Chalcones as Emerging Antibacterial Scaffolds: A Mini Review.

The mounting threat of antimicrobial resistance has intensified the global search for novel antibacterial agents, and chalcones - the aromatic ketones characterized by an α, β-unsaturated carbonyl system has emerged as promising scaffolds against the threat of antimicrobial resistance. This review presents a detailed exploration of chalcones as potent antibacterial agents, emphasizing their structural versatility, mechanisms of action, and therapeutic potential. With a modular backbone that supports diverse substitutions and heterocyclic extensions, chalcones can be easily synthesized and chemically optimized to target a broad spectrum of bacterial pathogens, including multidrugresistant strains such as MRSA and VRE. Mechanistically, chalcones exert antibacterial effects through multiple pathways, like disrupting bacterial membranes, inhibiting cell wall biosynthesis, interfering with DNA replication via DNA gyrase and topoisomerase IV, and suppressing protein synthesis. Their amphipathic nature and ability to bind critical bacterial enzymes offer an advantage in circumventing classical resistance mechanisms. Structure-activity relationships and computational studies have further elucidated the influence of electron-donating and electron-withdrawing groups, positional isomerism, and heterocyclic integration on antibacterial potency. A review of recent literature underlines the efficacy of chalcone derivatives against Gram-positive and Gramnegative strains, with many compounds demonstrating promising activity, such as compound 85 with MIC 3.4 nM against Ciprofloxacin with MIC 4.7 nM. The review also highlights advancements in green synthesis, QSAR modeling, and molecular docking, which collectively facilitate the rational design of next-generation chalcone-based antibacterials. Altogether, chalcones represent a structurally simple yet biologically robust class of compounds, offering significant promise as adaptable and effective agents in the evolving landscape of antimicrobial therapy.