Flavonoids as promising drug leads: Structural diversity, synthetic strategies, and drug-likeness optimization

Flavonoids are a major class of natural polyphenolic compounds with diverse physiological and pharmacological activities, and their privileged scaffolds have long attracted interest in natural product based drug discovery. As their physicochemical properties and biological functions are strongly structure-dependent, variations in substitution patterns can markedly influence solubility, membrane permeability, metabolic stability and overall bioactivity. However, the relationships between structural diversity, functional activities, and druggability remain insufficiently summarized. In this review, the biological activities associated with four representative flavonoid subclasses, including flavones, isoflavones, flavonols, and dihydroflavones, are first summarized. It then focuses on the chemical synthesis of these core scaffolds, systematically reviewing the main synthetic strategies developed over the past two decades and comparing their efficiency, safety, and practical feasibility. Given that poor solubility and limited metabolic stability commonly restrict the drug-likeness of natural flavonoids, the review further examines how structural modifications influence physicochemical and pharmacokinetic properties, and summarizes strategies for selective methylation, acylation, glycosylation, halogenation, and arylation. Finally, the structure-activity relationships (SARs) of representative flavonoids are summarized to guide rational structural optimization and the design of improved flavonoid derived drug candidates. Overall, this review integrates advances in pharmacology, synthetic chemistry, and medicinal chemistry, providing strategic insights for the future development of flavonoid based therapeutics.