Structure-Based Optimization of 2,4,5-Trisubstituted Pyrimidines as Potent HIV‑1 Non-Nucleoside Reverse Transcriptase Inhibitors: Exploiting the Tolerant Regions of the Non-Nucleoside Reverse Transcriptase Inhibitors’ Binding Pocket

Although non-nucleoside reverse transcriptase inhibitors
(NNRTIs)
exhibit potent anti-HIV-1 activity and play an important role in the
active antiretroviral therapy of AIDS, the emergence of drug-resistant
strains has seriously reduced their clinical efficacy. Here, we report
a series of 2,4,5-trisubstituted pyrimidines as potent HIV-1 NNRTIs
by exploiting the tolerant regions of the NNRTI binding pocket. Compounds 16b and 16c were demonstrated to have excellent
activity (EC50 = 3.14–22.1 nM) against wild-type
and a panel of mutant HIV-1 strains, being much superior to that of
etravirine (EC50 = 3.53–52.2 nM). Molecular modeling
studies were performed to illustrate the detailed interactions between
RT and 16b, which shed light on the improvement of the
drug resistance profiles. Moreover, 16b possessed favorable
pharmacokinetic (T1/2 = 1.33 h, F = 31.8%) and safety profiles (LD50 > 2000
mg/kg),
making it a promising anti-HIV-1 drug candidate for further development.

尽管非核苷类逆转录酶抑制剂（non-nucleoside reverse transcriptase inhibitors, NNRTIs）具备强效抗HIV-1活性，且在艾滋病的抗逆转录病毒治疗中发挥关键作用，但耐药毒株的出现已严重削弱了其临床疗效。本研究报道了一系列通过靶向NNRTI结合口袋耐受区域开发得到的2,4,5-三取代嘧啶类强效HIV-1 NNRTIs。化合物16b与16c对野生型及一组突变型HIV-1毒株均表现出优异活性（半数有效浓度EC₅₀=3.14~22.1 nM），其活性显著优于依曲韦林（EC₅₀=3.53~52.2 nM）。本研究通过分子建模实验阐明了逆转录酶与16b之间的详细相互作用机制，为优化药物耐药谱提供了理论依据。此外，16b展现出良好的药代动力学特性（血浆半衰期T₁/₂=1.33 h，生物利用度F=31.8%）与安全性（半数致死量LD₅₀>2000 mg/kg），是一款极具开发前景的抗HIV-1候选药物。