Discovery of 3,4-dihydropyrimidine derivatives as novel Anti-PEDV agents targeting viral internalization through a unique calcium homeostasis disruption mechanism

文献类型： 外文期刊

第一作者： Lv, Sai

作者： Lv, Sai;Ma, Rumeng;Tang, Qun;Wang, Xiaoyang;Wang, Chunmei;Zhang, Keyu;Ye, Wenchong;Zhou, Wen;Lv, Sai;Ma, Rumeng;Tang, Qun;Wang, Xiaoyang;Wang, Chunmei;Zhang, Keyu;Ye, Wenchong;Zhou, Wen;Li, Houkai

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关键词： 3,4-dihydropyrimidine derivatives; Anti-PEDV; Structure-activity relationship; Ca2+ modulation

期刊名称：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：5.9； 五年影响因子：6.4 ）

ISSN： 0223-5234

年卷期： 2025 年 291 卷

页码：

收录情况： SCI

摘要： Porcine epidemic diarrhea virus (PEDV) poses critical challenges to global swine production, with current vaccines showing limited efficacy against emerging strains. To address this gap, we designed 41 novel 3,4-dihydropyrimidine derivatives via systematic structure-activity relationship (SAR) optimization. Compound D39, incorporating a C-4 2 '-substituted biphenyl, C-2 thione, C-6 phenyl, and C-5 isopropanol substituents, emerged as the most potent anti-PEDV agent (EC50 = 0.09 mu M, SI = 358.9), outperforming remdesivir (EC50 = 3.14 mu M, SI > 40.8) by 35-fold. D39 exhibited broad-spectrum anti-coronavirus activity (FIPV, IDV) at micromolar levels and demonstrated acceptable metabolic stability (T-1/2 = 78.75 min, Cl-int = 8.8 mu L/min/mg) in porcine liver microsomes. Mechanistic studies revealed the antiviral actions was achieved by blocking PEDV early internalization via intracellular Ca2+ homeostasis modulation. These findings highlight D39 as a first-in-class anti-PEDV candidate with a unique dihydropyrimidine scaffold and a calcium-targeting mechanism, offering a promising therapeutic strategy against coronaviral infections.

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