A critical review on the sustainable synthesis of pyrimidine-based heterocycles and their biological activities

Pyrimidine scaffolds exhibit diverse biological and pharmacological activities, serving as inhibitors of specific biological systems and demonstrating analgesic, antiviral, antibacterial, antifungal, and anticonvulsant properties. A vast array of structurally significant derivatives, encompassing scaffolds generated via aryl ring substitution or by the derivatization at N1, N3, C5, and C6 positions of the pyrimidine ring, were produced as a result of the synthetic diversity of pyrimidines. The versatile nature of pyrimidines allow chemists to synthetically formulate and produce novel moieties through different synthetic routes. Recent developments in synthetic strategies have emphasized greener, more sustainable methods, such as microwave-assisted synthesis, one-pot reactions, ultrasonification, photochemical, electrochemical and metal-catalyzed cross-coupling reactions. Furthermore, bioinspired approaches and the use of renewable resources are gaining popularity in the synthesis of functionalized pyrimidines which have also been explored. This review aims to systematically evaluate both conventional and eco-friendly approaches for synthesizing these scaffolds, while also highlighting recent discoveries and technological advancements in their production. The pharmacological properties of various substituted pyrimidines, along with an exploration of their synthesis methods, provide a foundation for studying their future structure-activity relationships and mechanisms of action.