Coumarin as a privileged natural product scaffold towards the development of antibacterial agents targeting ESKAPE pathogens.

The emergence of multidrug-resistant pathogens, particularly the ESKAPE group, has reached an alarming level, posing a serious global health concern. Coumarin-based heterocyclic motifs have emerged as promising scaffolds for expanding the chemical space in the development of novel antibacterial agents targeting ESKAPE pathogens. Numerous coumarin-based derivatives have been designed and synthesized to generate lead compounds effective against both gram-positive and gram-negative bacteria, including drug-resistant ESKAPE strains. This review summarises recent advancements over the past five years in the design, synthesis, and antibacterial evaluation of coumarin-based derivatives, with a particular focus on their activity against ESKAPE pathogens. The structure-activity relationships (SAR) of these compounds, along with various structural modifications aimed at enhancing antibacterial potency, are discussed in detail. Coumarin-based derivatives have demonstrated antibacterial activity through multiple mechanisms, including inhibition of DNA gyrase and FabI enzymes, disruption of quorum sensing pathways, and prevention of biofilm formation. The diverse chemical space offered by the coumarin scaffold has been extensively explored for the rational development of antibacterial leads targeting high-priority ESKAPE pathogens. ADMET analysis identified six coumarin-scaffold-based lead molecules 10, 35, 47, 53, 57, and 65i that exhibited favourable pharmacokinetic parameters and drug-likeness properties, making them promising candidates for optimization as antibacterial agents against ESKAPE pathogens.