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

  • Eur J Med Chem. 2025 Apr 15:291:117637. doi: 10.1016/j.ejmech.2025.117637.
Sai Lv  1 ,  Rumeng Ma  1 ,  Qun Tang  1 ,  Xiaoyang Wang  1 ,  Chunmei Wang  1 ,  Keyu Zhang  1 ,  Houkai Li  2 ,  Wenchong Ye  3 ,  Wen Zhou  4
Affiliations
  • 1. Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China; Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241, China.
  • 2. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 3. Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China; Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241, China. Electronic address: [email protected].
  • 4. Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China; Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241, China. Electronic address: [email protected].
PMID: 40262295 DOI: 10.1016/j.ejmech.2025.117637
Abstract

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.

Keywords
3,4-dihydropyrimidine derivatives; Anti-PEDV; Ca(2+) modulation; Structure-activity relationship.
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