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 EC₅₀ values in a range of 5.7 to 0.0086 μM and against RT with IC₅₀ 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 (EC₅₀ = 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.

地拉韦啶和哌啶-4-基-氨基嘧啶(DPAPY)杂合体是由两种优良的HIV-1 NNRTIs地拉韦啶和哌啶-4-基-氨基嘧啶通过分子杂交设计而成。制备了目标化合物4a-r，并评估了其细胞抗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均表现出中等至优异的抗野生型 (WT) HIV-1 效力，EC ₅₀值在 5.7 至 0.0086 μM 范围内，而对抗 RT，IC ₅₀值在 12.0 至 0.11 μM 范围内，表明 DPAPY是特异性 RT 抑制剂。其中，4d显示出针对 WT HIV-1 的最有效活性（EC ₅₀  = 8.6 nM，SI = 2151）。令人欣慰的是，它对单一 HIV-1 突变体 L100I、K103N、Y181C、Y188L、E138K 以及双突变体 F227L + V106A 表现出良好至优异的效力。此外，还总结了初步的构效关系，并进行了分子建模来探索DPAPYs与HIV-1 RT的结合模式，并预测了它们的理化性质。