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.
Eur J Med Chem. 2020 Jan 1;185:111874. doi: 10.1016/j.ejmech.2019.111874. Epub 2019 Nov 10.
The fragment hopping approach is widely applied in drug development. A series of diarylpyrimidines (DAPYs) were obtained by hopping the thioacetamide scaffold to novel human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitors (NNRTIs) to address the cytotoxicity issue of Etravirine and Rilpivirine. Although the new compounds (11a-l) in the first-round optimization possessed less potent anti-viral activity, they showed much lower cytotoxicity. Further optimization on the sulfur led to the sulfinylacetamide-DAPYs exhibiting improved anti-viral activity and a higher selectivity index especially toward the K103N mutant strain. The most potent compound 12a displayed EC values of 0.0249 μM against WT and 0.0104 μM against the K103N mutant strain, low cytotoxicity (CC > 221 μM) and a high selectivity index (SI > 8873, SI > 21186). In addition, this compound showed a favorable in vitro microsomal stability across species. Computational study predicted the binding models of these potent compounds with HIV-1 reverse transcriptase thus providing further insights for new developments.
片段跳跃法广泛应用于药物研发中。通过将硫代乙酰胺骨架跳跃到新型人类免疫缺陷病毒 1（HIV-1）非核苷逆转录酶抑制剂（NNRTIs）上，得到了一系列二芳基嘧啶（DAPYs），以解决依曲韦林和利匹韦林的细胞毒性问题。虽然第一轮优化得到的新化合物（11a-l）的抗病毒活性较弱，但它们的细胞毒性要低得多。进一步对硫原子进行优化，得到的亚磺酰基乙酰胺-DAPYs 表现出改善的抗病毒活性和更高的选择性指数，尤其是对 K103N 突变株。最有效的化合物 12a 对 WT 的 EC 值为 0.0249 μM，对 K103N 突变株的 EC 值为 0.0104 μM，细胞毒性低（CC > 221 μM），选择性指数高（SI > 8873，SI > 21186）。此外，该化合物在不同物种的体外微粒体稳定性良好。计算研究预测了这些有效化合物与 HIV-1 逆转录酶的结合模型，从而为新的开发提供了进一步的见解。
