Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
Institute of Pharmacology, School of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
Eur J Med Chem. 2014 Jun 10;80:112-21. doi: 10.1016/j.ejmech.2014.04.036. Epub 2014 Apr 13.
Guided by crystal structures of HIV-1 RT/DAPY complex and molecular modeling studies, a series of novel DAPY derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities. Among them, 16 compounds significantly inhibited HIV-1 IIIB replication with EC50 values lower than 66 nM. Particularly, compound 7a was the most potent inhibitor against HIV-1 wild-type and double RT mutant HIV-1 strain K103N/Y181C, with an EC50 value of 2.5 nM (SI = 13,740) and 0.33 μM (SI = 107), respectively. Unexpectedly, compound 8c was found to show moderate anti-HIV-2 potency (EC50 = 5.57 μM). Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogues were also discussed in detail.
受 HIV-1 RT/DAPY 复合物晶体结构和分子建模研究的指导，我们设计、合成了一系列新型 DAPY 衍生物，并对它们的抗 HIV 活性进行了评估。其中，有 16 种化合物对 HIV-1 IIIB 的复制具有显著的抑制作用，EC50 值低于 66 nM。特别是化合物 7a 对 HIV-1 野生型和双 RT 突变型 HIV-1 株 K103N/Y181C 的抑制作用最强，EC50 值分别为 2.5 nM（SI = 13,740）和 0.33 μM（SI = 107）。出乎意料的是，化合物 8c 对 HIV-2 也具有中等的抑制活性（EC50 = 5.57 μM）。我们还详细讨论了这些新类似物的构效关系（SAR）和分子建模。
