Further exploring the tolerant region II: Identification of 2,4,5-trisubstituted pyrimidines as HIV-1 reverse transcriptase allosteric inhibitors with desirable antiviral activities and reduced cytotoxicity

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-07-21 DOI:10.1016/j.ejmech.2025.117992

Zhenzhen Zhou , Lin Zheng , Wenbo Jiang , Wenbo Zhang , Fabao Zhao , Zhening Liang , Erik De Clercq , Christophe Pannecouque , Peng Zhan , Dongwei Kang , Xinyong Liu

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Abstract

Here, we report a series of 2,4,5-trisubstituted pyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) by further exploring the potential tolerant region II within NNIBP. Most compounds were identified with potent inhibitory activity against HIV-1 wild-type (WT) strain with lower cytotoxicity. Among them, 14l exhibited the most outstanding antiviral activity (EC₅₀ = 6.50–52.9 nM) against WT and a panel of mutant HIV-1 strains with much-reduced cytotoxicity (CC₅₀ = 228 μM) and higher selectivity index (SI = 31434) than that of the lead 36a (CC₅₀ = 45.6 μM; SI = 20550). Furthermore, the detailed molecular modeling studies revealed that the 3-thienyl substituent of 14l engages in multiple stable contacts with conserved residues within tolerant region II, providing a structural basis for the observed potent antiviral efficacy and enhanced anti-resistance profile. These findings collectively position 14l as a promising candidate for subsequent development as a novel lead compound.

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进一步探索耐受区II：鉴定2,4,5-三取代嘧啶作为HIV-1逆转录酶变构抑制剂具有理想的抗病毒活性和降低细胞毒性

在这里，我们通过进一步探索NNIBP中潜在的耐受区II，报道了一系列2,4,5-三取代嘧啶作为有效的HIV-1非核苷逆转录酶抑制剂（NNRTIs）。大多数化合物被鉴定为对HIV-1野生型（WT）菌株具有较低的细胞毒性的有效抑制活性。其中，14l对WT和一组HIV-1突变株表现出最显著的抗病毒活性（EC50 = 6.50 ~ 52.9 nM），其细胞毒性（CC50 = 228 μM）显著降低，选择性指数（SI = 31434）高于36a (CC50 = 45.6 μM)；Si = 20550)。此外，详细的分子模拟研究表明，14l的3-噻吩基取代基与耐受区II内的保守残基进行了多次稳定的接触，为观察到的有效抗病毒效果和增强的抗抗性谱提供了结构基础。这些发现共同将14l定位为一种有希望的新型先导化合物。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.