Exploration of 1-(indolin-1-yl)-2-(thiazol-2-yl)ethan-1-one derivatives as novel anti-HBV agent with potential TLR7-agonistic effect,European Journal of Medicinal Chemistry

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Exploration of 1-(indolin-1-yl)-2-(thiazol-2-yl)ethan-1-one derivatives as novel anti-HBV agent with potential TLR7-agonistic effect
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-06-08 , DOI: 10.1016/j.ejmech.2024.116575
Shuqiong Li ₁ , Lihua Yang ₂ , Qiuting Xu ₂ , Xincheng Li ₃ , Jiangyan Zhao ₃ , Zhoupeng Tan ₃ , Xiaoke Gu ₃ , Jingying Qiu ₁

Affiliation

Hepatitis B virus (HBV) infection, as a serious global public health issue, is closely related to the immune dysfunction. Herein, thirty-seven 1-(indolin-1-yl)-2-(thiazol-4-yl)ethan-1-one derivatives were prepared as potential immunomodulatory anti-HBV agents. Anti-HBV activity evaluation confirmed compound could significantly suppress the HBV DNA replication in both wild and resistant HBV stains, with IC values of 0.13 μM and 0.36 μM, respectively. Preliminary action mechanism studies showed that had an inhibitory effect on cellular HBsAg secretion and could effectively activate TLR7, thereby inducing the secretion of TLR7-regulated cytokines IL-12, TNF-α and IFN-α in human PBMC cells. SPR analysis confirmed that could bind to TLR7 protein with an affinity of 7.06 μM. MD simulation predicted that could form tight interactions with residues in the binding pocket of TLR7. Physicochemical parameters perdition and pharmacokinetic analysis indicated that displayed relatively favorable drug-like properties. Considering all the results, compound might be a promising lead for developing novel immunomodulatory anti-HBV agents.

中文翻译：

1-(吲哚啉-1-基)-2-(噻唑-2-基)乙烷-1-酮衍生物作为具有潜在TLR7激动作用的新型抗HBV药物的探索

乙型肝炎病毒（HBV）感染作为一个严重的全球公共卫生问题，与免疫功能失调密切相关。在此，制备了 37 种 1-(二氢吲哚-1-基)-2-(噻唑-4-基)乙烷-1-酮衍生物作为潜在的免疫调节抗 HBV 药物。抗 HBV 活性评估证实该化合物可显着抑制野生型和耐药 HBV 染色中的 HBV DNA 复制，IC 值分别为 0.13 μM 和 0.36 μM。初步作用机制研究表明，对细胞HBsAg分泌有抑制作用，并能有效激活TLR7，从而诱导人PBMC细胞分泌TLR7调节的细胞因子IL-12、TNF-α和IFN-α。 SPR分析证实可以与TLR7蛋白结合，亲和力为7.06 μM。 MD模拟预测其可以与TLR7结合口袋中的残基形成紧密的相互作用。理化参数和药代动力学分析表明显示出相对良好的药物样特性。考虑到所有结果，该化合物可能是开发新型免疫调节抗乙型肝炎药物的有希望的先导者。

更新日期：2024-06-08

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