Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Bioorg Chem. 2020 Jun;99:103825. doi: 10.1016/j.bioorg.2020.103825. Epub 2020 Apr 8.
Oxime is a key pharmacophore in drug development. The biphenyl diarylpyrimidines (DAPYs) have been developed by our group as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs). In this study, fourteen oxime-biphenyl-DAPYs were designed and synthesized through a privileged scaffold inspired design strategy. They exhibited promising activity toward wild type HIV-1 and single mutant strains. Compound 7d was found to be the most potent one against both wild type (EC = 12.1 nM) and E138K mutant strains (EC = 0.0270 µM). It also had a much lower cytotoxicity (CC > 292 µM) and higher selective index (SI > 24105) than those of the FDA-approved drugs efavirenz and etravirine. Molecular docking and dynamics simulation predicted and disclosed the binding mode of compound 7d with the RT, providing the explanation on the antiviral activity. These results were helpful for subsequent structural optimizations in anti-HIV-1 drug discovery.
肟是药物开发中的关键药效团。我们小组已经将联苯二芳基嘧啶（DAPYs）开发为新型非核苷逆转录酶抑制剂（NNRTIs）。在这项研究中，通过受保护的支架启发式设计策略设计并合成了十四种肟-联苯-DAPYs。它们对野生型 HIV-1 和单突变株表现出有希望的活性。化合物 7d 对野生型（EC=12.1 nM）和 E138K 突变株（EC=0.0270 µM）均具有最强的抑制活性。与 FDA 批准的药物依非韦伦和埃替拉韦相比，它的细胞毒性（CC>292 µM）更低，选择性指数（SI>24105）更高。分子对接和动力学模拟预测并揭示了化合物 7d 与 RT 的结合模式，为抗病毒活性提供了解释。这些结果有助于随后在抗 HIV-1 药物发现中进行结构优化。
