期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 186, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.111864
关键词
AIDS; Anti-HIV; NNRTIs; Piperidin-4-yl-aminopyrimidines; Molecular hybridization; Indazole analogues; Diaryl ethers
资金
- National Natural Science Foundation of China [21877087, 21602164, 21807082, 21402148]
- Wuhan International Scientific and Technological Cooperation Project [2017030209020257]
- Natural Science Foundation of Hubei Province of China [2017CFB121]
- Hubei Provincial Department of Education of China [Q20171503]
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 ECK values ranging from 1.5 to 0.0064 mu M. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC50 = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC50 = 0.077 mu M), Y181C (EC50 = 0.11 mu M), E138K (EC50 = 0.057 mu M), and moderate activity against double mutants RES056 (EC50 = 8.7 mu 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. (C) 2019 Elsevier Masson SAS. All rights reserved.
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