymers,
           biosurfactants, and fodder
    • Abstract: Publication date: Available online 18 March 2019Source: Bioorganic ChemistryAuthor(s): Damian Konkol, Ida Szmigiel, Marta Domżał-Kędzia, Marek Kułażyński, Anna Krasowska, Sebastian Opaliński, Mariusz Korczyński, Marcin Łukaszewicz After extracting the oil from rapeseed, the remaining meal byproduct is used in animal feed, particularly for cattle, and represents an effective, high-protein substitute for soybean meal. The biotransformation of rapeseed meal using Generally Recognized as Safe (GRAS) bacteria increases its nutritional value and enriches it with a variety of additives including polymers, biosurfactants, and enzymes. Polymers produced in SSF process with rapeseed meal (e.g., levan) have probiotic prosperities and can even serve as alternatives to antibiotics, which are banned from animal feed by law. Due to their moisturizing properties, these polymers are also incorporated into cosmetics. The biosurfactants produced by bacteria and yeast confer their strong antimicrobial effects to preserve the feed. In turn, the many enzymes produced during the biotransformation of rapeseed meal increase its nutritional value by reducing fibers, detrimental substances (e.g., tannins, erucic acid, phytic acid), and mycotoxins. Taken together, rapeseed meal biotransformation results in numerous benefits, for the animal and industry alike.Graphical abstractGraphical abstract for this article
  • Synthesis, Modeling and Biological Evaluation of Some
           Pyrazolo[3,4-d]pyrimidinones and
           Pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinones as Anti-inflammatory
    • Abstract: Publication date: Available online 12 March 2019Source: Bioorganic ChemistryAuthor(s): Gina N. Tageldin, Tamer M. Ibrahim, Salwa M. Fahmy, Hayam M. Ashour, Mounir A. Khalil, Rasha A. Nassra, Ibrahim M. Labouta New pyrazolo[3,4-d]pyrimidinone and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinone derivatives were synthesized. They have been evaluated for their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay. Moreover, compounds with promising in vitro activity and COX-1/COX-2 selectivity indices were subjected for in vivo anti-inflammatory testing using formalin induced paw edema and cotton-pellet induced granuloma assays for acute and chronic models, respectively. Compounds (2c, 3i, 6a, 8 and 12) showed promising COX-2 inhibitory activity and high selectivity compared to celecoxib. Most of the compounds exhibited potential anti-inflammatory activity for both in vivo acute and chronic models. Almost all compounds displayed safe gastrointestinal profile and low ulcerogenic potential guided by histopathological examination. Furthermore, molecular docking experiments rationalized the observed in vitro anti-inflammatory activity of selected candidates. In silico predictions of the pharmacokinetic and drug-likeness properties recommended accepted profiles of the majority of compounds. In conclusion, this work provides an extension of the chemical space of pyrazolopyrimidinone and pyrazolotriazolopyrimidinone chemotypes for the anti-inflammatory activity.Graphical abstractGraphical abstract for this article
  • Hollow silica microspheres as robust immobilization carriers
    • Abstract: Publication date: Available online 2 March 2019Source: Bioorganic ChemistryAuthor(s): Wojciech Snoch, Mateusz Tataruch, Olga Zastawny, Ewelina Cichoń, Mathilde Gosselin, Hubert Cabana, Maciej Guzik Hollow silica microspheres provide an ideal solid support for enzyme immobilization. We tested one of the newest development, namely MATSPHERES®, a silica openwork material as a carrier for the covalent immobilization of enzymes used to synthesize bioactive compounds. Two model enzymes – ethylbenzene dehydrogenase and EL070 lipase – were considered. They belong to two different enzyme classes and catalyse reactions taking place in various environments (aqueous and non-aqueous, aerobic and anaerobic). The enzymes were immobilized by covalent bonds (via divinyl sulfone and glutaraldehyde) on new silica material. Effectiveness of immobilization processes on the spheres grafted with amine groups and on the analogues without functionalization was determined for both enzymes. Microspheres were characterized morphologically and also their mechanical stability was examined during exposure to varying physical conditions. It was shown that MATSPHERES® due to their openwork structure and relative stability under batch and flow conditions can be a competitive SBA support for enzyme immobilization and production of bioactive compounds.Graphical abstractGraphical abstract for this article
  • The studies on chemoselective promiscuous activity of hydrolases on
           acylals transformations
    • Abstract: Publication date: Available online 27 February 2019Source: Bioorganic ChemistryAuthor(s): Dominik Koszelewski, Ryszard Ostaszewski Chemoselective, mild and convenient protocol for the hydrolysis of the synthetically relevant acylals via promiscuous enzyme-catalyzed hydrolysis has been developed. It has been shown that promiscuous activity of the used hydrolases dominates their native activity related with carboxylic esters hydrolysis. The main advantage of the present methodology is that it can be conducted under neutral conditions at room temperature. Moreover, complete deprotection of acylals takes place within 10–20 min. Developed protocol can be used with compounds having a variety of hydrolytic labile groups since the cleavage is proceeded under neutral conditions and occurs exclusively on acylal moiety. Further this protocol was extended by the tandem Passerini multicomponent reaction leading to the α-acetoxy amides using acylals as the surrogates of the carbonyl components to P-MCR.Graphical abstractGraphical abstract for this article
  • Reductive capabilities of different cyanobacterial strains towards
           acetophenone as a model substrate – Prospect of applications for chiral
           building blocks synthesis
    • Abstract: Publication date: Available online 26 February 2019Source: Bioorganic ChemistryAuthor(s): Ewa Żymańczyk-Duda, Agata Głąb, Monika Górak, Magdalena Klimek-Ochab, Małgorzata Brzezińska-Rodak, Daniel Strub, Agnieszka Śliżewska Bioreductive capabilities of four morphologically different strains of cyanobacteria have been assessed in this work. Arthrospira maxima, Leptolyngbya foveolarum, Nodularia sphaerocarpa and Synechococcus bigranulatus were applied as catalysts for the reduction of acetophenone to the corresponding chiral phenylethyl alcohol. The process was modified regarding substrate concentration, duration of pre-cultivation period, duration of biotransformation, light regime and glucose addition to the culture media. Obtained results clearly showed that cyanobacteria were active towards acetophenone what resulted in the substrate reduction to (S)-1-phenylethanol with high enantiomeric excess. The reaction efficiency increased with the biotransformation time, but the higher concentration of substrate limited the process yield. Also, all tested strains performed reaction with the highest efficacy under continuous light regime. The most active strains – N. sphaerocarpa and S. bigranulatus carried out the conversion of 1 mM acetophenone with high efficiency of respectively 97.6% and 96.2% after 13 days of biotransformation. A. maxima reached 45.8% of conversion after 13 days of biotransformation whereas L. foveolarum did not exceed 20%. The enantiomeric excesses were respectively 98.8%- A. maxima, 91.7%- L. foveolarum, 72.6%- S. bigranulatus and N. sphaerocarpa 16.2%.Graphical abstractGraphical abstract for this article
  • The influence of the isocyanoesters structure on the course of enzymatic
           Ugi reactions
    • Abstract: Publication date: Available online 26 February 2019Source: Bioorganic ChemistryAuthor(s): Monika Wilk, Anna Brodzka, Dominik Koszelewski, Arleta Madej, Daniel Paprocki, Anna Żądło-Dobrowolska, Ryszard Ostaszewski The impact of isocyanoesters structure on enzymatic three-component Ugi reactions course has been determined. The significant promiscuous ability of enzyme in Ugi-type reaction switching between four (U-4CR) and three (U-3CR) components reactions depending on the size of used isocyanoester. The application of short-chain cyanoesters up to isocyanpropionate leading to product of three component reaction exclusively while longer isocyanobutyrate gives only the product of four component reaction. The limitation of studied enzymatic Ugi reaction is a substrate selectivity of lipases.Graphical abstractGraphical abstract for this article
  • The possible mechanism of the formation of silver nanoparticles by
           Penicillium cyclopium
    • Abstract: Publication date: Available online 22 February 2019Source: Bioorganic ChemistryAuthor(s): Ewelina Wanarska, Irena Maliszewska This contribution describes the biomineralization of silver nanoparticles by the microbial reduction of Ag (I) ions using the mycelium and the cell-free extract of Penicillium cyclopium. Different techniques, such as UV–Vis, SEM, TEM, FT-IR and GPC were used to characterize the obtained nanoparticles and understand the mechanism of their biosynthesis. The SEM and TEM images demonstrated the presence of silver nanoparticles on the mycelia surface suggesting that these particles are synthesized on the fungal cell wall. FT-IR analysis of the mycelium revealed two main types of compounds (saccharides and proteins) and these molecules might be involved in the formation of silver nanoparticles on the surface of mycelium. Ultraviolet–visible spectroscopy and TEM analysis confirmed the formation of silver nanoparticles with different shapes by the cell-free extract of P. cyclopium. Their size ranges from 12 to 25 nm and possess an average size of 16 ± 6 nm. GPC analysis of this filtrate revealed a few peaks responsible for polysaccharides and proteins presence. The only protein fraction with the mass approximately to 5000 Da indicated the formation of silver nanoparticles. Polypeptide(s) as the major molecules involved in biomineralization of silver by the cell-free extract of P. cyclopium are suggested. Enzymatic synthesis of silver nanoparticles by the mycelium and the cell-free extract of P. cyclopium is excluded.Graphical abstractGraphical abstract for this article
  • Synthesis of (E)-α,β-unsaturated carboxylic esters derivatives from
           cyanoacetic acid via promiscuous enzyme-promoted cascade
           esterification/Knoevenagel reaction
    • Abstract: Publication date: Available online 22 February 2019Source: Bioorganic ChemistryAuthor(s): Monika Wilk, Damian Trzepizur, Dominik Koszelewski, Anna Brodzka, Ryszard Ostaszewski A new enzymatic protocol based on lipase-catalyzed cascade toward (E)-α,β-unsaturated carboxylic esters is presented. The proposed methodology consists of elementary organic processes starting from acetals and cyanoacetic acid leading to the formation of desired products in a cascade sequence. The combination of enzyme promiscuous abilities gives a new opportunity to synthesize complex molecules in the one-pot procedure. Results of studies on the influence of an enzyme type, solvent, and temperature on the cascade reaction course are reported. The presented methodology provides meaningful qualities such as significantly simplified process, excellent E-selectivity of obtained products and recycling of a biocatalyst.Graphical abstractGraphical abstract for this article
  • Determination of mechanisms of action of active carbons as a feed additive
    • Abstract: Publication date: Available online 16 February 2019Source: Bioorganic ChemistryAuthor(s): Ewa Burchacka, Marcin Łukaszewicz, Marek Kułażyński Activated carbon’s porous structure allows it to adsorb a substrates, products and catalysts from the environment thus modificated the biocatalysis processes in digestive tract. Active carbons are currently used to remove solvents from gas streams and for water purification; however, few studies have examined the mechanisms of action of active carbon during the biotransformation processes in the digestive tracks. The potential benefits of using activated carbon in feed are uncertain because both its chemical and physical properties can vary significantly depending on the type of carbonaceous feedstock. However, the use of active carbons as dietary supplements can also bring many benefits during biotransformation processes in the gastrointestinal tract. Active carbons can adsorb toxins from the gastrointestinal tract and reduce excessive intestinal gas accumulation. The study concerning the adsorption of bacteria and vitamins on the porous structure of various species of active carbons is an important factor to determine their mechanism of action in biocatalysis in digestive system. The use of properly modified activated carbons as feed additives may have a beneficial effect on the development and functioning of breeding animals in the future.The results of our research show that the active carbon obtained from beech (KB), which contained, on average, 14% oxygen content by weight adsorbed bacteria, such as E. coli and S. aureus, better than all the other active carbons tested. Moreover, the meso- and macropores of carbon seem to contribute little to bacterial adsorption by active carbons. The electron microscopy studies confirmed that the bacteria adhered mainly to the active carbon surface. Our results also indicate that the examined active carbons from beech (KB), coconut shells (TE50), and hard coal (RB2) do not adsorb (or adsorb with very limited efficiency) the vitamins that are routinely added to feed, such as A, B1, D, and K. Broilers fed with feed mixtures supplemented with activated carbon (KB) resulted in increases in the weight of the chickens (∼2%) after 14 days of application and 2% lower feed consumption (conversion) relative to a control sample. Our data indicate that modifying the surface area and elementary content of active carbon may affect its specificity and selectivity and its capacity to absorb particles used in veterinary, human pharmacy, and cosmetology.Graphical abstractGraphical abstract for this article
  • A facile lipase-catalyzed KR approach toward enantiomerically enriched
           homopropargyl alcohols
    • Abstract: Publication date: Available online 11 February 2019Source: Bioorganic ChemistryAuthor(s): Paweł Borowiecki, Maciej Dranka Compounds possessing propargylic (prop-2-ynylic) system are very important building blocks for organic chemistry. Among them, preparation of enantiomeric homopropargyl alcohols (but-3-yn-1-ols) constitutes a key-challenge for asymmetric synthesis and thus drawn tremendous attention from the synthetic community in the last few decades. In this work, the catalytic performance of a set of commercial lipases has been investigated for enantioselective transesterification of 1-phenylhomopropargylic alcohols under kinetically–controlled conditions. Lipase from Burckholderia cepacia (BCL) immobilized either on ceramic (Amano PS-C II) or diatomaceous earth (Amano PS-IM) turned out to be the most active and enantioselective enzyme preparations (E ≫ 500) furnishing both resolution products of the racemic 1-phenylbut-3-yn-1-ol in highly enantiomerically enriched form (up > 99% ee). Variable reaction parameters, such as the acyl-group donor reagent as well as solvent, were additionally screened to establish their impact on the stereochemical outcome. For optimal biocatalytic systems established with model substrate, the enzymatic transformations were extended toward preparative-scale KR of 8 other differently para-phenyl-substituted homopropargylic sec-alcohols, which resulted in the synthesis of (S)-alcohols (96–100% ee) and the respective (R)-acetates (92–100% ee) in 19–44% yield, accordingly. Additionally, the crystal structure of (1R)-1-(4-nitrophenyl)but-3-yn-1-yl acetate has been evaluated for the first time and helped to assess stereopreference of the studied BCL.Graphical abstractGraphical abstract for this article
  • Fermentation parameters and conditions affecting levan production and its
           potential applications in cosmetics
    • Abstract: Publication date: Available online 11 February 2019Source: Bioorganic ChemistryAuthor(s): Marta Domżał-Kędzia, Agnieszka Lewińska, Anna Jaromin, Marek Weselski, Robert Pluskota, Marcin Łukaszewicz Levan is a polysaccharide composed of fructose units with β-2,6-glycoside bonds. Microorganisms synthesize levan by levansucrase as a mixture of low- and high-molecular-weight fractions. Due to its properties, it has a wide range of applications in cosmetics, pharmaceuticals, food and medicine; it appears that the molecular weight of levan might impact its industrial use. To obtain one fraction of levan after biotransformation, ethanol precipitation with an increasing volume of alcohol was conducted. This precipitation process was also optimized. Several types of analyses were used. Low-molecular-weight levan was evaluated for toxicity in a normal human dermal fibroblast cell line and hemolytic potential on human erythrocytes. Levan was found to be non-cytotoxic and non-hemolytic in concentrations ranging from 0.01 to 1.00 mg/ml. Moreover, levan demonstrated antioxidant potential expressed as an ability to inhibit of oil/water emulsion oxidation and DPPH radical scavenging.Graphical abstractGraphical abstract for this article
  • Bioconversion of xylose to xylonic acid via co-immobilized dehydrogenases
           for conjunct cofactor regeneration
    • Abstract: Publication date: Available online 7 February 2019Source: Bioorganic ChemistryAuthor(s): Karolina Bachosz, Karol Synoradzki, Maciej Staszak, Manuel Pinelo, Anne S. Meyer, Jakub Zdarta, Teofil Jesionowski Enzymatic cofactor-dependent conversion of monosaccharides can be used in the bioproduction of value-added compounds. In this study, we demonstrate co-immobilization of xylose dehydrogenase (XDH, EC and alcohol dehydrogenase (ADH, EC using magnetite-silica core-shell particles for simultaneous conversion of xylose into xylonic acid (XA) and in situ cofactor regeneration. The reaction conditions were optimized by factorial design, and were found to be: XDH:ADH ratio 2:1, temperature 25 °C, pH 7, and process duration 60 min. Under these conditions enzymatic production of xylonic acid exceeded 4.1 mM and was more than 25% higher than in the case of a free enzymes system. Moreover, the pH and temperature tolerance as well as the thermo- and storage stability of the co-immobilized enzymes were significantly enhanced. Co-immobilized XDH and ADH make it possible to obtain higher xylonic acid concentration over broad ranges of pH (6–8) and temperature (15–35 °C) as compared to free enzymes, and retained over 60% of their initial activity after 20 days of storage. In addition, the half-life of the co-immobilized system was 4.5 times longer, and the inactivation constant (kD = 0.0141 1/min) four times smaller, than those of the free biocatalysts (kD = 0.0046 1/min). Furthermore, after five reaction cycles, immobilized XDH and ADH retained over 65% of their initial properties, with a final biocatalytic productivity of 1.65 mM of xylonic acid per 1 U of co-immobilized XDH. The results demonstrate the advantages of the use of co-immobilized enzymes over a free enzyme system in terms of enhanced activity and stability.Graphical abstractGraphical abstract for this article
  • Regioselective O-glycosylation of flavonoids by fungi Beauveria bassiana,
           Absidia coerulea and Absidia glauca
    • Abstract: Publication date: Available online 7 February 2019Source: Bioorganic ChemistryAuthor(s): Sandra Sordon, Jarosław Popłoński, Tomasz Tronina, Ewa Huszcza In the present study, the species: Beauveria bassiana, Absidia coerulea and Absidia glauca were used in biotransformation of flavones (chrysin, apigenin, luteolin, diosmetin) and flavanones (pinocembrin, naringenin, eriodictyol, hesperetin). The Beauveria bassiana AM 278 strain catalyzed the methylglucose attachment reactions to the flavonoid molecule at positions C7 and C3′. The application of the Absidia genus (A. coerulea AM 93, A. glauca AM 177) as the biocatalyst resulted in the formation of glucosides with a sugar molecule present at C7 and C3′ positions of flavonoids skeleton. Nine of obtained products have not been previously reported in the literature.Graphical abstractGraphical abstract for this article
  • First biological conversion of chiral heterophosphonate derivative –
           Scaling and paths of conversion discussion
    • Abstract: Publication date: Available online 30 January 2019Source: Bioorganic ChemistryAuthor(s): Ewa Żymańczyk-Duda, Natalia Dunal, Małgorzata Brzezińska-Rodak, Angelika Osiewała, Tomasz K. Olszewski, Magdalena Klimek-Ochab, Monika Serafin-Lewańczuk Presented work describes the first approach for the biocatalytic resolution of racemic mixtures of heterophosphonate derivative. Penicillium funiculosum and Rhodotorula mucilaginosa were successfully applied for the biological conversion of racemic mixture of 1-amino-1-(3′-pyridyl)methylphosphonic acid 3. Both microorganisms carried out the kinetically driven process leading to conversion of one from the substrate enantiomers, leaving the second one unreacted. Application of R. mucilaginosa allowed obtaining pure enantiomer of the substrate (yield 100%, e.e 100% - unreacted isomer) after 24 h of biotransformation of 3 in the laboratory scale process (Method E), applying biocatalyst pre-treatment step − 24 h of starvation. In case of other biocatalyst, application of whole cells of P. funiculosum in laboratory scale process, also resulted in conversion of the racemic mixture of substrate 3 via oxidative deamination into ketone derivative, which was then bioreduced (second step of the process) into 1-hydroxy-1-(3′-pyridyl)methylphosphonic acid 4. This time two products were isolated: unreacted substrate and hydroxy compound 4. Conversion degree ranged from 30% (standard procedure, method A) to even 70% (with extra addition of sodium pyruvate - method B2). However, in this case, bioconversion was not enantioselective – products: amino- and hydroxyderivative were obtained as racemic mixtures. Both biocatalysts were also tested towards the scaling so other biocatalytic procedures were introduced - with immobilized fungal mycelium. In case of Rhodotorula mucilaginosa this approach failed (data not shown) but Penicillium funiculosum turned out to be active and also selective. Thus, application of this biocatalyst in the half-preparative scale, continuous-flow bioprocess (Method C2) resulted in the obtaining of pure S-3 (100% e.e.) isomer with the 100% of conversion degree, without any side products. Recorded NMR spectra allowed confirming the reaction progress and its selectivity and also postulating possible mechanism of conversion.Graphical abstractGraphical abstract for this article
  • Burkholderia cepacia lipase immobilization for hydrolytic reactions and
    • Abstract: Publication date: Available online 26 January 2019Source: Bioorganic ChemistryAuthor(s): Zofia Hrydziuszko, Daniel Jan Strub, Karolina Labus, Jolanta Bryjak The major drawbacks of native lipase applications in processes occurring in water or in organic solvents include: difficulties in catalyst recycling, low activity and operational instability. The immobilization of Burkholderia cepacia lipase by adsorption or covalent binding onto 5 differently functionalized carriers (silica, acrylic, cellulose-based) was performed to overcome this problem. The optimization of the reaction preparation in water-rich media was based on the hydrolytic reactivity of the preparations, as well as the thermal, operational and storage stabilities. Aminated silica carrier, activated with glutaraldehyde, was determined to be the carrier of choice. Regarding processes in water-restricted media, carrier selection was based on reactivity after drying and five preparations were chosen for the resolution of a non-equimolar isomer mixture (85:15 ratio of R to S isomers), treating the kinetic resolution of ((+)-(S/R)-1-[(1S,5R)-6,6-dimethylbicyclo[3.1.0]hex-2-en-2-yl)]ethanol as a model. The resulting acetate of R configuration exhibits interesting sensory properties. The operational stability of the chosen catalysts was tested over 15 consecutive batch processes; the most beneficial results were obtained with lipase adsorbed on an acrylic carrier. Conversion increased gradually from 10 to 84% over the first five processes, which could be explained by the product sorption onto the carrier. Full kinetic resolution with maximal substrate conversion (approximately 84%) was achieved and remained stable during the next 10 runs, an excellent result, and thus, the proposed system might be regarded as an exceptionally attractive solution for the perfume and cosmetic industries.Graphical abstractGraphical abstract for this article
  • Benzoxazinone-thiosemicarbazones as antidiabetic leads via aldose
           reductase inhibition: Synthesis, biological screening and molecular
           docking study
    • Abstract: Publication date: Available online 11 December 2018Source: Bioorganic ChemistryAuthor(s): Muhammad Tariq Shehzad, Aqeel Imran, Guy Sedar Singor Njateng, Abdul Hameed, Muhammad Islam, Mariya al-Rashida, Maliha Uroos, Asnuzilawati Asari, Zahid Shafiq, Jamshed Iqbal Aldose reductase is an important enzyme in the polyol pathway, where glucose is converted to fructose, and sorbitol is released. Aldose reductase activity increases in diabetes as the glucose levels increase, resulting in increased sorbitol production. Sorbitol, being less cell permeable tends to accumulate in tissues such as eye lenses, peripheral nerves and glomerulus that are not insulin sensitive. This excessive build-up of sorbitol is responsible for diabetes associated complications such as retinopathy and neuropathy. In continuation of our interest to design and discover potent inhibitors of aldo-keto reductases (AKRs; aldehyde reductase ALR1 or AKR1A, and aldose reductase ALR2 or AKR1B), herein we designed and investigated a series of new benzoxazinone-thiosemicarbazones (3a-r) as ALR2 and ALR1 inhibitors. Most compounds exhibited excellent inhibitory activities with IC50 values in lower micro-molar range. Compounds 3b and 3l were found to be most active ALR2 inhibitors with IC50 values of 0.52 ± 0.04 and 0.19 ± 0.03 μM, respectively, both compounds were more effective inhibitors as compared to the standard ALR2 inhibitor (sorbinil, with IC50 value of 3.14 ± 0.02 μM).Graphical abstractGraphical abstract for this article
  • Investigation of the interaction between salvianolic acid C and xanthine
           oxidase: Insights from experimental studies merging with molecular docking
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Hongjin Tang, Dongsheng Zhao Xanthine oxidase (XO) has emerged as an important target for gout. In our previous study, salvianolic acid C (SAC) was found to show potent XO inhibitory activity, whereas the interaction mechanism was still not clear. Herein, an integrated approach consisting of enzyme kinetics, multi-spectroscopic methods and molecular docking was employed to investigate the interaction between SAC and XO. Consequently, SAC exhibited a rapid and mixed-type inhibition of XO with IC50 of 5.84 ± 0.18 μM. The fluorescence data confirmed that SAC presented a strong fluorescence quenching effect through a static quenching procedure. The values of enthalpy change, entropy change and Gibbs free energy change indicated that their binding was spontaneous and driven mainly by hydrophobic interactions. Analysis of synchronous fluorescence, circular dichroism and fourier transform infrared spectra demonstrated that SAC induced conformational changes of the enzyme. Besides, further molecular docking revealed that SAC occupied the catalytic center resulting in the inhibition of XO activity. This study provides a comprehensive understanding on the interaction mechanism of SAC on XO.Graphical abstractGraphical abstract for this article
  • Synthesis and identification of quinoline derivatives as topoisomerase I
           inhibitors with potent antipsoriasis activity in an animal model
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Wen-Jin Zhang, Peng-Hui Li, Min-Cong Zhao, Yao-Hao Gu, Chang-Zhi Dong, Hui-Xiong Chen, Zhi-Yun Du Psoriasis is a chronic inflammatory and immune-mediated skin disease. Although certain agents have shown clinical success in treating psoriasis, development of safe and effective strategies for the treatment of this condition remains important. Research suggests that DNA topoisomerase I (Topo I) inhibitors may have potent psoriasis-ameliorating effects. Here, 25 quinoline derivatives were synthesized and identified as Topo I inhibitors. These compounds inhibited the 12–O–tetradecanoylphorbol-13-acetate-induced mouse ear inflammation. The most potent analogs, 5i and 5l, suppressed the expression of inflammatory cytokines in lipopolysaccharide-stimulated HaCaT cells. Additionally, the lead compounds significantly improved imiquimod-induced psoriasis-like inflammation in mice. Moreover, the expression levels of cytokines and inflammatory mediators, such as interleukin (IL)-17A, IL-22, IL-23, nuclear factor-κB subunit p65, tumor necrosis factor-α, and interferon-γ, were dramatically inhibited in the dorsal skin of 5i- and 5l-treated mice. These findings indicate that the inhibition of Topo I activity may potentially be an effective strategy for psoriasis treatment.Graphical abstractGraphical abstract for this article
  • Design, synthesis and molecular modeling studies on novel moxifloxacin
           derivatives as potential antibacterial and antituberculosis agents
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Aslı Türe, Necla Kulabaş, Serap İpek Dingiş, Kaan Birgül, Arif Bozdeveci, Şengül Alpay Karaoğlu, Vagolu Siva Krishna, Dharmarajan Sriram, İlkay Küçükgüzel Twenty-one novel alkyl/acyl/sulfonyl substituted fluoroquinolone derivatives were designed, synthesized and evaluated for their anti-tuberculosis and antibacterial activity. The targeted compounds were synthesized by the introduction of alkyl, acyl or sulfonyl moieties to the basic secondary amine moiety of moxifloxacin. Structures of the compounds were enlightened by FT-IR, 1H NMR, 13C NMR and HRMS data besides elemental analysis. Compounds were initially tested in vitro for their anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv using microplate alamar blue assay. Minimal inhibitory concentration (MIC) values of all compounds were found between> 25.00–0.39 µg/mL while compounds 1, 2 and 13 revealed an outstanding activity against M. tuberculosis H37Rv with MIC values of 0.39 µg/mL. Activities of compounds 1–21 against to a number of Gram-positive and Gram-negative bacteria and fast growing mycobacterium strain were also investigated by agar well diffusion and microdilution methods. According to antimicrobial activity results, compound 13 was found the most potent derivative with a IC50 value of
  • Dipyridamole inhibits α-amylase/α-glucosidase at sub-micromolar
           concentrations; in-vitro, in-vivo and theoretical studies
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Sajjad Esmaeili, Sarwar Azizian, Bahareh Shahmoradi, Sajad Moradi, Mohsen Shahlaei, Reza Khodarahmi Dipyridamole (DP) elevates cyclic Adenosine Monophosphate (cAMP) levels in platelets, erythrocytes, and endothelial cells and also blocks adenosine reuptake. It is used to dilate blood vessels in people with peripheral arterial disease and coronary artery disease (CAD). The flexible backbone, hydrophobic nature, and several available hydrogen bond (H-bond) donors and acceptors are well suited structural features of DP for inhibition/activation of enzymes. Substrates of α-amylase (α-Amy) and α-Glucosidase (α-Glu), known as key absorbing enzymes, have functional groups (OH groups) similar to DP. Since hypoglycemia can occur in diabetes disease and there is a significant link between diabetes and cardiovascular diseases (CVD), thus this study aimed to evaluate the inhibitory properties of DP against α-Amy and α-Glu, as enzyme targets of interest under hypoglycemia condition. DP inhibited the α-Glu and α-Amy activity in a dose dependent manner with IC50 values 19.4 ± 0.3 and 30.1 ± 0.4 µM, respectively. Further, the Ki values of DP for α-Glu and α-Amy were determined as 2.9 ± 0.2 and 3.1 ± 0.4 µM in a competitive-mode and mixed-mode inhibition, respectively. Also, DP had binding energies of −7.3 and −6.5 kcal/mol, to communicate with the active site of α-Glu and α-Amy, respectively. In addition, in-vivo studies revealed that the blood glucose concentration diminished after taking of DP compared to positive control group (p 
  • Novel 9-(2-(1-arylethylidene)hydrazinyl)acridine derivatives: Target
           Topoisomerase 1 and growth inhibition of HeLa cancer cells
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Md Rafi Haider, Kamal Ahmad, Nadeem Siddiqui, Zulphikar Ali, Md Jawaid Akhtar, Neeraj Fuloria, Shivkanya Fuloria, Manickam Ravichandran, M. Shahar Yar A series of 9-(2-(1-arylethylidene)hydrazinyl)acridine and its analogs were designed, synthesized and evaluated for biological activities. Various biochemical assays were performed to determine the free radical scavenging capacity of synthesized compounds (4a–4j). Anticancer activity of these compounds was assessed against two different human cancer cell lines viz cervical cancer cells (HeLa) and liver cancer cells (HepG2) as well as normal human embryonic kidney cell line (HEK 293). Compounds 4b, 4d and 4e showed potential anti-proliferative effects on HeLa cells. Based on results obtained from antioxidant and cytotoxicity studies, 4b, 4d and 4e were further studied in detail for different biological activities. 4b, 4d and 4e reduced the cell growth, inhibited metastatic activity and declined the potential of cell migration in HeLa cell lines. Topoisomerase1 (Top1) treated with compounds 4b, 4d and 4e exhibited inhibition of Top1 and prevented DNA replication. Molecular docking results validate that interaction of compounds 4b, 4d and 4e with Top1-DNA complex, which might be accountable for their inhibitory effects. Further it was concluded that compounds 4b, 4d and 4e arrests the cells at S phase and consequently induces cell death through DNA damage in HeLa cells.Graphical abstractGraphical abstract for this article
  • Click chemistry-assisted synthesis of novel
           aminonaphthoquinone-1,2,3-triazole hybrids and investigation of their
           cytotoxicity and cancer cell cycle alterations
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Maryam Gholampour, Sara Ranjbar, Najmeh Edraki, Maryam Mohabbati, Omidreza Firuzi, Mehdi Khoshneviszadeh A series of 12 novel 1,4-naphthoquinone-1,2,3-triazole hybrids were designed and synthesized through copper-catalyzed click reaction of 2-(prop-2-ynylamino)naphthalene-1,4-dione (3) and different azidomethyl-benzene derivatives. The synthesized compounds were assessed for their anticancer activity against three cancer cell lines (MCF-7, HT-29 and MOLT-4) by MTT assay. The results showed that the majority of the synthesized compounds displayed cytotoxic activity. Derivatives 6f and 6h, bearing 4-trifluoromethyl-benzyl and 4-tert-butyl-benzyl groups, respectively, as well as intermediate 3 demonstrated good cytotoxic potential against all tested cancer cell lines, among which compound 6f showed the highest activity. Flow cytometric analysis revealed that compounds 3, 6f and 6h arrested cell cycle at G0/G1 phase in MCF-7 cells. Therefore, synthesized aminonaphthoquinone-1,2,3-triazole derivatives can be introduced as promising molecules for further development as potential anticancer agents.Graphical abstractGraphical abstract for this article
  • Current development of 5-nitrofuran-2-yl derivatives as antitubercular
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Tilal Elsaman, Malik Suliman Mohamed, Magdi A. Mohamed Pulmonary tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB) and still remains one of the foremost fatal infectious diseases, infecting nearly a third of the worldwide population. The emergencies of multidrug-resistant and extensively drug-resistant tuberculosis (MDR and XDR-TB) prompt the efforts to deliver potent and novel anti-TB drugs. Research aimed at the development of new anti-TB drugs based on nitrofuran scaffold led to the identification of several candidates that were effective against actively growing as well as latent mycobacteria with unique modes of action. This review focuses on the recent advances in nitrofurans that could provide intriguing potential leads in the area of anti-TB drug discovery.Graphical abstractGraphical abstract for this article
  • Nimesulide analogues: From anti-inflammatory to antitumor agents
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Mafalda Catarro, João L. Serrano, Susana S. Ramos, Samuel Silvestre, Paulo Almeida Nimesulide is a nonsteroidal anti-inflammatory drug possessing analgesic and antipyretic properties. This drug is considered a selective cyclooxygenase-2 (COX-2) inhibitor and, more recently, has been associated to antitumor activity. Thus, numerous works have been developed to modify the nimesulide skeleton aiming to develop new and more potent and selective COX-2 inhibitors as well as potential anticancer agents. This review intends to provide an overview on analogues of nimesulide, including the general synthetic approaches used for their preparation and structural diversification and their main anti-inflammatory and/or antitumor properties.Graphical abstractGraphical abstract for this article
  • Identification of anti-inflammatory polyketides from the coral-derived
           fungus Penicillium sclerotiorin: In vitro approaches and
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Zhaoming Liu, Pei Qiu, Hongju Liu, Jing Li, Changlun Shao, Tao Yan, Wenhao Cao, Zhigang She Four new polyketides, including an unusual naphthoquinone derivative (1), two azaphilone analogous (2, 7) and an α-pyrone (12), were isolated from the gorgonian-derived fungus Penicillium sclerotiorum CHNSCLM-0013 together with nine known compounds. Their structures were identified based on the 1D, 2D NMR, HRESIMS, single crystal X-ray diffraction and the absolute configurations were determined by comparing the 1H NMR chemical shift and optical rotations with those reported in literature. In the bioassay, compounds 2, 6, 7, 10 and 12 exhibited significant inhibitory activities against the nitric oxide (NO) production in the LPS-induced macrophage RAW 264.7 with the IC50 values in the range of 2.5–18.0 μM. Compounds 2, 6 and 7 exhibited the possible mechanism of downregulating the expression of iNOS and COX-2 in mRNA level. The primary structure-activity relationship was also discussed based on the molecular-modeling. This study will make a contribution to the chemical diversities of polyketides especially the azaphilone derivatives and the discovery of potential anti-inflammatory agent from marine fungi.Graphical abstractGraphical abstract for this article
  • Structural modifications of 2,3-indolobetulinic acid: Design and synthesis
           of highly potent α-glucosidase inhibitors
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Elmira F. Khusnutdinova, Anastasiya V. Petrova, Ha Nguyen Thi Thu, Anh Le Thi Tu, Tra Nguyen Thanh, Cham Ba Thi, Denis A. Babkov, Oxana B. Kazakova A series of nineteen nitrogen-containing lupane triterpenoids was obtained by modification of C2, C3, C20 and C28 positions of betulonic acid and their α-glucosidase inhibiting activity was investigated. Being a leader compound from our previous study, 2,3-indolo-betulinic acid was used as the main template for different modifications at C-(28)-carboxyl group to obtain cyano-, methylcyanoethoxy-, propargyloxy- and carboxamide derivatives. 20-Oxo- and 29-hydroxy-20-oxo-30-nor-analogues of 2,3-indolo-betulinic acid were synthesized by ozonolysis of betulonic acid followed by Fischer indolization reaction. To compare the influence of the fused indole or the seven-membered A-ring on the inhibitory activity, lupane A-azepanones with different substituents at C28 were synthesized. The structure-activity relationships revealed that the enzyme inhibition activity dramatically increased (up to 4730 times) when the carboxylic group of 2,3-indolo-betulinic acid was converted to the corresponding amide. Thus, the IC50 values for glycine amide and L-phenylalanine amides were 0.04 and 0.05 μM, respectively. This study also revealed that 2,3-indolo-platanic acid is 4.5 times more active than the parent triterpenoid with IC50 of 0.4 μM. Molecular modeling suggested that improved potency is due to additional polar interactions formed between C28 side chain and a sub-pocket of the α-glucosidase allosteric site.Graphical abstractGraphical abstract for this article
  • Synthesis and evaluation of Quinoline-3-carbonitrile derivatives as
           potential antibacterial agents
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Salman A. Khan, Abdullah M. Asiri, Hadi Mussa Basisi, Mohammad Asad, Mohie E.M. Zayed, Kamlesh Sharma, Mohmmad Younus Wani New quinoline-3-carbonitrile derivatives were synthesized and evaluated for their potential antibacterial behavior. Compounds were obtained by a one-pot multicomponent reaction of appropriate aldehyde, ethyl cyanoacetate, 6-methoxy-1,2,3,4-tetrahydro-naphthalin-1-one and ammonium acetate. Structures were established by different physical and spectroscopic techniques. The molecular geometry, vibration frequencies, HOMO–LUMO energy gap, molecular hardness (g), ionization energy (IE), electron affinity (EA), and total energy of these compounds was assessed by DFT studies, employing DFT/RB3LYP method. Preliminary antibacterial studies using both Gram-positive and Gram-negative bacterial strains and cytotoxicity studies on mammalian cells revealed their promising antibacterial activity, without causing any severe host toxicity. All the compounds (QD1-QD5) in this study obeyed the ‘Lipinski’s Rule of Five’ with logP values
  • Selective cyclooxygenase inhibition and ulcerogenic liability of some
           newly prepared anti-inflammatory agents having thiazolo[4,5-d]pyrimidine
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Rania B. Bakr, Amira A. Ghoneim, Amany A. Azouz Novel candidates of thiazolo[4,5-d]pyrimidines (9a-l) were synthesized and their structures were elucidated by spectral and elemental analyses. All the novel derivatives were screened for their cyclooxygenase inhibitory effect, anti-inflammatory activity and ulcerogenic liability. All the new compounds exhibited anti-inflammatory activity, especially 1-(4-[7-(4-nitrophenyl)-5-thioxo-5,6-dihydro-3H-thiazolo[4,5-d]pyrimidin-2-ylideneamino]phenyl)ethanone (9g) was the most active derivative with 57%, 88% and 88% inhibition of inflammation after 1, 3 and 5h, respectively. Furthermore, this derivative 9g recorded higher anti-inflammatory activity than celecoxib which showed 43%, 43% and 54% inhibition after 1, 3 and 5h, sequentially. Moreover, the target derivatives 9a-l demonstrated moderate to high potent inhibitory action towards COX-2 (IC50 = 0.87–3.78 µM), in particular, the derivatives 9e (IC50 = 0.92 µM), 9g (IC50 = 0.87 µM) and 9k (IC50 = 1.02 µM) recorded higher COX-2 inhibitory effect than the selective COX-2 inhibitor drug celecoxib (IC50 = 1.11 µM). The in vivo potent compounds (9e, 9g and 9k) caused variable ulceration effect (ulcer index = 5–12.25) in comparison to that of celecoxib (ulcer index = 3). Molecular docking was performed to the most potent COX-2 inhibitors (9e, 9g and 9k) to explore the binding mode of these derivatives with Cyclooxygenase-2 enzyme.Graphical abstractNew thiazolo[4,5-d]pyrimidines (9a-l) were prepared and screened for their cyclooxygenase inhibitory effect, anti-inflammatory activity and ulcerogenic liability. All the new compounds exhibited anti-inflammatory activity; especially 9g was the most active derivative with 57%, 88% and 88% inhibition of inflammation after 1, 3 and 5h, respectively.Graphical abstract for this article
  • Evaluation of cytotoxic activity and genotoxicity of structurally well
           characterized potent cobalt(II) phen–based antitumor drug entities: An
           in vitro and in vivo approach
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Huzaifa Yasir Khan, Mohd Owais Ansari, G.G.H.A. Shadab, Sartaj Tabassum, Farukh Arjmand Cobalt (II) phen–based drug candidates of the formulation Co(phen)2Cl2, 1, Co(phen)2L, 2 where L = 1H–pyrazole–3,5–dicarboxylic acid were synthesized and thoroughly characterized by spectroscopic methods and single X–ray crystallography. DNA binding interaction of 1 and 2 was carried out employing biophysical techniques {UV–visible, fluorescence, thermal denaturation and cyclic voltammetry} to validate their potential to act as antitumor agents. The interpretations of these biophysical studies of 1 and 2 supported the non–covalent intercalative binding mode; furthermore, a higher binding trend of 2 was observed as compared to 1, phen and 1H–pyrazole–3,5–dicarboxylic acid alone. Cleavage studies of 1 and 2 with pBR322 were assessed by gel electrophoresis and it was observed that both drug candidates cleave DNA by hydrolytic pathway involving hydroxyl radical (OH). Cytotoxic activity of 1 and 2 against human cancer cell lines [MCF–7 (breast), HeLa (cervical), MIA–PA–CA 2 (pancreatic), A–498 (kidney), Hep–G2 (hepatoma)] was evaluated by SRB assay. The obtained results showed that drug candidate 1 showed significantly low GI50 value (
  • New perspective on the metabolism of AD-1 in vivo: Characterization of a
           series of dammarane-type derivatives with novel metabolic sites and
           anticancer mechanisms of active oleanane-type metabolites
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Meng Ding, Xude Wang, Yumeng Zhang, Weihui Yuan, Huixing Zhang, Lei Xu, Ziyi Wang, Jincai Lu, Wei Li, Yuqing Zhao 20(R)-25-methoxyl-dammarane-3β,12β,20-triol (AD-1, CN Patent: 201010107476.7) is a novel derivative of dammarane-type ginsenoside. AD-1 has been shown to inhibit cancer cell proliferation without significant host toxicity in vivo, and has excellent development potential as a new anti-cancer agent. This study was designed systematically to explore the metabolic pathway of ginseng sapogenins. The metabolism of drugs in the body is a complex biotransformation process where drugs are structurally modified to different molecules (metabolites) through various metabolizing enzymes. The compounds responsible for the effects of orally administered ginseng are believed to be metabolites produced in the gastrointestinal tract, so understanding the metabolism of the drug candidate can help to optimize its pharmacokinetics. In this study, faeces samples were collected and extracted after oral administration of AD-1. The 16 metabolites of AD-1 were isolated and identified for the first time with various chromatographic techniques, including semi-preparative high performance liquid chromatography, nuclear magnetic resonance spectroscopy, and mass spectrometry; of these 16 metabolites, 10 were novel compounds. We first discovered the biotransformation of dammarane-type sapogenins into oleanane-type sapogenins in rats and found a series of metabolites that changed, mainly at C-25 and C-29. This study provides new ideas for the metabolic pathway of ginseng sapogenins. The isolated compounds were screened for their effect on the viability and proliferation against cancer cell lines (Human A549, MCF-7, HELA, HO-8901 and U87). The discovery of novel active metabolites 3β,12β,21α,22β-Hydroxy-24-norolean-12-ene (M6) may lead to a new or improved drug candidate. For one, M6 could inhibit the growth of all the tested cancer cells. Among the tested cell lines, M6 exhibited the most remarkable inhibitory effect on ovarian cancer HO-8901 cells, with IC50 value of 2.086 μM. On this basis, we studied the anticancer mechanisms of M6. The results indicated that the pro-apoptotic feature of M6 acts via a mitochondrial pathway. Our results indicated that M6 exhibited a higher inhibitory effect on cancer-cell proliferation than AD-1 by inducing cell apoptosis. Our work provides data for future investigations on the metabolic mechanism of AD-1 in vivo and the potential for future research on developing a new drug.Graphical abstractGraphical abstract for this article
  • Multifunctional nanoparticles from albumin for stimuli-responsive
           efficient dual drug delivery
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Hamed Nosrati, Fatemeh Abhari, Jalil Charmi, Soodabeh Davaran, Hossein Danafar In this project methotrexate (MTX) conjugated albumin based nanoparticles (MTX-BSA) loaded with curcumin (CUR) drug (CUR-MTX-BSA) for simultaneous delivery of multi-chemotherapeutic drugs and combination cancer therapy were designed. Co-delivery is a new strategy which minimize the amount of each drug, reduce of side effects and also to achieve the synergistic effect for cancer therapies. The MTX was conjugated to albumin via covalent bond. Next, this synthesized prodrug loaded with CUR. Afterward, the formulations were evaluated for physical and chemical properties by DLS, TEM, FTIR, UV/Vis, DSC analysis, in vitro cytotoxicity and in vivo biocompatibility studies. Furthermore, the drug loading and release study were evaluated. Proteinase K enzyme was used to break amid bond between MTX and BSA and also amidic bonds in BSA structure. Administration of up to 2000 mg/kg of BSA to healthy animals was non-toxic and all treated mice were still alive after 24 h. The result of this study proved that CUR-MTX-BSA can be used as a proficient vehicle for effective co-delivery of CUR and MTX in the treatment of cancer.Graphical abstractGraphical abstract for this article
  • Synthesis, computational molecular docking analysis and effectiveness on
           tyrosinase inhibition of kojic acid derivatives
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Gülşah Karakaya, Aslı Türe, Ayşe Ercan, Selin Öncül, Mutlu Dilsiz Aytemir Tyrosinase inhibitors have become increasingly important as whitening agents and for the treatment of pigmentary disorders. In this study, the synthesis of kojic acid derivatives having 2-substituted-3-hydroxy-6-hyroxymethyl/chloromethyl/methyl/morpholinomethylpiperidinyl- methyl/pyrrolidinylmethyl-4H-pyran-4-one structure (compounds 1–30) with inhibitory effects on tyrosinase enzyme were described. One-pot Mannich reaction was carried out by using kojic acid/chlorokojic acid/allomaltol and substituted benzylpiperazine derivatives in presence of formaline. Subsequently, cyclic amine (morpholine, piperidine and pyrrolidine) derivatives of the 6th-position of chlorokojic acid were obtained with nucleophilic substitutions in basic medium. The structures of new compounds were identified by FT-IR, 1H- and 13C NMR, ESI-MS and elemental analysis data. The potential mushroom tyrosinase inhibitory activity of the compounds were evaluated by the spectrophotometric method using l-DOPA as a substrate and kojic acid as the control agent. The potential inhibitory activity was also investigated in silico using molecular docking simulation method. Tyrosinase inhibitory action was significantly more efficacious for several compounds (IC50: 86.2–362.1 µM) than kojic acid (IC50: 418.2). Compound 3 bearing 3,4-dichlorobenzyl piperazine moiety was proven to have the highest inhibitory activity. The results of docking studies showed that according to the predicted conformation of compound 3 in the enzyme binding site, hydroxymethyl group provides a metal complex with copper ions and enzyme. Thus, this interaction explain the high inhibitory activities of the compounds 1, 3 and 4 possessing hydroxymethyl substituent supporting the mushroom assay results with docking studies. In accordance with the results, it is suggested that Mannich bases of kojic acid bearing substituted benzyl piperazine groups (compounds 1, 3, 4, 11, 13, 14, 23, 24, 28, and 29) could be promising antityrosinase agents. Additionally, considering the relationship between tyrosinase inhibitory activity results and molecular docking, a new tyrosinase inhibition mechanism can be proposed.Graphical abstractGraphical abstract for this article
  • Discovery of Baicalin as NDM-1 inhibitor: Virtual screening, biological
           evaluation and molecular simulation
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Cheng Shi, Jingxiao Bao, Ying Sun, Xinyue Kang, Xingzhen Lao, Heng Zheng The emergence and worldwide spreads of carbapenemase producing bacteria, especially New Delhi metallo-β-lactamase (NDM-1), has made a great challenge to treat antibiotics-resistant bacterial infections. It can hydrolyse almost all β-lactam antibacterials. Unfortunately, there are no clinically useful inhibitors of NDM-1. In this study, structure-based virtual screening method led to the identification of Baicalin as a novel NDM-1 inhibitor. Inhibitory assays showed that Baicalin possessed a good inhibition of NDM-1 with IC50 values of 3.89 ± 1.1 μM and restored the susceptibility of E.coli BL21(DE3)/pET28a-NDM-1 to clinically used β-lactam antibiotics. Molecular docking and molecular dynamics simulations obtained a complex structure between the relatively stable inhibitor molecule Baicalin and NDM-1 enzyme. The results showed that the carboxyl group in Baicalin directly interacted with the Zn2+ in the active center of the enzyme, and the residues such as Glu152, Gln123, Met67, Trp93 and Phe70 in the enzyme formed hydrogen bonds with Baicalin to further stabilize the complex structure.Graphical abstractGraphical abstract for this article
  • Design, synthesis and molecular docking of 1,4-benzodioxane
           thiazolidinedione piperazine derivatives as FabH inhibitors
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Juan Sun, Wen He, Han-Yu Liu, Jie Qin, Chun-Lin Ye A series of novel 1,4-benzodioxane thiazolidinedione piperazine derivatives targeting FabH were designed and synthesized. The compounds exhibited better inhibitory activity against Gram-negative bacteria by computer-assisted screening, antibacterial activity test and E. coli FabH inhibitory activity test, wherein compound 6j exhibited the most significant inhibitory activity (MIC = 1.80 μΜ for P. aeruginosa, MIC = 1.56 μΜ for E. coli). Besides, compound 6j still showed the best E. coli FabH inhibitory activity (IC50 = 0.06 μΜ). Moreover, the antibacterial activities of all compounds were strongly correlated with the inhibitory ability of FabH, with a correlation coefficient of 0.954. Computational docking studies also showed that compound 6j has interacting with FabH key residues in the active site.Graphical abstractA series of novel 1,4-benzodioxane thiazolidinedione piperazine derivatives targeting FabH were designed and synthesized as antibacterial agents.Graphical abstract for this article
  • Exploration of
           derivatives as anticancer and radiosensitizing agents
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Aiten M. Soliman, Mostafa M. Ghorab Multitargeted therapy is considered a successful approach to cancer treatment. The development of small molecule multikinase inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. A library of N-alkyl-2-[(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio]acetamide derivatives 5–18 was designed and synthesized. The synthesized compounds were screened for cytotoxic activity against MDA-MB-231 breast cancer cell line and showed IC50 in the range of 0.34–149.10 µM. The inhibition percentage of VEGFR-2 was measured for all the compounds and found to be in the range of 90.09–20.44%. The promising compounds 8, 12, 13, 16 and 17 were selected to measure their possible multikinase inhibitory activity against VEGFR-2 and EGFR. IC50 of the promising compounds were in the range of 247–793 nM for VEGFR-2 in reference to sunitinib (IC50 320 nM), and 369–725 nM for EGFR in reference to erlotinib (IC50 568 nM). Compounds 12 and 13 showed the most potent activity towards VEGFR-2 & EGFR, respectively. Measuring the cytotoxicity of 12 and 13 against MCF-10 normal breast cell line indicates their relative safety to normal breast cells (IC50 37 & 97 µM, respectively). As radiotherapy is considered the primary treatment for some types of solid tumors, the radiosensitizing ability of 12 and 13 was measured by subjecting the MDA-MB-231 cells to a single dose of 8 Gy of gamma radiation. IC50 of 12 and 13 decreased from 1.91 & 0.51 µM to 0.79 & 0.43 µM, respectively. Molecular docking was performed to gain insights into the ligand-binding interactions of 12 inside VEGFR-2 and EGFR binding sites in comparison to their co-crystallized ligands.Graphical abstractGraphical abstract for this article
  • Natural urease inhibitors from Aloe vera resin and Lycium shawii and their
           structural-activity relationship and molecular docking study
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Najeeb Ur Rehman, Ajmal Khan, Ahmed Al-Harrasi, Mohammed Khiat, Hidayat Hussain, Abdul Wadood, Muhammad Riaz Bio-assay guided fractionation of the methanolic extract of Aloe vera resin and Lycium shawii stem successively afforded twenty three compounds; fourteen (1–14) from A. vera and nine (15–23) from L. shawii. All these compounds were characterized by 1D and 2D NMR spectroscopic techniques viz., 1H, 13C, DEPT, HSQC, HMBC, and COSY, and NEOSY, ESI-MS and compared with the reported literature. These compounds were assessed for their potential as urease inhibitors targeted in peptic ulcer. Among crude extracts and fractions of A. vera resin, n-butanol fraction (23.5 ± 1.7 μg·mL−1) showed the most potent urease inhibition followed by methanol (30.9 ± 0.3 μg/mL) and ethyl acetate (31.7 ± 0.5 μg·mL−1). In case of L. shawii, ethyl acetate fraction exhibited the highest urease activity (41.0 ± 1.4 μg/mL) trailed by dichloromethane (55.2 ± 1.5 μg/mL) fraction. Among the isolates, compounds 7, 11 and 23 were found to be excellent urease inhibitors with IC50 values of 14.5 ± 0.90 µM, (16.7 ± 0.16 µM) and 14.0 ± 0.8 µM, respectively. To the best of our knowledge, this is the first report on the urease enzyme inhibitory activity of the said compounds excluding compound 18. In addition, the urease activity of different fractions of L. shawii stem was also reported for the first time. The molecular docking studies showed that all the active compounds well accommodate in the active site of the urease enzyme by interacting with key amino acids.Graphical abstractGraphical abstract for this article
  • Synthesis, characterization, anticancer evaluation and mechanisms of
           cytotoxic activity of novel 3-hydroxy-3-pyrrolin-2-ones bearing thenoyl
           fragment: DNA, BSA interactions and molecular docking study
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Nenad Joksimović, Jelena Petronijević, Nenad Janković, Dejan Baskić, Suzana Popović, Danijela Todorović, Sanja Matić, Goran A. Bogdanović, Milan Vraneš, Aleksandar Tot, Zorica Bugarčić In order to make a progress in discovering a new agents for chemotherapy with improved properties and bearing in mind the fact that substituted 3-hydroxy-3-pyrrolin-2-ones belong to a class of biologically active compounds, series of novel 1,5-diaryl-4-(2-thienylcarbonyl)-3-hydroxy-3-pyrrolin-2-ones were synthesized and characterized by spectral (UV–Vis, IR, NMR, ESI-MS), X-ray and elemental analysis. All compounds were examined for their cytotoxic effect on human cancer cell lines HeLa and MDA-MB 231 and normal fibroblasts (MRC-5). Four compounds, 3-hydroxy-1-(p-tolyl)-4-(2-thienylcarbonyl)-5-(4-chlorophenyl)-2,5-dihydro-1H-pyrrol-2-one (D10), 3-hydroxy-1-(3-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D13), 3-hydroxy-1-(4-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D14), and 3-hydroxy-1-(4-chlorophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D15), that showed the highest cytotoxicity against malignant cells and the best selectivity towards normal cells were selected for further experiments. Results obtained by investigating mechanisms of cytotoxic activity suggest that selected 3-hydroxy-3-pyrrolin-2-one derivatives in HeLa cells induce apoptosis that is associated with S phase arrest (D13, D15, and D10) or unrelated to cell cycle distribution (D14). Additionally, to better understand their suitability for potential use as anticancer medicaments we studied the interactions between biomacromolecules (DNA or BSA) and D13 and D15. The results indicated that D13 and D15 have great affinity to displace EB from the EB-DNA complex through intercalation [Ksv = (3.7 ± 0.1) and (3.4 ± 0.1) × 103 M−1, respectively], an intercalative mode also confirmed through viscosity measurements. Ka values, obtained as result of fluorescence titration of BSA with D13 and D15 [Ka = (4.2 ± 0.2) and (2.6 ± 0.2) × 105 M, respectively], support the fact that a significant amount of the tested compounds could be transported and distributed through the cells. In addition, by DNA and BSA molecular docking study for D13, D14 and D15 is determined and predicted the binding mode and the interaction region.Graphical abstractGraphical abstract for this article
  • Design and synthesis of the novel oleanolic acid-cinnamic acid ester
           derivatives and glycyrrhetinic acid-cinnamic acid ester derivatives with
           cytotoxic properties
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Rui Wang, Wei Yang, Yiqing Fan, Wim Dehaen, Yang Li, Huijing Li, Wei Wang, Qingxuan Zheng, Qiyong Huai Oleanolic acid (OA) and glycyrrhetinic acid (GA) are natural products with anticancer effects. Cinnamic acid (CA) and its derivatives also exhibited certain anticancer activity. In order to improve the anticancer activity of OA and GA, we designed and synthesized a series of novel OA-CA ester derivatives and GA-CA ester derivatives by using molecular hybridization approach. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to assess their in vitro cytotoxicity on three cell lines (HeLa (cervical cancer), MCF-7 (breast cancer) and L-O2 (a normal hepatic cell)). Among the evaluated compounds, 3o presented the strongest selective cytotoxicity on HeLa cells (IC50 = 1.35 μM) and showed no inhibitory activity against MCF-7 cells (IC50 > 100 μM) and L-O2 cells (IC50 > 100 μM), and 3e presented the strongest selective inhibition of the MCF-7 cells (IC50 = 1.79 μM). What’s more, compound 2d also showed very strong selective inhibitory activity against HeLa cells (IC50 = 1.55 μM). The further research using Hoechst 33342, AO/EB dual-staining, flow cytometric analysis and DCFH-DA fluorescent dye staining assay presented that 2d and 3o could induce HeLa cells apoptosis and autophagy.Graphical abstractGraphical abstract for this article
  • Highly selective carbamate-based butyrylcholinesterase inhibitors derived
           from a naturally occurring pyranoisoflavone
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Chuanhai Wu, Yan-bei Tu, Ziyuan Li, Yan-fang Li This current study described the design and synthesis of a series of derivatives based on a natural pyranoisaflavone, which was obtained from the seeds of Millettia pachycarpa and displayed attractive BChE inhibition and high selectivity in our previous study. The inhibitory potential of all derivatives against two cholinesterases was evaluated. Only a few compounds demonstrated AChE inhibitory activity at the tested concentrations, while 26 compounds showed significant inhibition on BChE (the IC50 values varied from 9.34 μM to 0.093 μM), most of them presented promising selectivity to ward BChE. Prediction of ADME properties for 7 most active compounds was performed. Among them, 9g (IC50 = 222 nM) and 9h (IC50 = 93 nM) were found to be the most potent BChE inhibitors with excellent selectivity over AChE (SI ratio = 1339 and 836, respectively). The kinetic analysis demonstrated both of them acted as mixed-type BChE inhibitors, while the molecular docking results indicated that they interacted with both residues in the catalytic active site. A cytotoxicity test on PC12 cells showed that both 9g and 9h had a therapeutic safety range similar to tacrine. Overall, the results indicate that 9h could be a good candidate of BChE inhibitors.Graphical abstractGraphical abstract for this article
  • Magmenthanes A-H: Eight new meroterpenoids from the bark of Magnolia
           officinalis var. Biloba
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Chuan Li, Chuang-Jun Li, Jie Ma, Ji-Wu Huang, Xu-Yan Wang, Xiao-Liang Wang, Fei Ye, Dong-Ming Zhang Eight new meroterpenoids with different types of monoterpene units, namely, magmenthanes A-H (1–8), were identified from the bark of Magnolia officinalis var. biloba. Magmenthane A (1) possesses a 1,3-dioxabicyclo [4.3.01,5] nonane skeleton, 1–5 possess five pairs of enantiomers and 6 possesses a 1,1′-diallyl-biphenyl fragment. The structures of 1–8 were elucidated on the basis of 1D and 2D NMR, HRESIMS and electronic circular dichroism (ECD) calculations. Compounds 5 and 8 displayed significant PTP1B inhibitory activities with IC50 values of 4.38 and 3.88 μM, respectively.Graphical abstractGraphical abstract for this article
  • Synthesis, antimicrobial, antioxidant, cytotoxic, antiurease and molecular
           docking studies of N-(3-trifluoromethyl)benzoyl-N′-aryl thiourea
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Aneela Maalik, Hina Rahim, Muhammad Saleem, Nighat Fatima, Abdur Rauf, Abdul Wadood, Muhammad Imran Malik, Ayaz Ahmed, Hummera Rafique, Muhammad Naveed Zafar, Muhammad Riaz, Lubna Rasheed, Amara Mumtaz An irrefutable advancement has been noted for the infectious diseases caused due to ureolytic bacteria through the development of various drugs. Keeping in mind the extremely valuable synthetic utility and medicinal significance of thiourea derivatives, synthesis of new 3-trifluoromethyl benzoic acid thiourea derivatives (3a–j) were carried out. The biological potential of all compounds in terms of antimicrobial, antioxidant, cytotoxic and antiurease activities were studied. The compounds 3a, 3c and 3i with dichloro and methoxy groups substitution on the aryl group showed significant activity against all strain of bacteria while moderate to no activity was observed in remaining compounds. Whereas the antifungal evaluation showed that all compounds were active againts C. Albican and no activity was observed against C. Prapsilosis. The cytotoxic findings revealed the non-toxic nature of these compounds as IC50 values of majority of the compounds are above 100 μm except for compounds 3f and 3g. In addition, these compounds exhibited better antioxidant potential as 100 μm concentration inhibited>50% reactive oxygen species (ROS) production except compounds 3e, 3f and 3j. The compound 3a proved to be the most potent urease inhibitor showing the highest enzyme % inhibition (93.1%) with IC50 value of 8.17 ± 0.24 µM and found more active as compare to standard followed by compound 3e (92.6%), 3h (91.6%), 3d (90.8%), 3b (90.6%) and 3f (90.0%) with their respective IC50 values. All the synthesized compounds were docked into the binding cavity of Urease (PDB ID: 4ubp). The most active compound 3a was also ranked as top on the docking score as it was found to show valuable interactions with the target protein along with good docking scores. Hence our results revealed that the synthesized compounds have potential to be used as potent urease inhibitors after further detailed mechanistic studies.Graphical abstractGraphical abstract for this article
  • Synthesis and evaluation of redox-sensitive gonadotropin-releasing hormone
           receptor-targeting peptide conjugates
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Yuxuan Dai, Na Yue, Chunxia Liu, Xingguang Cai, Xin Su, Xinzhou Bi, Qifei Li, Chengye Li, Wenlong Huang, Hai Qian Lytic peptides have been demonstrated to exhibit obvious advantages in cancer therapy with binding ability toward tumor cells via electrostatic attractions, which are lack of active targeting and aggregation to tumor tissue. In the present study, five conjugated lytic peptides were redesigned and constructed to target gonadotropin releasing hormone receptors (GnRHr), meanwhile, the disulfide bridge was introduced to achieve redox sensitive delivery based on the experience from the preliminary work of lytic peptides P3 and P7. YX-1, was considered to be the most promising for in-depth study. YX-1 possessed high potency (IC50 = 3.16 ± 0.3 μM), low hemolytic effect, and cell membrane permeability in human A2780 ovarian cancer cells. Moreover, YX-1 had prominent pro-apoptotic activity by activating the mitochondria–cytochrome c–caspase apoptotic pathway. The study yielded the conjugate YX-1 with superior properties for antineoplastic activity, which makes it a promising potential candidate for targeting cancer therapy.Graphical abstractGraphical abstract for this article
  • Design, synthesis and anticancer evaluation of thieno[2,3-d]pyrimidine
           derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Souad A. Elmetwally, Khaled F. Saied, Ibrahim H. Eissa, Eslam B. Elkaeed Deregulation of many kinases is directly linked to cancer development and the tyrosine kinase family is one of the most important targets in current cancer therapy regimens. In this study, we have designed and synthesized a series of thieno[2,3-d]pyrimidine derivatives as an EGFR and HER2 tyrosine kinase inhibitors. All the synthesized compounds were evaluated in vitro for their inhibitory activities against EGFRWT; and the most active compounds that showed promising IC50 values against EGFRWT were tested in vitro for their inhibitory activities against mutant EGFRT790M and HER2 kinases. Moreover, the antitumor activities of these compounds were tested against four cancer cell lines (HepG2, HCT-116, MCF-7 and A431). Compounds 13g, 13h and 13k exhibited the highest activities against the examined cell lines with IC50 values ranging from 7.592 ± 0.32 to 16.006 ± 0.58 µM comparable to that of erlotinib (IC50 ranging from 4.99 ± 0.09 to 13.914 ± 0.36 µM). Furthermore, the most potent antitumor agent (13k) was selected for further studies to determine its effect on the cell cycle progression and apoptosis in MCF-7 cell line. The results indicated that this compound arrests G2/M phase of the cell cycle and it is a good apoptotic agent. Finally, molecular docking studies showed a good binding pattern of the synthesized compounds with the prospective target, EGFRWT and EGFRT790M.Graphical abstractGraphical abstract for this article
  • Fluoro-benzimidazole derivatives to cure Alzheimer’s disease: In-silico
           studies, synthesis, structure-activity relationship and in vivo evaluation
           for β secretase enzyme inhibition
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Sayyad Ali, Muhammad Hassham Hassan Bin Asad, Soham Maity, Wahid Zada, Albert A. Rizvanov, Jamshed Iqbal, Borhan Babak, Izhar HussainGraphical abstractGraphical abstract for this article
  • Evaluation of thioamides, thiolactams and thioureas as hydrogen sulfide
           (H2S) donors for lowering blood pressure
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Ewelina Zaorska, Tomasz Hutsch, Marta Gawryś-Kopczyńska, Ryszard Ostaszewski, Marcin Ufnal, Dominik Koszelewski Hydrogen sulfide (H2S) is a biologically important gaseous molecule that exhibits promising protective effects against a variety of pathological processes. For example, it was recognized as a blood pressure lowering agent. Aligned with the need for easily modifiable platforms for the H2S supply, we report here the preparation and the H2S release kinetics from a series of structurally diversified thioamides, thiolactams and thioureas. Three different thionation methods based on the usage of a phosphorus pentasulfide and Lawesson reagent were applied to prepare the target thioamides and thiolactams. Furthermore, obtained H2S donors were evaluated both in in vivo and in vitro studies. The kinetic parameters of the liberating H2S was determined and compared with NaHS and GYY4137 using two different detection technics i.e.; fluorescence labeling 7-azido-4-methyl-2H-chromen-2-one and 5,5‘-dithiobis (2-nitrobenzoic acid), sulfhydryl probe, also known as the Ellman’s reagent. We have proved that the amount of releasing H2S from these compounds is controllable through structural modifications. Finally, the present study shows a hypotensive response to an intravenous administration of the developed donors in the anesthetized rats.Graphical abstractGraphical abstract for this article
  • Synthesis of thymol-based pyrazolines: An effort to perceive novel
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Dushyant Singh Raghuvanshi, Narsingh Verma, Shiv Vardan Singh, Sonam Khare, Anirban Pal, Arvind Singh Negi A series of thymol based substituted pyrazolines and chalcones was synthesized and evaluated for antimalarial activity, using in-vitro and in-vivo malaria models. All the target compounds (5a-k and 6a-j) were found to be active against human malaria parasite strain Plasmodium falciparum NF54. Among all, compounds 5e and 5f of chalcone series and 6c and 6f of pyrazoline series exhibited prominent antimalarial activity with IC50 less than 3 and 2 μM respectively, while other pyrazolines also significantly inhibited the P. falciparum with IC50 less than 10 μM. The designed pharmacophores were found to be effective against P. falciparum. Compound 6f was found to be able to retard malaria progression in mice. This was evident through decreased parasitemia, increased mean survival time and hemoglobin content in the treated animals. Moreover, 6f was observed as an inhibitor of heme polymerization pathway of the malaria parasite. It also inhibited free heme degradation, which could be possibly responsible for higher reactive oxygen species (ROS) in parasite, thus inhibiting the rapid proliferation of the parasite. In addition to this, compound 6f was found to be non-toxic with a good selectivity index. Based on these observations, the compound 6f could be taken up for further antimalarial lead optimization studies.Graphical abstractGraphical abstract for this article
  • Synthesis and biological evaluation of 3-functionalized 2-phenyl- and
           2-alkylbenzo[b]furans as antiproliferative agents against human melanoma
           cell line
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Halina Kwiecień, Magdalena Perużyńska, Karolina Stachowicz, Katarzyna Piotrowska, Joanna Bujak, Patrycja Kopytko, Marek Droździk The key function of microtubules and mitotic spindle in cell division make them attractive targets in anticancer therapy. In the present study, functionalized in 3 position 2-phenyl- and 2-alkylbenzo[b]furans were synthesized and evaluated as antitumor agents. Among the synthesized derivatives 13a, 13b and 14 exhibited the most potent antiproliferative activity against human melanoma A375 cell line with IC50 values of 2.85 µM, 0.86 µM, 0.09 µM, respectively. The most promising compound defined was 14 with three methoxy groups in the 3-aroyl substituent and 7-methoxy group in 2-phenylbenzo[b]furan skeleton. Tubulin polymerization assay, confocal microscopy imaging and flow cytometry analysis revealed that 2-phenyl-3-aroylbenzo[b]furans (13a, 13b and 14) inhibited tubulin polymerization leading to disruption of mitotic spindle formation, cell cycle arrest in G2/M phase and apoptosis.Graphical abstractGraphical abstract for this article
  • Design, synthesis and molecular docking of new N-4-piperazinyl
           ciprofloxacin-triazole hybrids with potential antimicrobial activity
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Hamada H.H. Mohammed, El-Shimaa M.N. Abdelhafez, Samar H. Abbas, Gamal A.I. Moustafa, Glenn Hauk, James M. Berger, Satoshi Mitarai, Masayoshi Arai, Rehab M. Abd El-Baky, Gamal El-Din A. Abuo-Rahma New N-4-piperazinyl ciprofloxacin-triazole hybrids 6a-o were prepared and characterized. The in vitro antimycobacterial activity revealed that compound 6a experienced promising antimycobacterial activity against Mycobactrium smegmatis compared with the reference isoniazide (INH). Additionally, compound 6a exhibited broad spectrum antibacterial activity against all the tested strains either Gram-positive or Gram-negative bacteria compared with the reference ciprofloxacin. Also, compounds 6g and 6i displayed considerable antifungal activity compared with the reference ketoconazole. DNA cleavage assay of the highly active compounds 6c and 6h showed a good correlation between the Mycobactrium cleaved DNA gyrase assay and their in vitro antimycobactrial activity. Moreover, molecular modeling studies were done for the designed ciprofloxacin derivatives to predict their binding modes towards Topoisomerase II enzyme (PDB: 5bs8).Graphical abstract3D Diagrams of compounds 6a interacted with the active site of Mycobacterium gyrase enzyme.Graphical abstract for this article
  • Synthesis and in vitro antitumor activity of novel acylspermidine
           derivative N-(4-aminobutyl)-N-(3-aminopropyl)-8-hydroxy-dodecanamide
           (AAHD) against HepG2 cells
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Abdulrahman L. Al-Malki, Syed Shoeb Razvi, Furkhan Ahmed Mohammed, Mazin A. Zamzami, Hani Choudhry, Taha A. Kumosani, Khadijah S. Balamash, Fawzia A. Alshubaily, Shareefa A. ALGhamdi, Khalid O. Abualnaja, Wesam H. Abdulaal, Mustafa A. Zeyadi, Maryam H. Al-Zahrani, Mahmoud Alhosin, Tadao Asami, Said S. Moselhy Naturally occurring polyamines like Putrescine, Spermidine, and Spermine are polycations which bind to the DNA, hence stabilizing it and promoting the essential cellular processes. Many synthetic polyamine analogues have been synthesized in the past few years, which have shown cytotoxic effects on different tumours. In the present study, we evaluated the antiproliferative effect of a novel, acylspermidine derivative, (N-(4-aminobutyl)-N-(3-aminopropyl)-8-hydroxy-dodecanamide) (AAHD) on HepG2 cells. Fluorescence staining was performed with nuclear stain (Hoechst 33342) and acridine orange/ethidium bromide double staining. Dose and the time-dependent antiproliferative effect were observed by WST-1 assays, and radical scavenging activity was measured by ROS. Morphological changes such as cell shrinkage & blebbing were analyzed by fluorescent microscopy. It was found that AAHD markedly suppressed the growth of HepG2 cells in a dose- and time-dependent manner. It was also noted that the modulation of ROS levels confirmed the radical scavenging activity. In the near future, AAHD can be a promising drug candidate in chalking out a neoplastic strategy to control the proliferation of tumour cells. This study indicated that AAHD induced anti-proliferative and pro-apoptotic activities on HCC. Since AAHD was active at micromolar concentrations without any adverse effects on the healthy cells (Fibroblasts), it is worthy of further clinical investigations.Graphical abstractGraphical abstract for this article
  • α-bisabolol β-D-fucopyranoside as a potential modulator of β-amyloid
           peptide induced neurotoxicity: An in vitro & in silico study
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Mahalingam Jeyakumar, Sethuraman Sathya, Soniya Gandhi, Prabhakarrao Tharra, Venkatesan Suryanarayanan, Sanjeev Kumar Singh, Beeraiah Baire, Kasi Pandima Devi Alzheimer’s disease (AD) is a multifaceted neurodegenerative disorder affecting the elderly people. For the AD treatment, there is inefficiency in the existing medication, as these drugs reduce only the symptoms of the disease. Since multiple pathological proteins are involved in the development of AD, searching for a single molecule targeting multiple AD proteins will be a new strategy for the management of AD. In view of this, the present study was designed to synthesize and evaluate the multifunctional neuroprotective ability of the sesquiterpene glycoside α-bisabolol β-D-fucopyranoside (ABFP) against multiple targets like acetylcholinesterase, oxidative stress and β-amyloid peptide aggregation induced cytotoxicity. In silico computational docking and simulation studies of ABFP with acetylcholinesterase (AChE) showed that it can interact with Asp74 and Thr75 residues of the enzyme. The in vitro studies showed that the compound possess significant ability to inhibit the AChE enzyme apart from exhibiting antioxidant, anti-aggregation and disaggregation properties. In addition, molecular dynamics simulation studies proved that the interacting residue between Aβ peptide and ABFP was found to be involved in Leu34 and Ile31. Furthermore, the compound was able to protect the Neuro2 a cells against Aβ25-35 peptide induced toxicity. Overall, the present study evidently proved ABFP as a neuroprotective agent, which might act as a multi-target compound for the treatment of Alzheimer’s disease.Graphical abstractGraphical abstract for this article
  • Design, synthesis and photoinduced DNA cleavage studies of
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Garima Sumran, Ranjana Aggarwal, Ashwani Mittal, Aviral Aggarwal, Amit Gupta An expedient and eco-friendly synthesis of 1-aryl/heteroaryl-[1,2,4]-triazolo[4,3-a]quinoxalin-4(5H)-ones (4) has been accomplished via iodobenzene diacetate mediated oxidative intramolecular cyclization of 3-(2-(aryl/heteroarylidene)hydrazinyl)-quinoxalin-2(1H)-ones (3). Ten synthesized compounds 3 and 4 (10–40 μg) on irradiation with UV light at λmax 312 nm could lead to cleavage of supercoiled pMaxGFP DNA (Form I) into the relaxed DNA (Form II) without any additive. Further, DNA cleaving ability of triazoles was quantitatively evaluated and was found to be dependent on its structure, concentration, and strictly on photoirradiation time. Mechanistic investigations using several additives as potential inhibitors/activator revealed that the DNA photocleavage reaction involves Type-I pathway leading to formation of superoxide anion radicals (O2−) as the major reactive oxygen species responsible for photocleavage process.Graphical abstractGraphical abstract for this article
  • Hypoglycemic activity and mechanism of the sulfated rhamnose
           polysaccharides chromium(III) complex in type 2 diabetic mice
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Han Ye, Zhaopeng Shen, Jiefen Cui, Yujie Zhu, Yuanyuan Li, Yongzhou Chi, Jingfeng Wang, Peng Wang The sulfated rhamnose polysaccharides found in Enteromorpha prolifera belong to a class of unique polyanionic polysaccharides with high chelation capacity. In this study, a complex of sulfated rhamnose polysaccharides with chromium(III) (SRPC) was synthesized, and its effect on type 2 diabetes mellitus (T2DM) in mice fed a high-fat, high-sucrose diet was investigated. The molecular weight of SRPC is 4.57 kDa, and its chromium content is 28 μg/mg. Results indicated that mice treated by oral administration of SRPC (10 mg/kg and 30 mg/kg body mass per day) for 11 weeks showed significantly improved oral glucose tolerance, decreased body mass gain, reduced serum insulin levels, and increased tissue glycogen content relative to T2DM mice (p 
  • Phenanthroimidazole derivatives act as potent inducer of autophagy by
           activating DNA damage pathway
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Hao Zhang, Yue Song, Li Li, Shuang-Yan Zhang, Qiong Wu, Wen-Jie Mei, Hui-Min Liu, Xi-Cheng Wang A series of imidazo[4,5f][1,10]phenanthroline derivatives (1–6) have been synthesized in this study, and their inhibitory activity was evaluated by MTT assay. Results showed that all of these compounds demonstrate a promising inhibitory activity against a panel of human cancer cell lines. The 6, the most effective compound with IC50 of approximately 2.3 ± 0.1 µM, was against the growth and could induce autophagy of HepG2 cells. This condition was confirmed by abundant autophagic vacuoles appearing in cells and evident ultrastructural changes observed under transmission electron microscopy. The autophage induced by 6 has also been demonstrated by up-regulating LC3-II and Beclin1. The apoptosis and G2/M phase cell cycle arrest through DSB damage have also been confirmed after the HepG2 cells were treated by 6. These multiple effects, especially induction apoptosis and autophagy, indicate the potential of 6 for development as a novel anticancer drug.Graphical abstractGraphical abstract for this article
  • Synthesis and systemic toxicity assessment of quinine-triazole scaffold
           with antiprotozoal potency
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Adarsh Sahu, Ram Kishore Agrawal, RajKishor Pandey A series of hybrid antiprotozoal compounds with quinine-triazolyl scaffold were prepared by copper catalyzed Huisgen 1,3-dipolar cycloaddition via O-mesylation with mesyl chloride followed by azide displacement. The synthesized azide derivative was made to react with various aromatic and aliphatic alkynes. The triazolyl-linked quinine scaffolds were synthesized under solvent-free mechanochemical ball milling conditions. Products (6a-s) were screened for in-vitro antimalarial and antileishmanial activity. Screening results indicated that out of the synthesized series of 19 products, compounds 6d, 6h, 6l, 6m, and 6n showed significant antimalarial (P. falciparum) and antileishmanial activities (L. donavani) with IC50 values 0.28, 0.28, 0.25, 0.33, 0.76 µM and 8.26, 4.4, 1.78, 3.95, and 4.06 µM, respectively. Further toxicological analysis established the Median lethal dose (LD50), No observed adverse effect level (NOAEL) and human equivalent dose (HED) of the most potent compounds by acute and sub acute toxicity studies performed in rodent animal model. The studies revealed that compounds (6d, 6h, 6l and 6m) did not reveal any toxic manifestation at dose 1000 mg/Kg and from which the corresponding HED was calculated to be 13.84 mg/kg.Graphical abstractGraphical abstract for this article
  • Discovery and development of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic
           acid derivatives as Bcl-2/Mcl-1 inhibitors
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Renshuai Liu, Lulu Liu, Xinying Yang, Hao Fang Bcl-2 family proteins play a vital role for cancer cell in escaping apoptosis, and small-molecule anti-apoptotic Bcl-2 protein inhibitors have been developed as new anticancer therapies. In current study, a series of substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were developed based on the lead compound 1 (Ki = 5.2 µM against Bcl-2 protein). The fluorescence polarization assays suggested that active compounds possessed potent binding affinities to both Bcl-2 and Mcl-1 protein, but had minor or no binding affinities to Bcl-XL protein. MTT assays showed that these compounds had certain anti-proliferative activities against cancer cells. Furthermore, it was found that active compound 11t could induce cell apoptosis and caspase-3 activation in a dose-dependent manner in Jurkat cells.Graphical abstractGraphical abstract for this article
  • Isolation, identification, and quantification of Pentylcurcumene from
           Geophila repens: A new class of cholinesterase inhibitor for Alzheimer’s
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Umesh Chandra Dash, Satish Kanhar, Anshuman Dixit, Jagnehswar Dandapat, Atish Kumar Sahoo The aerial part of Geophila repens (L.) I.M. Johnst (Rubiaceae) has been used in India to improve intelligence and memory for a long time. As part of our ongoing efforts in discovering potential bioactive compounds from G. repens, we have studied the isolation, identification, and quantification of a new class of cholinesterase inhibitor from G. repens for Alzheimer’s disease (AD). Terpene was isolated from hydroalcohol extract of G. repens (GRHA) and its structure was identified “Pentylcurcumene” by spectroscopic data. HPTLC fingerprint analysis was performed and good separation was achieved in mobile phase (benzene:methanol; 7.5:2.5, v/v, 254 and 366 nm; Rf 0.51). The method was validated using ICH guidelines in terms of linearity, specificity, sensitivity, accuracy, precision, robustness and stability. In cellular antioxidant studies e.g. DPPH, oxygen-radical-absorbance-capacity (ORAC) and cell-based-antioxidant-protection-in-erythrocytes (CAP-e) assays showed that, Pentylcurcumene showed remarkably different degrees of antioxidant activities in dose-dependent manner. Pentylcurcumene demonstrated anticholinesterase activities e.g. IC50 of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition were 73.12 ± 0.56 and 97.65 ± 0.46 μg/ml, respectively. To better understand enzyme kinetics, Lineweaver-Burk plot of Pentylcurcumene displayed the highest affinity with competitive inhibition (reversible) towards both AChE (Vmax 0.8) and BChE (Vmax 0.6). An improved and advanced HPTLC tool of bioautography detection of Pentylcurcumene has been successfully demonstrated its anticholinesterase activities. Molecular docking simulations of Pentylcurcumene (ligand) and enzymes (proteins) exhibited the binding of ligand at active sites of AChE (human/rat) and BChE (human/homology) efficiently and also predicted the hydrophobic interaction of drug towards different amino acid residue within proteins. As per the results of antioxidant study and with the support of molecular docking analysis, it is concluded that Pentylcurcumene could be a potential first-line cholinesterase-inhibitor for AD.Graphical abstractGraphical abstract for this article
  • Synthesis and molecular docking study of some
           3,4-dihydrothieno[2,3-d]pyrimidine derivatives as potential antimicrobial
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Omaima G. Shaaban, Doaa A.E. Issa, Alaa A. El-Tombary, Shrouk M. Abd El Wahab, Abeer E. Abdel Wahab, Ibrahim A. Abdelwahab In continuation of our research program aiming at developing new potent antimicrobial agents, new series of substituted 3,4-dihydrothieno[2,3-d]pyrimidines was synthesized. The newly synthesized compounds were preliminary tested for their in vitro activity against six bacterial and three fungal strains using the agar diffusion technique. The results revealed that compounds 7, 8a, 10b, 10d and 11b exhibited half the potency of levofloxacine against the Gram-negative bacterium, Pseudomonas aeruginosa, while compounds 5a, 8b, 10c and 12 displayed half the potency of levofloxacine against Proteus Vulgaris. Whereas, compounds 7, 10b, 10d and 11b showed half the activity of ampicillin against the Gram-positive bacterium, B. subtilis. Most of the compounds showed high antifungal potency. Compounds 3, 6, 7, 9b, 10a, 11a, 11b, 15 and 16 exhibited double the potency of clotrimazole against A. fumigatus. While compounds 3, 4, 5a, 5b, 9b, 10a, 10b, 10c, 13, 15, 16 and 18 displayed double the activity of clotrimazole against R. oryazae. Molecular docking studies of the active compounds with the active site of the B. anthracis DHPS, showed good scoring for various interactions with the active site of the enzyme compared to the co-crystallized ligand.Graphical abstractGraphical abstract for this article
  • Synthesis and anti-tumor activity of [1,4] dioxino [2,3-f] quinazoline
           derivatives as dual inhibitors of c-Met and VEGFR-2
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Dengshuai Wei, Haoru Fan, Kun Zheng, Xuemei Qin, Leifu Yang, Yajuan Yang, Ye Duan, Qiang Zhang, Chengchu Zeng, Liming Hu Both c-Met and VEGFR-2 were important targets for cancer therapies. In order to develop reversible and non-covalent c-Met and VEGFR-2 dual inhibitors, a series of [1,4]dioxino[2,3-f]quinazoline derivatives were designed and synthesized. The enzyme assay demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2 with IC50 values in nanomolar range especially compounds 7m and 7k. Based on further cell proliferation assay in vitro, compound 7k showed significantly anti-tumor activity in vivo on a hepatocellular carcinoma (MHCC97H cells) xenograft mouse model. We docked the compound 7m with c-Met and VEGFR-2 kinases, and interpreted the SAR of these analogues. All results indicated that the target compounds were dual inhibitors of c-Met and VEGFR-2 kinases that held promising potential in cancer therapy.Graphical abstractGraphical abstract for this article
  • An exhaustive compilation on chemistry of triazolopyrimidine: A journey
           through decades
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Pankaj Kumar Singh, Shalki Choudhary, Aanchal Kashyap, Himanshu Verma, Swati Kapil, Manoj Kumar, Mohit Arora, Om Silakari The triazolopyrimidine scaffold represents one of the privileged structure in chemistry, and there has been an increase in number of studies utilizing this scaffold and its derivatives. Optimization of synthetic protocols such as aza-Wittig reaction, [3 + 2] cycloaddition reaction along with previous methods including condensation with 1,3-dicarbonyl substrates and oxidation of aminopyrimidine Schiff bases have been performed to obtain desired triazolopyrimidines. The triazolopyrimidine ring has been extensively used as a template in medicinal chemistry for its diverse pharmacological properties. Several medicinally active molecules possessing triazolopyrimidine scaffold, either fused or coupled with other heterocycles, have been reported in the literature, highlighting the significance of this nucleus. Interestingly, the unique triazolopyrimidine scaffold also exhibits an impressive potential as a ligand for the synthesis of several metal complexes with significant biological potential. Literature provides enough evidence of exhaustive exploration of this scaffold as a ligand for the chelates of platinum, ruthenium and other metals. This review aims to be a comprehensive and general summary of the different triazolopyrimidine syntheses, their use as ligands for the synthesis and development of metal complexes as medicinal agents and their main biological activities.Graphical abstractGraphical abstract for this article
  • Design, synthesis, anticancer evaluation, molecular docking and cell cycle
           analysis of 3-methyl-4,7-dihydropyrazolo[1,5-a]pyrimidine derivatives as
           potent histone lysine demethylases (KDM) inhibitors and apoptosis inducers
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Nadia Hanafy Metwally, Mona Said Mohamed, Eman Ali Ragb A novel series of pyrazolo[1,5-a]pyrimidines were synthesized and proved by their spectral and elemental analysis, some elected of the newly synthesized compounds were examined for their cytotoxic activity employing MTT assay on two cancer cell lines (Breast and Hela cancers). Compounds 5, 7e and 7i showed the higher cytotoxicity against two cancer cell lines with (IC50 = 13.91 ± 1.4 and 22.37 ± 1.8 μM/L), (IC50 = 6.56 ± 0.5 and 8.72 ± 0.9 μM/L) and (IC50 = 4.17 ± 0.2 and 5.57 ± 0.4 μM/L) for two cancer cell lines breast and hela respectively, using doxorubicin as a reference drug. The most potent cytotoxic active compounds 5, 7e and 7i presented inhibitory activity against KDM (histone lysine demethylases) with IC50 = 4.05, 1.91 and 2.31 μM, respectively. The most potent KDM inhibitor 7e (IC50 = 1.91 μM) showed to cause cell cycle arrest at G2/M phase by 4 folds than control and induce total apoptotic effect by 10 folds more than control. In silico studies performed on the more potent cytotoxic active compounds 5, 7e and 7i included lipinisk's rule of five. Moreover, molecular docking study was utilized to explore the binding mode of the most active compounds to the target enzyme (PDB-ID: 5IVE). Also, some bioinformatics studies were carried out for compounds 7e and 7i using Swiss ADME (Swiss Institute of bioinformatics 2018).Graphical abstractGraphical abstract for this article
  • In-silico design and synthesis of N9-substituted β-Carbolines as PLK-1
           inhibitors and their in-vitro/in-vivo tumor suppressing evaluation
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Gomathi Priya Jeyapal, Rajendiran Krishnasamy, Carolyn K. Suzuki, Sundararajan Venkatesh, M.J.N. Chandrasekar A new series of β-Carboline/Schiff bases was designed, synthesized, characterised and biologically evaluated as inhibitors of PLK-1. The synthesized compounds exhibited strong to moderate cytotoxic activities against NCI-60 panel cell assay. Compound SB-2 was the most potent, particularly against colon with GI50 of 3–45 µM on NCI-60 panel cell lines. SB-2 selectively inhibited PLK-1 at 15 µM on KinomeScan screening. It also showed a dose-dependent cell cycle arrest at S/G2 phase on HCT-116 and induced apoptosis by the activation of procaspase-3 and cleaved PARP. Further, the antitumor studies on DLA and EAC model revealed that SB-2, at 100 mg/kg/bd.wt significantly increased their average lifespan. Further, a decrease in the body weight of the tumor-bearing mice was also observed when compared to the tumor controlled mice. SB-2 thus shows good potential as antitumor agent.Graphical abstractGraphical abstract for this article
  • Virtual screening of active compounds from Artemisia argyi and potential
           targets against gastric ulcer based on Network pharmacology
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Yue Wang, Yi-wei Sun, Yu-meng Wang, Yan Ju, Da-li Meng Artemisia argyi (AA) is one of the renowned herbs in China often used in the treatment of gastric ulcer (GU). Aiming to predict the active compounds and systematically investigate the mechanisms of Artemisia argyi for GU treatment, the approach of network pharmacology, molecular docking, gene ontology (GO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were adopted, respectively, in present study. A total of 13 predicted targets of the 103 compounds in Artemisia argyi were obtained. Sorted by pathogenic mechanisms of targets and structure types of compounds, it was revealed that flavonoids and sesquiterpenes had better performance than monoterpenes. The network analysis showed that Phospholipase a2 (PA21B), Sulfotransferase family cytosolic 2b member 1 (ST2B1), Nitric-oxide synthase, endothelial (NOS3), Gastrin (GAST), neutrophil collagenase (MMP-8), Leukotriene A-4 hydrolase (LKHA4), Urease maturation factor HypB (HYPB), and Periplasmic serine endoprotease DegP (HtrA) were the key targets with intensely interaction. The functional enrichment analysis indicated that AA probably produced the gastric mucosa protection effects by synergistically regulating many biological pathways, such as NF-κB signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, VEGF signaling pathway, and Toll-like receptor signaling pathway, etc. In addition, C73 and C15 might be promising leading compounds with good molecular docking score. As a consequence, this study holistically illuminates the active constituents and mechanisms based on data analysis, which contributes to searching for leading compounds and the development of new drugs for gastric ulcer.Graphical abstractGraphical abstract for this article
  • Synthesis of some new C2 substituted dihydropyrimidines and their
           electrophysiological evaluation as L-/T-type calcium channel blockers
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Mohamed Teleb, Ola H. Rizk, Fang-Xiong Zhang, Frank R. Fronczek, Gerald W. Zamponi, Hesham Fahmy Drugs targeting different calcium channel subtypes have strong therapeutic potential for future drug development for cardiovascular disorders, neuropsychiatric diseases and cancer. This study aims to design and synthesize a new series of C2 substituted dihydropyrimidines to mimic the structure features of third generation long acting dihydropyridine calcium channel blockers and dihydropyrimidines analogues. The target compounds have been evaluated as blockers for CaV1.2 and CaV3.2 utilizing the whole-cell patch clamp technique. Among the tested compounds, compound 7a showed moderate calcium channel blockade activity against CaV3.2. Moreover, the predicted physicochemical properties and pharmacokinetic profiles of the target compounds recommend that they can be considered as drug-like candidates. The results highlight some significant information for the future design of lead compounds as calcium channel blockers.Graphical abstractNew series of C2 substituted dihydropyrimidines were designed and synthesized to mimic the structure features of third generation long acting dihydropyridine calcium channel blockers and dihydropyrimidines analogues. They are evaluated as blockers for CaV1.2 and CaV3.2 utilising the whole-cell patch clamp technique. Compound 7a showed moderate calcium channel activity against CaV3.2.Graphical abstract for this article
  • Hydrazones as novel epigenetic modulators: Correlation between TET 1
           protein inhibition activity and their iron(II) binding ability
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Milan Jakubek, Zdeněk Kejík, Robert Kaplánek, Veronika Antonyová, Róbert Hromádka, Viera Šandriková, David Sýkora, Pavel Martásek, Vladimír Král Ten-eleven translocation protein (TET) 1 plays a key role in control of DNA demethylation and thereby of gene expression. Dysregulation of these processes leads to serious pathological states such as oncological and neurodegenerative ones and thus TET 1 targeting is highly requested. Therefore, in this work, we examined the ability of hydrazones (acyl-, aroyl- and heterocyclic hydrazones) to inhibit the TET 1 protein and its mechanism of action. Inhibitory activity of hydrazones 1–7 towards TET 1 was measured. The results showed a high affinity of the tested chelators for iron(II). The study clearly showed a significant correlation between the chelator’s affinity for iron(II) ions (represented by the binding constant) and TET 1 protein inhibitory activity (represented by IC50 values).Graphical abstractGraphical abstract for this article
  • Synthesis of novel schiff bases and azol-β-lactam derivatives starting
           from morpholine and thiomorpholine and investigation of their
           antitubercular, antiurease activity, acethylcolinesterase inhibition
           effect and antioxidant capacity
    • Abstract: Publication date: Available online 16 April 2019Source: Bioorganic ChemistryAuthor(s): Yıldız Uygun Cebeci, Hacer Bayrak, Yakup Şirin In this study, new Schiff bases and β-lactam derivatives containing morpholine and thio morpholine nuclei were synthesized. Antimicrobial, antioxidant, antimicrobial and antioxidant properties of all synthesized compounds were investigated and highly effective products were obtained. In this context, new effective structures were introduced to the literature.Graphical abstractGraphical abstract for this article
  • Novel Eugenol Bearing Oxypropanolamines: Synthesis, Characterization,
           Antibacterial, Antidiabetic, and Anticholinergic Potentials
    • Abstract: Publication date: Available online 16 April 2019Source: Bioorganic ChemistryAuthor(s): Hayriye Genc Bilgicli, Ali Kestane, Parham Taslimi, Oguz Karabay, Arlinda Bytyqi-Damoni, Mustafa Zengin, İlhami Gulçin Five oxypropanol amine derivatives that four of them are novel have been synthesized with high yields and practical methods. in vitro antibacterial susceptibility of Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus strains to synthesized substances were evaluated with agar well-diffusion method by comparison with commercially available drugs. Most of the bacteria were multidrug resistant. It was concluded that these compounds are much more effective than reference drugs. These eugenol bearing oxypropanolamine derivatives were also effective inhibitors against α-glycosidase, cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase (AChE) enzymes with Ki values in the range of 0.80±0.24–3.52±1.01 µM for hCA I, 1.08±0.15-3.64±0.92 µM for hCA II, 5.18±0.84-12.46±2.08 µM for α-glycosidase, and 11.33±2.83-32.81±9.73 µM for AChE, respectively.Graphical abstractGraphical abstract for this article
  • Discovery of Cycloneolignan Enantiomers from Isatis indigotica Fortune
           with Neuroprotective Effects against MPP+-Induced SH-SY5Y Cell Injury
    • Abstract: Publication date: Available online 15 April 2019Source: Bioorganic ChemistryAuthor(s): Yu-Fei Xi, Si-Fan Liu, Wei Hong, Xiao-Yu Song, Li-Li Lou, Le Zhou, Guo-Dong Yao, Bin Lin, Xiao-Bo Wang, Xiao-Xiao Huang, Shao-Jiang Song A pair of new cycloneolignan enantiomers (1a and 1b) were isolated from the leaves of Isatis indigotica Fortune. Their structures were elucidated by extensive spectroscopic data analysis, including 1D and 2D NMR, HRESIMS, MS/MS analysis, together with theoretical electronic circular dichroism (ECD) calculations. Compounds 1a and 1b were then evaluated for their neuroprotective effects against MPP+-induced SH-SY5Y cell injury. As a result, compounds 1a (77.64 %) and 1b (78.62 %) exhibited moderate neuroprotective activity at the concentration of 12.5 µM compared with that of MPP+ treated group (62.00% at 1mM) by MTT assay. Furthermore, Annexin V-FITC/PI analysis showed that apoptosis ratios of 1a and 1b were reduced to 10.99 % and 9.31 %, respectively.Graphical abstractGraphical abstract for this article
  • Targeting hepatocellular carcinoma: Synthesis of new pyrazole-based
           derivatives, biological evaluation, DNA binding, and molecular modeling
    • Abstract: Publication date: July 2019Source: Bioorganic Chemistry, Volume 88Author(s): Dina M. Omran, Mariam A. Ghaly, Shahenda M. El-Messery, Farid A. Badria, Ehab Abdel-Latif, Ihsan A. Shehata A new series of pyrazole derivatives was prepared in this work, including pyrazolopyrimidines, pyrazolotriazines, pyrazolylthienopyridines, and 2-(pyrazolylamino)thiazol-4-ones, utilizing 3-amino-5-methyl-1H-pyrazole as a synthetic precursor. Their in vitro anticancer activity was tested on hepatocellular carcinoma cell line, HepG2. The results revealed that the pyrazolylhydrazonoyl cyanide 8, the pyrazolopyrimidine 3, and the pyrazolylaminothiazolone 17 were the most active with IC50 values of 2, 7, and 7 µM respectively in comparison with 5.5 µM for cisplatin as a reference drug. Interestingly, all the synthesized compounds showed higher selectivity index than cisplatin. DNA binding assay was also carried out for the synthesized compounds to rationalize their mechanism of action. Molecular modeling studies, including docking into DNA minor groove, flexible alignment, and surface mapping, were conducted. Results obtained proved the superior DNA-binding affinity of the most active anticancer compounds.Graphical abstractA new series of pyrazole-based derivatives was synthesized. Their anticancer activity was tested against hepatocellular carcinoma (HepG2) cell line. The DNA-binding activity of the synthesized compounds was evaluated. Compounds 8, 3, and 17 showed the most potent activity.Graphical abstract for this article
  • 6-Methoxyflavonols from the aerial parts of Tetragonia tetragonoides
           (Pall.) Kuntze and their anti-inflammatory activity
    • Abstract: Publication date: Available online 11 April 2019Source: Bioorganic ChemistryAuthor(s): Yeong-Geun Lee, Hwan Lee, Jin Ah Ryuk, Joo Tae Hwang, Hyoung-Geun Kim, Dong-Sung Lee, Yeon-Ju Kim, Deok-Chun Yang, Byoung Seob Ko, Nam-In Baek Dried aerial parts of Tetragonia tetragonoides were extracted with 70% EtOH, and the evaporated residue was successively separated into EtOAc, n-BuOH, and H2O fractions. As a result of repeated SiO2, ODS, and Sephadex LH-20 column chromatography, four new 6-methoxyflavonol glycosides (2-4, 8) along with four known ones (1, 5-7) were isolated. Several spectroscopic data led to determination of chemical structures for four new 6-methoxyflavonol glycosides (2-4, 8) and four known ones, 6-methoxykaempferol 3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-7-O-(6''''-(E)-caffeoyl)-β-D-glucopyranoside (1), 6-methoxyquercetin (5), 6-methoxykaempferol (6), and 6-methoxykaempferol 7-O-β-D-glucopyranoside (7). Methoxyflavonol glycosides 2-8 also have never been reported from T. tetragonoides in this study. 6-Methoxyflavonols 5 and 6 showed high radical scavenging potential in DPPH and ABTS test. Also, all compounds showed significant anti-inflammatory activities such as reduction of NO and PGE2 formation and suppression of TNF-α, IL-6, IL-1β, iNOS, and COX-2 expression in LPS-stimulated RAW 264.7 macrophages. In general, the aglycones exhibited higher activity than the glycosides. In addition, quantitative analysis of 6-methoxyflavonols in the T. tetragonoides aerial parts extract was conducted through HPLC.Graphical abstractGraphical abstract for this article
  • Substituted 1,3-dioxoisoindoline-4-Aminoquinolines coupled via amide
           linkers: Synthesis, Antiplasmodial and Cytotoxic Evaluation
    • Abstract: Publication date: Available online 11 April 2019Source: Bioorganic ChemistryAuthor(s): Anu Rani, Jenny Legac, Philip.J. Rosenthal, Vipan Kumar Synthesis of C-5-substituted 1,3-dioxoisoindoline-4-aminoquinolines having amide group as a spacer was developed with an intent to evaluate their antiplasmodial activities. The synthesized dioxoisoindoline-aminoquinolines tethered with β-alanine as a spacer and secondary amine as substituent displayed good anti-plasmodial activities. Compound 7j, with an optimum combination of β-alanine and an ethyl chain length as linker along with diethylamine as the secondary amine counterpart at dioxoisoindoline proved to be most potent and non-cytotoxic with IC50 of 0.097 µM against W2 strain of P. falciparum and a selective index of>2000.Graphical abstractSynthesis of substituted 1,3-dioxoisoindoline-4-aminoquinolines coupled via amide group, along with their anti-plasmodial and cytotoxicity evaluation.Graphical abstract for this article
  • Cisplatin: The First Metal Based Anticancer Drug
    • Abstract: Publication date: Available online 11 April 2019Source: Bioorganic ChemistryAuthor(s): Sumit Ghosh Cisplatin or (SP-4-2)-diamminedichloridoplatinum(II) is one of the most potential and widely used drugs for the treatment of various solid cancers such as testicular, ovarian, head and neck, bladder, lung, cervical cancer, melanoma, lymphomas and several others. Cisplatin exerts anticancer activity via multiple mechanisms but its most acceptable mechanism involves generation of DNA lesions by interacting with purine bases on DNA followed by activation of several signal transduction pathways which finally lead to apoptosis. However, side effects and drug resistance are the two inherent challenges of cisplatin which limit its application and effectiveness. Reduction of drug accumulation inside cancer cells, inactivation of drug by reacting with glutathione and metallothioneins and faster repairing of DNA lesions are responsible for cisplatin resistance. To minimize cisplatin side effects and resistance, combination therapies are used and have proven more effective to defect cancers. This article highlights a systematic description on cisplatin which includes a brief history, synthesis, action mechanism, resistance, uses, side effects and modulation of side effects. It also briefly describes development of platinum drugs from very small cisplatin complex to very large next generation nanocarriers conjugated platinum complexes.Graphical abstractGraphical abstract for this article
  • Chemical constituents from Vietnamese mangrove Calophyllum inophyllum and
           their anti-inflammatory effects
    • Abstract: Publication date: Available online 11 April 2019Source: Bioorganic ChemistryAuthor(s): Nguyen Van Thanh, Hyun-Jae Jang, Le Ba Vinh, Kieu Thi Phuong Linh, Phan Thi Thanh Huong, Nguyen Xuan Cuong, Nguyen Hoai Nam, Chau Van Minh, Young Ho Kim, Seo Young Yang In a search for anti-inflammatory activity in resources from Vietnamese mangroves, we found that a methanolic extract from the leaves of Calophyllum inophyllum (CIL) showed significant anti-inflammatory effects in vitro. Using various chromatographic techniques, we subsequently isolated 12 compounds (1–12) from a methanolic extract of CIL, including two novel compounds (1−2). The inhibitory effects of these compounds on lipopolysaccharide-induced nitric oxide (NO) production in RAW264.7 cells were also evaluated. Compound 1 significantly suppressed NO production (IC50 = 2.44 ± 0.88 µM), the secretion of pro-inflammatory cytokines (including interleukin-1 beta and tumor necrosis factor alpha), and the expression of inducible nitric oxide synthase through downregulation of nuclear factor-kappa-B signaling cascades. These results suggest that C. inophyllum leaves might be a useful resource for the development of drugs for the treatment of inflammation.Graphical abstractGraphical abstract for this article
  • Potent and selective EGFR inhibitors based on
    • Abstract: Publication date: Available online 11 April 2019Source: Bioorganic ChemistryAuthor(s): Ann Christin Reiersølmoen, Thomas Aarhus, Sarah Eckelt, Kristin Gabestad Nørsett, Eirik Sundby, Bård Helge Hoff The epidermal growth factor receptor represents an important target in cancer therapy, and low molecular weight inhibitors based on quinazolines have reached the marked. Herein we report on a new scaffold, 5-aryl-7H-pyrrolo[2,3-d]pyrimidin-4-amines, and show that when employing (S)-phenylglycinol as C-4 substituent, potent inhibitors can be made. The two most active inhibitors have suitable druglike properties, were equipotent with Erlotinib in Ba/F3 cell studies, and showed lower cross reactivity than Erlotinib in a panel of 50 kinases.Graphical abstractGraphical abstract for this article
  • Synthesis, antitumor testing and molecular modeling study of some new 6-
           substituted amido, azo or thioureido-quinazolin-4(3H)-ones
    • Abstract: Publication date: Available online 10 April 2019Source: Bioorganic ChemistryAuthor(s): Mohamed A. Sabry, Heba A. Ewida, Ghada S. Hassan, Mariam A. Ghaly, Hussein I. El-Subbagh A new series of 6-substituted amido, azo or thioureido-quinazolin-4(3H)-one was synthesized and tested for their in-vitro antitumor activity. Compounds 21, 53 and 60 showed broad spectrum antitumor activity with average IC50 values of 6.7, 7.6 and 9.1 μM, respectively compared with methotrexate (1, IC50 19.26 μM). As an attempt to reveal the mechanism of the antitumor potency, cell cycle analysis and DHFR inhibition were performed. Compounds 59 and 61 induced their cytotoxicity in Hela (IC50 10.6 μM) and HCT-116 (IC50 15.5 μM) cell lines, respectively through Pre-G1 apoptosis, inhibiting cell growth at G2-M phase. Compounds 29, 33, 59 and 61 showed DHFR inhibitory potency at IC50 0.2, 0.2, 0.3 and 0.3 μM, respectively. The active DHFR inhibitors showed high affinity binding toward the amino acid residues Thr56, Ser59 and Ser118. The active compounds obeyed Lipinski’s rule of five and could be used as template model for further optimization.Graphical abstractGraphical abstract for this article
  • Vieloplains A-G, seven new guaiane-type sesquiterpenoid dimers from
           Xylopia vielana
    • Abstract: Publication date: Available online 10 April 2019Source: Bioorganic ChemistryAuthor(s): Yangguo Xie, Xianglong Zhong, Yongzhen Xiao, Shenglan zhu, Ishaq Muhammad, Shikai Yan, Huizi Jin, Weidong Zhang Seven new guaiane-type sesquiterpene dimers vieloplains A-G, connecting patterns through three different direct C−C bonds compounds 1-5 (C-3 to C-3′, C-4 to C-1′), compound 6 (C-2 to C-3′, C-4 to C-2′) and compound 7 (C-2 to C-1′, C-4 to C-2′) were isolated from the roots of Xylopia vielana. Their absolute configurations were established by NOESY analysis, the Cu Kα X-ray crystallographic the experiment circular dichroism (ECD) and the calculated ECD. Among them, only compound 6 showed a considerable cytotoxicity against DU145 cells with IC50 values of 9.5 μM. Flow cytometry analysis confirmed that 6 caused death of DU145 cells via apoptosis induction.Graphical abstractSeven new guaiane-type sesquiterpene dimers vieloplains A-G, connecting mode (C-3 to C-3′, C-4 to C-1′), (C-2 to C-3′, C-4 to C-2′) and (C-2 to C-1′, C-4 to C-2′), were isolated from the roots of Xylopia vielana. Flow cytometry analysis confirmed that 6 caused death of DU145 cells via apoptosis inductionGraphical abstract for this article
  • Facile one-pot synthesis, antiproliferative evaluation and
           structure–activity relationships of 3-amino-1H-indoles and
    • Abstract: Publication date: Available online 10 April 2019Source: Bioorganic ChemistryAuthor(s): Peng-Cheng Diao, Meng-Jin Hu, Hai-Kui Yang, Wen-Wei You, Pei-Liang Zhao A highly efficient method has been developed for the one-pot synthesis of substituted 3-amino-1H-indole and 3-amino-1H-7-azaindole derivatives starting from ethyl 2-cyanophenylcarbamate/ethyl 3-cyanopyridin-2-ylcarbamate, and α-bromoketones in good to excellent yields. All newly synthesized analogues were screened for their antiproliferative activities against four cancer cell lines. The most promising compound 8v demonstrated 13-, 5-, and 1.4-fold improvement compared to fluorouracil in inhibiting HeLa, HepG2, and MCF-7 cell proliferation with IC50 values of 3.7, 8.0, and 19.9 μM, respectively. Furthermore, 8v induced significant cell cycle arrest at the G2/M phase in HeLa cell lines via a concentration-dependent manner. These encouraging findings indicate that the common 3-amino-1H-7-azaindole is a very favorable scaffold for the design of novel anticancer small-molecule drugs.Graphical abstractA highly efficient method has been developed for the one-pot synthesis of 3-amino-1H-indoles and 3-amino-1H-7-azaindoles. All newly synthesized analogues were screened for their antiproliferative activities against four cancer cell lines.Graphical abstract for this article
  • Identification of novel imidazole flavonoids as potent and selective
           inhibitors of protein tyrosine phosphatase
    • Abstract: Publication date: Available online 9 April 2019Source: Bioorganic ChemistryAuthor(s): Ling Zhang, Yu Ge, Qing Ming Wang, Cheng-He Zhou A series of imidazole flavonoids as new type of protein tyrosine phosphatase inhibitors were synthesized and characterized. Most of them gave potent protein phosphatase 1B (PTP1B) inhibitory activities. Especially, compound 11a could effectively inhibit PTP1B with an IC50 value of 0.63 μM accompanied with high selectivity ratio (9.5-fold) over T-cell protein tyrosine phosphatase (TCPTP). This compound is cell permeable with relatively low cytotoxicity. The high binding affinity and selectivity was disclosed by molecular modeling and dynamics studies. The structural features essential for activity were confirmed by quantum chemical studies.Graphical abstractGraphical abstract for this article
  • Glucosamine-6-phosphate synthase inhibiting C3-β-cholesterol tethered
           spiro heterocyclic conjugates: Synthesis and their insight of DFT and
           docking study
    • Abstract: Publication date: Available online 9 April 2019Source: Bioorganic ChemistryAuthor(s): Govindasami Periyasami, Subban Kamalraj, Ramanathan Padmanaban, Santhakumar Yeswanth Kumar, Antony Stalin, Natarajan Arumugam, Raju Suresh Kumar, Mostafizur Rahaman, Periyan Durairaju, Abdulaziz Alrehaili, Ali Aldalbahi A series of novel covalent cholesterol-spiro pyrrolidine/pyrrolizidine heterocyclic hybrids possessing biologically active oxindole, indanedione, and acenaphthylene-1-one have been synthesized by the reaction of C3-β-cholesteroalacrylate with heterocyclic di- and tri- ketones. All the sixteen compounds were obtained as a single isomer in good yield through a stereo- and regio- selective 1,3-dipolar cycloaddition methodology. Stereochemistry of the spiranic cycloadducts has been established by spectroscopic analysis and the regioselectivity outcome of the spiro adducts has been accomplished by DFT calculations at B3LYP/6-31G (d,p) level study. In vitro antibacterial activity of the newly synthesized cycloadducts were evaluated against highly pathogenic Gram-positive and Gram-negative bacteria and the most active compounds 5a, 13, and 14 underwent automated in silico molecular docking analysis in order to validate their effective orientation as a inhibitors bound in the active site of glucosamine-6-phosphate synthase (1XFF) enzyme by employing AutoDock Tools.Graphical abstractGraphical abstract for this article
  • Probing the high potency of pyrazolyl pyrimidinetriones and
           thioxopyrimidinediones as selective and efficient non-nucleotide
           inhibitors of recombinant human ectonucleotidases
    • Abstract: Publication date: Available online 2 April 2019Source: Bioorganic ChemistryAuthor(s): Hina Andleeb, Shahid Hameed, Syeda Abida Ejaz, Imtiaz Khan, Sumera Zaib, Joanna Lecka, Jean Sévigny, Jamshed Iqbal With the aim to discover novel, efficient and selective inhibitors of human alkaline phosphatase and nucleotide pyrophosphatase enzymes, two new series of pyrazolyl pyrimidinetriones (PPTs) (6a-g) and thioxopyrimidinediones (PTPs) (6h-n) were synthesized in good chemical yields using Knoevenagel condensation reaction between pyrazole carbaldehydes (4a-g) and pharmacologically active N-alkylated pyrimidinetrione (5a) and thioxopyrimidinedione (5b). The inhibition potential of the synthesized hybrid compounds was evaluated against human alkaline phosphatase (h-TNAP and h-IAP) and ectonucleotidase (h-NPP1 and h-NPP3) enzymes. Most of the tested analogs were highly potent with a variable degree of inhibition depending on the functionalized hybrid structure. The detailed structure-activity relationship (SAR) of PPT and PTP derivatives suggested that the compound with unsubstituted phenyl ring from PPT series led to selective and potent inhibition (6a; IC50 = 0.33 ± 0.02 µM) of h-TNAP, whereas compound 6c selectively inhibited h-IAP isozyme with IC50 value of 0.86 ± 0.04 µM. Similarly, compounds 6b and 6h were identified as the lead scaffolds against h-NPP1 and h-NPP3, respectively. The probable binding modes for the most potent inhibitors were elucidated through molecular docking analysis. Structure-activity relationships, mechanism of action, cytotoxic effects and druglikeness properties are also discussed.Graphical abstractGraphical abstract for this article
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