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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
Author(s) -
Li Xiao,
Huang Boshi,
Zhou Zhongxia,
Gao Ping,
Pannecouque Christophe,
Daelemans Dirk,
De Clercq Erik,
Zhan Peng,
Liu Xinyong
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12751
Subject(s) - human immunodeficiency virus (hiv) , chemistry , stereochemistry , combinatorial chemistry , biology , virology
With the 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 EC 50 values ranging from 0.059 to 1.41 μ m in a cell‐based antiviral assay. Thereinto, compounds 12 and 13 were the most active two analogues possessing an EC 50 value of 0.059 and 0.073 μ m against wt HIV‐1, respectively, which was much more effective than the control drug nevirapine (EC 50 = 0.26 μ m ) and comparable to delavirdine (EC 50 = 0.038 μ m ). In addition, one selected compound showed a 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.