학술논문
Design and synthesis of tetrahydrophthalimide derivatives as inhibitors of HIV-1 reverse transcriptase
Document Type
Original Paper
Source
Organic and Medicinal Chemistry Letters. December 2013 3(1):1-8
Subject
Language
English
ISSN
2191-2858
Abstract
Background:Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are one of the key components in highly active anti-retroviral therapy because of their high specificity and less toxicity. NNRTIs inhibit reverse transcriptase enzyme by binding to the allosteric site, which is 10Å away from the active site. Rapid emergence of resistance is the major problem with all anti-HIV agents. Hence, there is continuous need to develop novel anti-HIV agents active against both drug sensitive and resistance strains.Results:All the 16 synthesized 2-(1,3-dioxo-3a,4-dihydro-1H-isoindol-2(3H,7H,7aH)-yl)-N-(substitutedphenyl) acetamide 4(a-p) analogs were characterized by Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, mass spectroscopy, and elemental analysis. Lipinski rule of five parameters and molecular parameters like solubility, drug likeness, and drug score were derived for designed analogs using online servers like Molinspiration and Osiris property explorer. Synthesized compounds were evaluated for their HIV-1 reverse transcriptase inhibitor activity by HIV-1 RNA-dependent DNA polymerase activity assay at 2 and 20 μM concentrations.Conclusions:Among the 16 synthesized compounds, 4a, 4b, 4f, 4g, 4k, and 4l showed weak reverse transcriptase inhibitor activity at 20 μM concentration. For the designed compounds, there was no correlation observed between molecular modeling and in vitro studies.