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Wiley, Chemical Biology & Drug Design, 2(88), p. 241-253, 2016

DOI: 10.1111/cbdd.12751

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Arylazolyl(azinyl)thioacetanilides. Part 19☆: Discovery of novel substituted imidazo[4,5-b]pyridin-2-ylthioacetanilides as potent HIV NNRTIs via a structure-based bioisosterism approach

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

With continuation of our unremitting efforts toward the discovery of potent HIV-1 NNRTIs, a series of novel imidazo[4,5-b]pyridin-2-ylthioacetanilides were designed, synthesized and evaluated for their antiviral activities through combining bioisosteric replacement and structure-based drug design. Almost all of the title compounds displayed moderate to good activities against wild-type (wt) HIV- 1 strain with EC50 values ranging from 0.059 μM to 1.41 μM in a cell-based antiviral assay. Thereinto, compounds 12 and 13 were the most active two analogues possessing an EC50 value of 0.059 μM and 0.073 μM against wt HIV-1 respectively, which was much more effective than the control drug Nevirapine (EC50 = 0.26 μM) and comparable to Delavirdine (EC50 = 0.038 μM). In addition, one selected compound showed remarkable reverse transcriptase inhibitory activity compared to Nevirapine and Etravirine. In the end of this manuscript, preliminary structure-activity relationships (SARs) and molecular modeling studies were detailedly discussed, which may provide valuable insights for further optimization. This article is protected by copyright. All rights reserved.