Structure-Based Optimization of Thiophene[3,2‑<i>d</i>]pyrimidine Derivatives as Potent HIV‑1 Non-nucleoside Reverse Transcriptase Inhibitors with Improved Potency against Resistance-Associated Variants

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.本研究接续我们团队最初发现的一系列哌啶取代噻吩并[3,2-d]嘧啶类HIV-1非核苷类逆转录酶抑制剂（non-nucleoside reverse transcriptase inhibitors, NNRTI）的前期工作（参考文献：J. Med. Chem. 2016, 59, 7991−8007）。在本研究中，我们设计、合成了多系列新型衍生物，并对其开展了生物学评价，旨在探索此前尚未被涉足的化学空间。部分合成得到的化合物在MT-4细胞模型中，对野生型（WT）病毒及一组NNRTI耐药突变病毒展现出个位数纳摩尔级的抗HIV活性。化合物25a对全部受试病毒株均展现出优异的抗病毒活性：在同一细胞实验体系中，相较于参照药物依曲韦林（ETV），其对WT、L100I、K103N、Y181C、Y188L、E138K及K103N+Y181C的体外抗病毒活性提升3~4倍，对F227L+V106A的活性提升10倍。本研究同时考察了该系列化合物的构效关系、药代动力学特性、急性毒性与心脏毒性。综上，研究结果表明化合物25a是一款极具开发潜力的HIV-1感染治疗候选新药。