A Comprehensive Review of Natural and Synthetic Flavonoids as Antibiofilm Agents Against Bacterial Biofilms.

Bacterial biofilms are a major contributor to antimicrobial resistance due to their ability to protect embedded cells from antibiotics and host immune responses. This review systematically summarizes and critically evaluates recent advances in the development of natural and synthetic flavonoids as antibiofilm agents against clinically relevant bacterial biofilms. The manuscript is organized to first outline the molecular basis of biofilm formation and resistance, followed by a detailed analysis of plant-derived flavonoids reported to inhibit biofilm formation, disrupt mature biofilms or interfere with quorum sensing pathways. The advances in synthetic flavonoid analogues including flavones, flavanones, aurones, and other functionalized derivatives are reviewed with emphasis on structure-activity relationships and antibiofilm mechanisms. Recent progress in synthetic strategies such as late-stage functionalization, C-H activation, and biocatalytic modifications is discussed in the context of improving potency, selectivity, and pharmacokinetic properties. The current limitations, challenges involved with in-vivo translation and future directions for flavonoid-based antibiofilm drug development are highlighted. This comprehensive assessment underscores the potential of flavonoids as versatile antibiofilm scaffolds while identifying critical gaps that must be addressed for clinical advancement.