Structure-Based Bioisosterism Yields HIV‑1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties

The
development of efficacious NNRTIs for AIDS therapy commonly
encountered the rapid generation of drug-resistant mutations, which
becomes a major impediment to effective anti-HIV treatment. Using
a structure-based bioisosterism strategy, a series of piperidine-substituted
thiophene­[2,3-d]­pyrimidine derivatives were designed
and synthesized. Compound 9a yielded the greatest potency,
exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition,
the phenotypic (cross)­resistance of 9a and other NRTIs
to the different selected HIV-1 strains was evaluated. As expected,
no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was
observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability,
and hERG inhibition. Remarkably, 9a exhibited optimal
pharmacokinetic properties in rats (F = 37.06%) and
safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.

艾滋病治疗用高效非核苷类逆转录酶抑制剂（NNRTIs，Non-Nucleoside Reverse Transcriptase Inhibitors）的研发历程中，常面临耐药突变快速产生的问题，这已成为抗人类免疫缺陷病毒1型（HIV-1）有效治疗的主要障碍。本研究采用基于结构的生物电子等排策略，设计并合成了一系列哌啶取代的噻吩并[2,3-d]嘧啶类衍生物。其中化合物9a活性最优，针对所有受试的NNRTI耐药HIV-1毒株，其抗HIV-1活性均显著优于ETR（依曲韦林）。此外，本研究评估了9a与其他核苷类逆转录酶抑制剂（NRTIs）对不同筛选获得的HIV-1毒株的表型（交叉）耐药性。正如预期，9ares突变株未表现出对AZT（齐多夫定）与PMPA两类NRTIs的表型交叉耐药性。进一步研究发现，9a具备更佳的溶解性、更低的CYP（细胞色素P450）代谢风险，且hERG（人类乙醚-à-go-go相关基因）通道抑制活性更弱。值得注意的是，9a在大鼠体内展现出优良的药代动力学特性（生物利用度F=37.06%），并在小鼠体内表现出良好的安全性（半数致死量LD50>2000 mg/kg），这充分证明9a是一款极具开发前景的抗HIV-1候选药物。