Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, China.
Department of Chemistry, Fudan University, Shanghai, 200433, China.
Eur J Med Chem. 2020 Jan 15;186:111864. doi: 10.1016/j.ejmech.2019.111864. Epub 2019 Nov 8.
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 values ranging from 1.5 to 0.0064 μM. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC = 0.077 μM), Y181C (EC = 0.11 μM), E138K (EC = 0.057 μM), and moderate activity against double mutants RES056 (EC = 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.
一系列吲唑取代的哌啶-4-基-氨基嘧啶（IPAPYs）是通过分子杂交策略，以两种有效的 HIV-1 NNRTIs（哌啶-4-基-氨基嘧啶 3c 和二芳基醚 4）为先导化合物设计的。目标分子 5a-q 被合成并在 MT-4 细胞中评估其抗 HIV 活性和细胞毒性。5a-q 对野生型（WT）HIV-1 表现出中等至优异的活性，EC 值范围为 1.5 至 0.0064 μM。其中，5q 被认为是对 WT HIV-1 最有效的化合物（EC = 6.4 nM，SI = 2500）。它对 K103N（EC = 0.077 μM）、Y181C（EC = 0.11 μM）、E138K（EC = 0.057 μM）具有很强的活性，对双重突变体 RES056（EC = 8.7 μM）也具有中等活性。此外，总结了构效关系（SARs），并进行了分子对接以研究 IPAPYs 和 HIV-1 逆转录酶的结合模式。
