Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities.

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-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC ₅₀ values ranging from 1.5 to 0.0064 μM. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC ₅₀  = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC ₅₀  = 0.077 μM), Y181C (EC ₅₀  = 0.11 μM), E138K (EC ₅₀  = 0.057 μM), and moderate activity against double mutants RES056 (EC ₅₀  = 8.7 μM). 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.
(Copyright © 2019 Elsevier Masson SAS. All rights reserved.)