PMID: 11931611Apr 5, 2002Paper

Synthesis, biological evaluation, and binding mode of novel 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles targeted at the HIV-1 reverse transcriptase

Journal of Medicinal Chemistry
Romano SilvestriAlessandra Pani

Abstract

A novel series of 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazole (DAMNI) analogues were synthesized and tested in cell-based assays and in enzyme assays against HIV-1 recombinant reverse transcriptase (RT). Preparation of the new derivatives was performed by reacting the appropriate benzhydrols or the corresponding bromides with 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole or the 3-hydroxypropyl homologue. Several compounds showed anti-HIV-1 activity in the submicromolar range. Structure-activity relationship studies suggested that meta substitution at one phenyl ring of the diarylmethane moiety strongly influences the antiviral activity. The 3,5-disubstitution at the same phenyl ring led to less potent derivatives. Molecular modeling and docking studies within the RT non-nucleoside binding site confirmed that DAMNIs, similar to other NNRTIs such as TNK-651 and delavirdine (BHAP U90152), assume a butterfly-like conformation that appears to be halfway between that of classical NNRTIs, such as nevirapine, HEPT, TBZ, TIBO, and DABOs, and the conformation of BHAPs. In particular, the diphenylmethane moiety mimics the wings whereas the 1-(2-methyl-5-nitroimidazolyl)ethane portion resembles the BHAP 5-methanesulfonamidoindole-2...Continue Reading

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Citations

Jun 21, 2011·Acta Pharmaceutica : a Quarterly Journal of Croatian Pharmaceutical Society and Slovenian Pharmaceutical Society, Dealing with All Branches of Pharmacy and Allied Sciences·Swastika GangulyAbhimanyu Dev
Jan 1, 2007·Expert Opinion on Drug Discovery·Rino RagnoRomano Silvestri
Dec 17, 2015·IEEE/ACM Transactions on Computational Biology and Bioinformatics·Chandrabhan SeniyaNand K Sah
Feb 15, 2020·Current Drug Delivery·Esmeralda Sánchez-PavónAngel Ramos-Ligonio
Nov 26, 2020·European Journal of Medicinal Chemistry·Om P S PatelRichard M Beteck
Jun 13, 2009·The Journal of Organic Chemistry·Frederick A Luzzio, Juan Chen
Jan 10, 2013·ACS Medicinal Chemistry Letters·Matshawandile TukululaKelly Chibale
Jun 13, 2018·The Journal of Organic Chemistry·Zhihua PengCuiyu Jiang
Mar 6, 2015·Organic Letters·Wataru Muramatsu, Kimihiro Nakano

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