Recent Advances in Pyrimidine Molecular Hybrids, Green Synthetic Strategies, and Diverse Biological Applications.

Pyrimidine-based molecular hybrids have emerged as a privileged class of bioactive scaffolds owing to their structural versatility and broad pharmacological potential. This review comprehensively covers recent advances in green synthetic strategies, including solvent-free, microwave-assisted, ultrasound-assisted, ionic liquid-mediated, and nanocatalyst-promoted Biginelli-type reactions, synthesis, and the biological applications of pyrimidine hybrids incorporating pharmacophores such as chalcones, quinolines, triazoles, pyrazoles, and coumarins. These hybrids demonstrate potent antibacterial, antifungal, anticancer, anti-inflammatory, and antiprotozoal activities through mechanisms including kinase inhibition, apoptosis induction, COX-2 selectivity, and NF-κB/MAPK modulation. Structure-activity relationship analysis highlights the critical influence of substituent electronic properties, substitution position, and linker design on biological potency and selectivity. Current challenges, including poor solubility and metabolic instability, are discussed alongside future directions emphasizing computational drug design, target expansion, and clinical translation.