Discovery of potent HIV‐1 non‐nucleoside reverse transcriptase inhibitors by exploring the structure–activity relationship of solvent‐exposed regions I. (22nd February 2019)

• Record Type: Journal Article
• Authors: Kang, Dongwei; Wang, Zhao; Chen, Meng; Feng, Da; Wu, Gaochan; Zhou, Zhongxia; Jing, Lanlan; Zuo, Xiaofang; Jiang, Xiangyi; Daelemans, Dirk; De Clercq, Erik; Pannecouque, Christophe; Zhan, Peng; Liu, Xinyong
• Is Part Of: Chemical biology & drug design. Volume 93:Number 4(2019)
• Page Start: 430
• Page End: 437
• Publication Date: 2019-02-22
• Subjects: DAPY -- HIV‐1 -- NNRTIs -- solvent‐exposed region I -- thiophene[3, 2‐d]pyrimidine; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13429
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract: Two novel series of human immunodeficiency virus‐1 (HIV‐1) non‐nucleoside reverse transcriptase inhibitors (NNRTIs) bearing a thiophene[3, 2‐ d ]pyrimidine scaffold and sulfonamide linker in the right wing have been identified, which demonstrated activity against the wild‐type (WT) HIV‐1 strain in MT‐4 cells with inhibitory concentrations ranging from micromolar to submicromolar. Especially, against the mutant strains K103N and E138K, most compounds exhibited more potent activity than against WT HIV‐1. Compound7 (EC50 = 0.014, 0.031 μM) achieved the most potent activity against the two mutants, being more effective than that of nevirapine (NVP, EC50 = 7.572, 0.190 μM) and comparable to that of etravirine (ETV, EC50 = 0.004, 0.014 μM). Molecular docking experiments on the novel analogs have also suggested that the extensive network of main chain hydrogen bonds are important in the binding mode, which may provide valuable insights for further optimization. Abstract : Most compounds exhibited more potent activity against the mutant strains K103N and E138K than against WT HIV‐1. Compound7 (EC50 = 0.014, 0.031 µM) achieved the most potent activity against the two mutations, being comparable to that of ETV (EC50 = 0.004, 0.014 µM). Molecular docking experiments on the novel analogs have also suggested that the extensive network of main chain hydrogen bonds are important in the binding mode, which may provide valuable insights for further optimization.