Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, People's Republic of China.
Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Bioorg Chem. 2021 Jun;111:104905. doi: 10.1016/j.bioorg.2021.104905. Epub 2021 Apr 20.
Fifteen naphthyl-carboxamide-DAPYs were generated to explore chemical space in reverse transcriptase (RT) binding site via lead optimization strategy. They displayed up to single-digit nanomolar activity against wild-type (WT) and rilpivirine-associated resistant mutant E138K viruses, as well as potent inhibitory ability toward the RT enzyme. Compound a1 showed exceptionally inhibitory effects with an EC value of 3.7 nM against HIV-1 wt strain, and an EC of 11 nM targeting mutant E138K. The structure-activity relationships (SARs) of the newly obtained DAPYs were also investigated. Molecular docking analysis elucidated the biological activity and offered a structural insight for follow-up research.
通过先导优化策略，生成了 15 个萘基-羧酰胺-DAPY 以探索逆转录酶（RT）结合位点的化学空间。它们对野生型（WT）和利匹韦林相关耐药突变体 E138K 病毒显示出高达个位数纳摩尔的活性，并且对 RT 酶具有很强的抑制能力。化合物 a1 对 HIV-1wt 株具有异常的抑制作用，EC 值为 3.7 nM，对突变体 E138K 的 EC 值为 11 nM。还研究了新获得的 DAPY 的构效关系（SAR）。分子对接分析阐明了生物活性，并为后续研究提供了结构见解。
