Discovery of potent HIV‐1 non‐nucleoside reverse transcriptase inhibitors by exploring the structure–activity relationship of solvent‐exposed regions I

• DOI: 10.1111/cbdd.13429
• Publication Date: 2018-11-01T01:44:38Z
• Authors: Dongwei Kang; Zhao Wang; Meng Chen; Da Feng; Gaochan Wu; Zhongxia Zhou; Lanlan Jing; Xiaofang Zuo; Xiangyi Jiang; Dirk Daelemans; Erik De Clercq; Christophe Pannec...; Peng Zhan; Xinyong Liu
• Keywords: 0303 health sciences; Binding Sites; HIV Reverse Transcriptase; 3. Good health; Molecular Docking Simulation; Pyridazines; Structure-Activity Relationship; 03 medical and health sciences; Pyrimidines; Catalytic Domain; Drug Design; Nitriles; HIV-1; Mutagenesis, Site-Directed; Solvents; Humans; Reverse Transcriptase Inhibitors; Nevirapine

AbstractTwo 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. Compound 7 (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.