Purine-centred fused, conformationally constrained, and ring-expanded analogues in antitumor and antiviral drug discovery: A comprehensive review.

Purine-derived scaffolds remain important in anticancer and antiviral drug discovery because their electronic properties, hydrogen-bonding capacity, and conformational adaptability support interactions with kinases, polymerases, nucleotide-processing enzymes, and nucleic acids. This review critically examines three major purine-centred classes: fused tricyclic purines, conformationally constrained purine nucleosides bearing bridged sugar or carbocyclic systems, and ring-expanded purines. Relevant publications from 1986 to 2026 were evaluated with emphasis on scaffold design, synthetic strategies, structure-activity relationships, biological activity, molecular mechanisms, computational studies, and reported physicochemical or pharmacokinetic properties. Key synthetic approaches include heteroannulation, intramolecular cyclisation, regioselective N7/N9 functionalization, construction of methanocarba pseudosugars, and seven-membered ring formation. Comparative analysis shows that ring fusion, tautomer control, sugar-pucker restriction, halogenation, aryl substitution, and polar side-chain modification can enhance potency, selectivity, metabolic stability, and target recognition. However, excessive rigidity, poor solubility, activation dependence, toxicity, and resistance remain important limitations. The novelty of this review lies in integrating the synthesis, medicinal chemistry, biological evaluation, physicochemical properties, and dual anticancer-antiviral potential of structurally distinct purine-centred analogues within a unified framework. These insights may support the rational development of next-generation purine-based therapeutic agents.