数字农科院2.0

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

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

作者机构：

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

期刊名称： European Journal of Medicinal Chemistry

ISSN： 0223-5234

年卷期： 2025 年 291 卷

页码：

收录情况： SCIE（2025版）

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 μM, SI = 358.9), outperforming remdesivir (EC50 = 3.14 μM, SI > 40.8) by 35-fold. D39 exhibited broad-spectrum anti-coronavirus activity (FIPV, IDV) at micromolar levels and demonstrated acceptable metabolic stability (T1/2 = 78.75 min, Clint = 8.8 μL/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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