Chrysin as a Bioactive Scaffold: Advances in Synthesis and Pharmacological Evaluation.

Chrysin (5,7-dihydroxyflavone) is a flavonoid widely distributed in propolis, honey, and various plant sources. It exhibits a wide range of pharmacological activities, including anti-inflammatory, antioxidant, anticancer, antimicrobial, and anti-diabetic effects. However, its clinical translation is hampered by poor aqueous solubility, low bioavailability, and rapid metabolic clearance. To address these limitations and expand the chemical space of this natural scaffold, extensive synthetic efforts have focused on generating structurally diverse chrysin derivatives that possess improved drug-like properties. This review systematically categorizes synthetic methodologies-such as etherification, esterification, transition-metal-mediated couplings, sigmatropic rearrangements, and electrophilic substitutions-and integrates them with corresponding biological outcomes. Particular emphasis is placed on recent (2020-present) advances that directly link structural modifications with pharmacological enhancements, thereby offering comparative structure-activity relationship (SAR) insights. In addition, transition-metal-catalyzed C-C bond-forming reactions are highlighted in a dedicated section, underscoring their growing role in accessing bioactive chrysin analogs previously unattainable by conventional chemistry. Unlike prior reviews that mainly summarized biological activities or broadly covered flavonoid scaffolds, this article bridges synthetic diversification with pharmacological evaluation. It provides both critical synthesis and mechanistic interpretation. Overall, this work consolidates current knowledge and suggests future directions that integrate synthetic innovation with pharmacological validation and address pharmacokinetic challenges in chrysin derivatives.