Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Jinan, Shandong, China.
Chem Biol Drug Des. 2024 Mar;103(3):e14510. doi: 10.1111/cbdd.14510.
In this study, a novel series of diarylpyrimidine derivatives with Fsp-enriched spirocycles were designed and synthesized to further explore the chemical space of the hydrophobic channel of the NNRTI-binding pocket. The biological evaluation results showed that most of the compounds displayed effective inhibitory potency against the HIV-1 wild-type strain, with EC values ranging from micromolar to submicromolar levels. Among them, TT6 turned out to be the most effective inhibitor with an EC value of 0.17 μM, demonstrating up to 47 times more active than that of reference drug 3TC (EC = 8.01 μM). More encouragingly, TT6 was found to potently inhibit the HIV-1 mutant strain K103N with an EC value of 0.69 μM, being about 6-fold more potent than 3TC (EC = 3.68 μM) and NVP (EC = 4.62 μM). Furthermore, TT6 exhibited the most potent inhibitory activity toward HIV-1 reverse transcriptase with an IC value of 0.33 μM. Additionally, molecular simulation studies were conducted to investigate the binding modes between TT6 and NNRTI-binding pocket, which may provide valuable clues for the follow-up structural optimizations.
在这项研究中，设计并合成了一系列具有 Fsp 富集的螺环的新型二芳基嘧啶衍生物，以进一步探索 NNRTI 结合口袋疏水性通道的化学空间。生物评价结果表明，大多数化合物对 HIV-1 野生型毒株表现出有效的抑制活性，EC 值范围为微摩尔至亚微摩尔水平。其中，TT6 是最有效的抑制剂，EC 值为 0.17 μM，比参考药物 3TC（EC=8.01 μM）活性高 47 倍。更令人鼓舞的是，TT6 对 HIV-1 突变株 K103N 表现出强大的抑制作用，EC 值为 0.69 μM，比 3TC（EC=3.68 μM）和 NVP（EC=4.62 μM）强约 6 倍。此外，TT6 对 HIV-1 逆转录酶表现出最强的抑制活性，IC 值为 0.33 μM。此外，还进行了分子模拟研究，以研究 TT6 与 NNRTI 结合口袋的结合模式，这可能为后续的结构优化提供有价值的线索。
