Inspired by our previous studies to discover novel human immunodeficiency virus-1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) by targeting the tolerant region II of the NNRTIs binding pocket (NNIBP), a series of novel benzo[4,5]thieno[2,3-]pyrimidine derivatives were designed through structure-based drug design as novel potent HIV-1 NNRTIs. The results showed that compound was the most active inhibitor, exhibiting 50% effective concentration (EC) values from 0.021 µmol/L to 0.298 µmol/L against wild-type (WT) and a panel of NNRTIs-resistant HIV-1 strains. Moreover, was demonstrated with a significantly low 50% cytotoxicity concentration (CC) value (>200 µmol/L) and high selectivity index (SI) values. In addition, yielded moderate reverse transcriptase (RT) enzyme inhibition with a 50% inhibition concentration (IC) value of 0.183 µmol/L, which demonstrated that it acted as HIV-1 NNRTIs. The binding mode of with RT was also illustrated molecular docking. Overall, this work provided a novel lead compound for developing potent HIV-1 NNRTIs.

中文翻译：

---

作为新型 HIV-1 NNRTI 的苯并[4,5]噻吩并[2,3-d]嘧啶衍生物的设计、合成和生物学评价

受我们之前的研究启发，通过靶向 NNRTIs 结合袋 (NNIBP) 的耐受区 II，发现新型人类免疫缺陷病毒 1 (HIV-1) 非核苷类逆转录酶抑制剂 (NNRTIs)，一系列新型苯并[4， 5]噻吩并[2,3-]嘧啶衍生物是通过基于结构的药物设计设计的，作为新型有效的HIV-1 NNRTIs。结果表明，该化合物是最活跃的抑制剂，对野生型 (WT) 和一组 NNRTIs 耐药的 HIV-1 菌株表现出 50% 有效浓度 (EC) 值，范围为 0.021 µmol/L 至 0.298 µmol/L。此外，它还具有显着低的 50% 细胞毒性浓度 (CC) 值 (>200 µmol/L) 和高选择性指数 (SI) 值。此外，它还具有中等程度的逆转录酶 (RT) 抑制作用，50% 抑制浓度 (IC) 值为 0.183 µmol/L，这表明它具有 HIV-1 NNRTI 的作用。分子对接还说明了其与RT的结合方式。总体而言，这项工作为开发有效的 HIV-1 NNRTI 提供了一种新型先导化合物。