Pyrimidine Derivatives: A Comprehensive Review of Synthetic Strategies, Biological Activities and In-Silico Studies

The pyrimidine nucleus is a six-membered aromatic ring in which nitrogen occupies the 1 and 3 positions. It underlies cytosine, thymine and uracil, the building blocks of nucleic acids, and this natural pedigree has made it a favorite framework for medicinal chemists. Both simple and ring-fused pyrimidines show antibacterial, anticancer, antiviral, antitubercular, antifungal and anti-inflammatory properties, and a number of marketed drugs are built on them. The article covers four areas: (i) routes to the ring, from classical condensations to multicomponent, environmentally friendly and metal-catalyzed methods; (ii) the main therapeutic activities, with representative scaffolds, targets and approved drugs; (iii) trends in structure–activity relationships (SAR) at positions 2, 4, 5 and 6 and in fused systems; and (iv) the growing use of docking, molecular dynamics (MD), ADME/ADMET prediction and drug-likeness filters when designing leads. Studies from 2020 to 2026 receive most attention. The review closes with a critical discussion, a list of unresolved gaps and a look ahead. Overall, we argue that progress is most likely when efficient synthesis, thorough biological testing and computational models backed by experimental evidence are pursued together.