Of all known small molecules targeting human immunodeficiency virus (HIV) capsid protein (CA), PF74 represents by far the best characterized chemotype, due to its ability to confer antiviral phenotypes in both early and late phases of viral replication. However, the prohibitively low metabolic stability renders PF74 a poor antiviral lead. We report herein our medicinal chemistry efforts toward identifying novel and metabolically stable small molecules targeting the PF74 binding site. Specifically, we replaced the inter-domain-interacting, electron-rich indole ring of PF74 with less electron-rich isosteres, including imidazolidine-2,4-dione, pyrimidine-2,4-dione, and benzamide, and identified four potent antiviral compounds (10, 19, 20 and 26) with markedly improved metabolic stability. Compared to PF74, analog 20 exhibited similar submicromolar potency, and much longer (51-fold) half-life in human liver microsomes (HLMs). Molecular docking corroborated that 20 binds to the PF74 binding site, and revealed distinct binding interactions conferred by the benzamide moiety. Collectively, our data support compound 20 as a promising antiviral lead.

在所有已知的靶向人免疫缺陷病毒（HIV）衣壳蛋白（CA）的小分子中，PF74由于其在病毒复制的早期和晚期均具有抗病毒表型的能力，因此代表了迄今最具特征的化学型。但是，过低的新陈代谢稳定性使PF74的抗病毒能力很差。我们在这里报告了我们的药物化学努力，以鉴定靶向PF74结合位点的新型和代谢稳定的小分子。具体来说，我们用较少电子的等排体（包括咪唑烷-2,4-二酮，嘧啶-2,4-二酮和苯甲酰胺）取代了PF74的域间相互作用，电子富集的吲哚环，并鉴定了四种有效的抗病毒药化合物（10，19，20和26）具有明显改善的代谢稳定性。与PF74相比，类似物20在人肝微粒体（HLM）中表现出相似的亚微摩尔效价，并且半衰期更长（51倍）。分子对接证实了20个与PF74结合位点结合，并揭示了苯甲酰胺部分赋予的独特结合相互作用。总的来说，我们的数据支持化合物20作为有前途的抗病毒药物。