A novel series of diarylpyrimidine (DAPY) derivatives bearing the biphenyl motif with multiple substituted groups was synthesized as human immunodeficiency virus (HIV)-1 non-nucleoside reverse transcriptase inhibitors. All of the target compounds were evaluated for their in vitro activity against HIV in MT-4 cells. Most of the compounds exhibited excellent activity with low nanomolar EC₅₀ values against wild-type, single and double mutant HIV-1 strains. Compound 4b displayed an EC₅₀ value of 1 nM against HIV-1 IIIB, 1.3 nM against L100I, 0.84 nM against K103 N, 1.5 nM against Y181C, 11 nM against Y188L, 2 nM against E138K, 10 nM against K103 N + Y181C, and almost 110 nM against F227L + V106. The improvement in the selectivity and potency of the target molecules against the wild-type and mutant HIV-1 strains validated our hypothesis. The biphenyl ring in the DAPY derivatives could strengthen the π-π stacking effect between the target molecule and the non-nucleoside inhibitor-binding pocket in the reverse transcriptase by extending the conjugating systems. This research represented a significant step toward the discovery of novel therapeutic DAPYs for treating acquired immunodeficiency syndrome in patients infected with HIV-1.

合成了具有多个取代基的带有联苯基序的一系列新的二芳基嘧啶（DAPY）衍生物，作为人类免疫缺陷病毒（HIV）-1非核苷逆转录酶抑制剂。评价所有目标化合物在MT-4细胞中抗HIV的体外活性。大多数化合物对野生型，单突变和双突变HIV-1菌株均表现出优异的活性，并具有低的纳摩尔EC ₅₀值。化合物4b的EC ₅₀针对HIV-1 IIIB的1 nM值，针对L100I的1.3 nM，针对K103 N的0.84 nM，针对Y181C的1.5 nM，针对Y188L的11 nM，针对E138K的2 nM，针对K103 N + Y181C的10 nM以及针对F227L的近110 nM的值+ V106。目标分子对野生型和突变型HIV-1菌株的选择性和效能的提高证实了我们的假设。DAPY衍生物中的联苯环可通过扩展缀合系统来增强目标分子与逆转录酶中非核苷抑制剂结合口袋之间的π-π堆叠效应。这项研究朝着发现新型治疗性DAPYs迈出了重要的一步，该DAPYs可用于治疗HIV-1感染患者的获得性免疫缺陷综合症。