ABSTRACT
A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4â¯cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC50 values ranging from 1.5 to 0.0064⯵M. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC50â¯=â¯6.4â¯nM, SIâ¯=â¯2500). And also, it displayed potent activities against K103â¯N (EC50â¯=â¯0.077⯵M), Y181C (EC50â¯=â¯0.11⯵M), E138K (EC50â¯=â¯0.057⯵M), and moderate activity against double mutants RES056 (EC50â¯=â¯8.7⯵M). Moreover, the structure-activity relationships (SARs) were summarized, and the molecular docking was performed to investigate the binding mode of IPAPYs and HIV-1 reverse transcriptase.