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

作者：Li, Xiao; Huang, Boshi; Zhou, Zhongxia; Gao, Ping; Pannecouque, Christophe; Daelemans, Dirk; De Clercq, Erik; Zhan, Peng^*; Liu, Xinyong^*

来源：Chemical Biology & Drug Design, 2016, 88(2): 241-253.

DOI：10.1111/cbdd.12751

• antiviral activity
• drug design
• HIV
• imidazo[4,5-b]pyridin-2-ylthioacetanilides
• molecular modeling
• NNRTIs
• SAR

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 mu M in a cell-based antiviral assay. Thereinto, compounds 12 and 13 were the most active two analogues possessing an EC50 value of 0.059 and 0.073 mu M against wt HIV-1, respectively, which was much more effective than the control drug nevirapine (EC50 = 0.26 mu M) and comparable to delavirdine (EC50 = 0.038 mu 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.

• 出版日期2016-8
• 单位山东大学; 河北医科大学