This work follows on from our initial discovery of a series of piperidine-substituted thiophene[3,2-d]pyrimidine HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) ( J. Med. Chem. 2016, 59, 7991−8007). In the present study, we designed, synthesized, and biologically tested several series of new derivatives in order to investigate previously unexplored chemical space. Some of the synthesized compounds displayed single-digit nanomolar anti-HIV potencies against wild-type (WT) virus and a panel of NNRTI-resistant mutant viruses in MT-4 cells. Compound 25a was exceptionally potent against the whole viral panel, affording 3-4-fold enhancement of in vitro antiviral potency against WT, L100I, K103N, Y181C, Y188L, E138K, and K103N+Y181C and 10-fold enhancement against F227L+V106A relative to the reference drug etravirine (ETV) in the same cellular assay. The structure–activity relationships, pharmacokinetics, acute toxicity, and cardiotoxicity were also examined. Overall, the results indicate that 25a is a promising new drug candidate for treatment of HIV-1 infection.

中文翻译：

---

噻吩[3,2- d ]嘧啶衍生物作为有效的HIV-1非核苷逆转录酶抑制剂的结构优化，具有增强的抗药性相关抗性

这项工作是基于我们最初发现的一系列哌啶取代的噻吩[3,2 - d ]嘧啶HIV-1非核苷逆转录酶抑制剂（NNRTI）（J. Med.Chem。 2016年， 59， 7991−8007）。在本研究中，我们设计，合成和生物学测试了一系列新的衍生物，以研究先前未开发的化学空间。一些合成的化合物在MT-4细胞中对野生型（WT）病毒和一组NNRTI抗性突变病毒表现出一位数的纳摩尔抗HIV效力。化合物25a对整个病毒群异常有效，对WT，L100I，K103N，Y181C，Y188L，E138K和K103N + Y181C的体外抗病毒效力提高了3到4倍，对F227L + V106A的相对抗性则提高了10倍在相同的细胞分析中与参考药物etravirine（ETV）相比。还检查了结构与活性之间的关系，药代动力学，急性毒性和心脏毒性。总体而言，结果表明25a是用于治疗HIV-1感染的有希望的新药物候选物。