Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, China.
KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000, Leuven, Belgium.
Eur J Med Chem. 2023 Feb 15;248:115114. doi: 10.1016/j.ejmech.2023.115114. Epub 2023 Jan 11.
The hybrids of delavirdine and piperdin-4-yl-aminopyrimidine (DPAPYs) were designed from two excellent HIV-1 NNRTIs delavirdine and piperidin-4-yl-aminopyrimidine via molecular hybridization. The target compounds 4a-r were prepared and evaluated for their cellular anti-HIV activities and cytotoxicities as well as the inhibitory activities against HIV-1 reverse transcriptase (RT). All the newly synthesized compounds demonstrated moderate to excellent potency against wild-type (WT) HIV-1 with EC values in a range of 5.7 to 0.0086 μM and against RT with IC values ranging from 12.0 to 0.11 μM, indicating that the DPAPYs were specific RT inhibitors. Among all, 4d displayed the most potent activity against WT HIV-1 (EC = 8.6 nM, SI = 2151). Gratifyingly, it exhibited good to excellent potency against the single HIV-1 mutants L100I, K103N, Y181C, Y188L, E138K, as well as the double mutant F227L + V106A. Furthermore, the preliminary structure-activity relationships were summarized, molecular modeling was conducted to explore the binding mode of DPAPYs and HIV-1 RT, and their physicochemical properties were also predicted.
-delavirdine 和哌啶-4-基-氨基嘧啶（DPAPYs）的混合物是通过分子杂交从两种优秀的 HIV-1 NNRTIs（delavirdine 和哌啶-4-基-氨基嘧啶）设计而来的。目标化合物 4a-r 已被制备并评估了它们对细胞抗 HIV 活性和细胞毒性以及对 HIV-1 逆转录酶（RT）的抑制活性。所有新合成的化合物对野生型（WT）HIV-1 均表现出中等至优异的效力，EC 值范围为 5.7 至 0.0086 μM，对 RT 的 IC 值范围为 12.0 至 0.11 μM，表明 DPAPYs 是特异性 RT 抑制剂。在所有化合物中，4d 对 WT HIV-1 表现出最强的活性（EC = 8.6 nM，SI = 2151）。令人高兴的是，它对单个 HIV-1 突变体 L100I、K103N、Y181C、Y188L、E138K 以及双突变体 F227L + V106A 均表现出良好至优异的效力。此外，总结了初步的构效关系，进行了分子建模以探索 DPAPYs 和 HIV-1 RT 的结合模式，并预测了它们的物理化学性质。
