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Design, Synthesis, Molecular Modeling, In Silico ADME Studies and Anti-HIV-1 Assay of New Diazocoumarin Derivatives.

ABSTRACT: Some new diazo incorporated coumarin compounds were designed and synthesized to evaluate their anti-HIV activity. Overall, compounds were active against HIV at 100 ?M. Additionally, no cytotoxic effect was observed at this concentration. The compound with 4-chlorobenzyl group indicated the best anti-HIV activity (52%). Docking studies using the later crystallographic data available for PFV integrase showed similar binding modes to HIV-1 integrase inhibitors. On the basis of these data, nitrogen atoms of 1,3,4-oxadiazole ring have been involved in the Mg2+ chelation and 4-chlorobenzyl group occupies the same position as 4-flourobenzyl group of raltegravir in the active site. In addition, in silico ADME assay demonstrated favorable physicochemical properties for the new designed compounds. Thus, synthesized structures could be introduced as a novel template for designing safe anti-HIV compounds with integrase inhibitory potential.

SUBMITTER: Alimi Livani Z

PROVIDER: S-EPMC6447871 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Design, Synthesis, Molecular Modeling, <i>In Silico</i> ADME Studies and Anti-HIV-1 Assay of New Diazocoumarin Derivatives.

Alimi Livani Zeynab Z Safakish Mahdieh M Hajimahdi Zahra Z Soleymani Sepehr S Zabihollahi Rezvan R Aghasadeghi Mohammad Reza MR Alipour Eskandanr E Zarghi Afshin A

Iranian journal of pharmaceutical research : IJPR 20180101 Suppl2

Some new diazo incorporated coumarin compounds were designed and synthesized to evaluate their anti-HIV activity. Overall, compounds were active against HIV at 100 μM. Additionally, no cytotoxic effect was observed at this concentration. The compound with 4-chlorobenzyl group indicated the best anti-HIV activity (52%). Docking studies using the later crystallographic data available for PFV integrase showed similar binding modes to HIV-1 integrase inhibitors. On the basis of these data, nitrogen ...[more]

PMID: 31011343

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Project description:The SARS-CoV-2 pandemic at the end of 2019 had major worldwide health and economic consequences. Until effective vaccination approaches were created, the healthcare sectors endured a shortage of operative treatments that might prevent the infection's spread. As a result, academia and the pharmaceutical industry prioritized the development of SARS-CoV2 antiviral medication. Pyranopyrazoles have been shown to play a prominent function in pharmaceutical chemistry and drug sighting because of their significant bioactive properties. We provide herein a novel sequence of pyranopyrazoles and their annulated systems whose antiviral efficacy and cytotoxicity were explored versus human coronavirus 229E (HCoV-229E) Vero-E6 cell lines as a model for the Coronaviridae family. Fifteen synthetic congeners pointed out miscellaneous antiviral efficacies against HCoV-229E with variable inhibition degrees. Compound 18 showed a high selectivity index (SI = 12.6) that established spectacular inhibitory capacity against human coronavirus 229E. Compounds 6, 7, and 14 exposed moderate efficacies. Compounds 6, 7, 14, and 18 exhibited substantial antiviral action through the replication phase with reduction percentages extending from 53.6%, 60.7%, and 55% to 82.2%, correspondingly. Likewise, when assessed to the positive control tipranavir (88.6%), the inhibitory efficiency of compounds 6, 7, 14, and 18 versus the SARS-CoV2 Mpro provided high percentages of 80.4%, 73.1%, 81.4% and up to 84.5%, respectively. In silico studies were performed to investigate further the biological activity and the target compounds' physical and chemical features, including molecular dynamic (MD) simulations, protein-ligand docking, ADME studies, and density functional theory (DFT) calculations. These inquiries demonstrated that this series of metabolically stable pyranopyrazoles and their annulated systems are effective human coronavirus inhibitors that inhibit the viral Mpro protein and may have emerged as a novel COVID-19 curative option.

Dataset Information

Design, Synthesis, Molecular Modeling, In Silico ADME Studies and Anti-HIV-1 Assay of New Diazocoumarin Derivatives.

Publications

Design, Synthesis, Molecular Modeling, <i>In Silico</i> ADME Studies and Anti-HIV-1 Assay of New Diazocoumarin Derivatives.

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