The novelty of this research lies in the development of unprecedented pyrimidinone-based scaffolds, prepared through simple synthetic routes, and their evaluation as promising inhibitors of the hepatitis A virus. Also, we introduce a new synthetic method for scaffold 5 that is driven by nanoscience. Among the several compound nanoparticles used in catalytic applications, nickel oxide nanoparticles are the most important and intriguing nanomaterials. Through reactions of 5 with different amines, aliphatic aldehydes, aliphatic halo carbonyls, and anhydrides, this approach made it possible to create a novel series of pyrimidinone derivatives. Advanced spectroscopy tools and DFT-based geometry optimization were used in a comprehensive strategy design. Strong binding affinities of the produced compounds to the Hepatitis A virus's 3C protease active site have been demonstrated by molecular docking analyses …