Design, Synthesis and Antiviral Evaluation of Pyrido[1,2-c]pyrimidin-1-one Derivatives Against Porcine Epidemic Diarrhea Virus (PEDV).

Porcine epidemic diarrhea virus (PEDV) is the pathogen responsible for porcine epidemic diarrhea, causing significant economic losses to the swine industry. During the replication of PEDV, the genome mutates rapidly, making the effectiveness of commercial vaccines uncertain when facing newly emerging prevalent variants. More importantly, there are currently no safe and effective specific antiviral drugs available. YT1418, a pyrido[1,2-c]pyrimidin-1-one (PPO) compound, exhibited anti-PEDV activity in a previous study. To expand the chemical space of the PPO scaffold and clarify the influence of substituents at different positions on the antiviral activity of the compounds, 36 new compounds were designed and synthesized, and then their abilities to inhibit viral replication in a PEDV-infected cell model were evaluated. Furthermore, the hepatic microsomal metabolic stabilities of compounds with potent antiviral activity were assessed. The results showed that compounds N1 and N2 exhibited antiviral activity (EC50 = 0.32, 0.37 μM, respectively) superior to that of YT1418, with selective index values of 43.78 and 42.89, respectively. Meanwhile, compound J4 demonstrated good hepatic microsomal stability and low cytotoxicity, which requires further investigation. This study identified lead compounds featuring a novel PPO core and established their structure-activity relationships, providing important insights for the development of anti-PEDV drugs.