Chalcones in Drug Discovery: A Comprehensive Review of Synthesis and Biological Activities

Chalcone derivatives represent an important class of bioactive compounds characterized by a versatile α,β-unsaturated carbonyl scaffold and broad pharmacological potential. Their structural simplicity, synthetic accessibility, and amenability to chemical modification have stimulated extensive investigation as promising leads in medicinal chemistry and drug discovery. This review provides a comprehensive overview of recent advances in the synthesis, structural diversification, biological activities, and structure–activity relationships (SAR) of chalcone derivatives. Classical Claisen–Schmidt condensation remains the predominant strategy for constructing the chalcone framework, while complementary approaches involving cross-coupling, nucleophilic substitution, oxidation, and amide bond formation have facilitated the incorporation of diverse pharmacophores. Particular attention is given to chalcones incorporating biologically relevant heterocyclic moieties, including pyridine, piperazine, benzimidazole, quinoline, thiazole, and related scaffolds. The biological potential of chalcone derivatives is discussed across a broad spectrum of activities, including anticancer, antioxidant, antimicrobial, antiviral, antimalarial, anti-inflammatory, and antidiabetic effects. Furthermore, SAR analysis highlights the influence of enone configuration, aromatic substitution, electronic properties, lipophilicity, and heterocyclic hybridization on biological performance. Collectively, the reviewed findings demonstrate that rational structural modification can substantially enhance the potency, selectivity, and pharmacological properties of chalcone-based compounds. Despite considerable preclinical progress, challenges remain regarding pharmacokinetic properties, toxicity, mechanistic validation, and clinical translation. Continued integration of synthetic chemistry, molecular design, biological evaluation, and pharmacological profiling may therefore facilitate the development of chalcone derivatives into clinically relevant therapeutic agents.