Purine and Pyrrolopyrimidine‐Based Small Molecules as Multitarget Therapeutics

Purines and pyrrolo[2,3-d]pyrimidines are privileged heterocyclic scaffolds widely represented in small molecules targeting a broad range of therapeutically relevant targets, including kinases, folate-metabolizing enzymes, histone deacetylases (HDACs), bromodomain containing proteins, membrane transporters, phosphodiesterases (PDEs), ion channels, and toll-like receptors (TLRs). While these scaffolds have been extensively investigated in medicinal chemistry, their role in multitarget drug design has received comparatively less attention. This review provides a comprehensive overview of purine- and pyrrolopyrimidine-based compounds reported over the last two decades from a multitarget medicinal chemistry perspective, with particular emphasis on the design principles and SAR underlying simultaneous modulation of multiple biological targets. By systematically comparing compounds across different target classes, we highlight the key structural features responsible for multitarget activity and discuss how specific scaffold modifications influence potency, selectivity, and polypharmacological profiles. Representative examples are presented to illustrate the successful application of these scaffolds in the development of dual- and multitarget inhibitors with promising anticancer, anti-inflammatory, and drug resistance-overcoming activities. Particular attention is devoted to compounds capable of overcoming drug resistance through the simultaneous modulation of complementary biological pathways. Overall, this review provides an integrated medicinal chemistry framework for understanding multitarget purine- and pyrrolopyrimidine-based ligands and identifies emerging opportunities and challenges for the development of next-generation polypharmacological agents.