Arylazolyl(azinyl)thioacetanilides: Part 191: Discovery of Novel Substituted Imidazo[4, 5‐b]pyridin‐2‐ylthioacetanilides as Potent HIV NNRTIs Via a Structure‐based Bioisosterism Approach. (24th March 2016)

• Record Type: Journal Article
• Authors: Li, Xiao; Huang, Boshi; Zhou, Zhongxia; Gao, Ping; Pannecouque, Christophe; Daelemans, Dirk; De Clercq, Erik; Zhan, Peng; Liu, Xinyong
• Is Part Of: Chemical biology & drug design. Volume 88:Number 2(2016)
• Page Start: 241
• Page End: 253
• Publication Date: 2016-03-24
• Subjects: antiviral activity -- drug design -- HIV -- imidazo[4, 5‐b]pyridin‐2‐ylthioacetanilides -- molecular modeling -- NNRTIs -- SAR; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12751
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : 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 EC50 values ranging from 0.059 to 1.41 μm in a cell‐based antiviral assay. Thereinto, compounds12 and13 were the most active two analogues possessing an EC50 value of 0.059 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 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. Abstract : 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 a moderate to excellent activities against wild‐type (wt) HIV‐1 strain with EC50 values ranging from 0.059 to 1.41 μm in a cell‐based antiviral assay. Preliminary structure–activity relationships (SARs) and molecular modeling studies were detailedly discussed, which may provide valuable insights for further optimization.