By means of structure-based molecular hybridization strategy, a series of novel diarylpyri(mi)dine derivatives targeting the entrance channel of HIV-1 reverse transcriptase (RT) were designed, synthesized and evaluated as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs). Encouragingly, all the tested compounds showed good activities against wild-type (WT) HIV-1 (IIIB) with EC₅₀ in the range of 1.36 nM–29 nM, which is much better than those of nevirapine (NVP, EC₅₀ = 125.42 nM) and azidothymidine (AZT, EC₅₀ = 11.36 nM). Remarkably, these compounds also displayed effective activity against the most of the single and double-mutated HIV-1 strains with low EC₅₀ values, which is comparable to the control drugs. Besides, these compounds were also exhibited favorable enzymatic inhibitory activity. Moreover, preliminary structure-activity relationships (SARs) and molecular modeling study were investigated and discussed in detail. Unexpectedly, four diarylpyrimidines yielded moderate anti-HIV-2 activities. To our knowledge, this is rarely reported that diarylpyrimidine-based NNRTIs have potent activity against both HIV-1 and HIV-2 in cell culture.

通过基于结构的分子杂交策略，设计，合成和评估了一系列针对HIV-1逆转录酶（RT）入口通道的新型二芳基吡啶（mi）dine衍生物，作为有效的非核苷逆转录酶抑制剂（NNRTIs） 。令人鼓舞的是，所有测试的化合物均显示出对野生型（WT）HIV-1（IIIB）的良好活性，其EC ₅₀为1.36 nM–29 nM，远优于奈韦拉平（NVP，EC ₅₀  = 125.42 nM）和叠氮胸苷（AZT，EC ₅₀  = 11.36 nM）。值得注意的是，这些化合物还对大多数具有低EC ₅₀的单突变和双突变HIV-1菌株表现出有效的活性。值，可与对照药物相比。此外，这些化合物还显示出有利的酶抑制活性。此外，初步的结构-活性关系（SARs）和分子建模研究进行了调查和讨论。出乎意料的是，四个二芳基嘧啶产生中等的抗HIV-2活性。据我们所知，很少有人报道基于二芳基嘧啶的NNRTIs在细胞培养中对HIV-1和HIV-2均具有有效的活性。