Lei Yuan, Han Sheng, Yang Yang, Pannecouque Christophe, De Clercq Erik, Zhuang Chunlin, Chen Fen-Er
Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
Molecules. 2020 Feb 26;25(5):1050. doi: 10.3390/molecules25051050.
The key problems of human immunodeficiency virus (HIV) therapy are the rapid emergence of drug-resistant mutant strains and significant cumulative drug toxicities. Therefore, there is an urgent demand for new anti-HIV agents with low toxicity and broad-spectrum antiviral potency. A series of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker were designed using a molecular hybridization strategy. The cell-based anti-HIV assay showed that most of the compounds exhibited moderate to good activities against wild-type HIV-1 and clinically relevant mutant strains with a more favorable toxicity, and the enzymatic assay showed they had nanomolar activity against reverse transcriptase (RT). Compound exhibited the best activity against wild-type HIV-1 with an EC (50% HIV-1 replication inhibitory concentration) value of 0.027 µM, an acceptable CC (50% cytotoxic concentration value of 36.4 µM, and selectivity index of 1361, with moderate activities against the single mutants (EC: E138K, 0.17 µM; Y181C, 0.87 µM; K103N, 0.9 µM; L100I, 1.21 µM, respectively), and an IC value of 0.059 µM against the RT enzyme, which was six-fold higher than nevirapine (NVP). The preliminary structure-activity relationship (SAR) of these new compounds was concluded. The molecular modeling predicted the binding modes of the new compounds with RT, providing molecular insight for further drug design.
人类免疫缺陷病毒（HIV）治疗的关键问题是耐药突变株的迅速出现和显著的累积药物毒性。因此，迫切需要具有低毒性和广谱抗病毒效力的新型抗HIV药物。采用分子杂交策略设计了一系列带有氰甲基连接基的联苯取代二芳基嘧啶。基于细胞的抗HIV试验表明，大多数化合物对野生型HIV-1和临床相关突变株表现出中度至良好的活性，且毒性更佳，酶学试验表明它们对逆转录酶（RT）具有纳摩尔活性。化合物对野生型HIV-1表现出最佳活性，其EC（50% HIV-1复制抑制浓度）值为0.027 µM，可接受的CC（50%细胞毒性浓度）值为36.4 µM，选择性指数为1361，对单一突变体具有中度活性（EC：E138K为0.17 µM；Y181C为0.87 µM；K103N为0.9 µM；L100I分别为1.21 µM），对RT酶的IC值为0.059 µM，比奈韦拉平（NVP）高六倍。总结了这些新化合物的初步构效关系（SAR）。分子模拟预测了新化合物与RT的结合模式，为进一步的药物设计提供了分子层面的见解。
