Coumarin derivatives combating antibacterial resistance: molecular modeling-driven insights and comprehensive SAR elucidation targeting DNA gyrase and topoisomerase IV.
TL;DR
Overall, the collective evidence establishes coumarin as a highly adaptable scaffold for the development of next-generation antibacterial agents and highlights integrated structure-based design, dual-target inhibition, and comprehensive biological validation as key priorities for future medicinal chemistry research.
Abstract
Antimicrobial resistance continues to threaten the effectiveness of current antibacterial therapies, creating an urgent need for novel chemotypes that act through alternative mechanisms. Among these, coumarin derivatives have emerged as promising inhibitors of bacterial type II topoisomerases, particularly DNA gyrase and topoisomerase IV, owing to their structural versatility and ability to target the ATP-binding domain. This review critically summarizes advances reported in the past decade in the design and biological evaluation of coumarin-based antibacterial agents targeting these enzymes. Recent medicinal chemistry efforts demonstrate that rational structural modification, including heterocycle hybridization, linker optimization, scaffold rigidification and electronic tuning, markedly enhances enzyme inhibition, antibacterial potency and, in several cases, dual-target activity. Computational investigations consistently support experimental findings by identifying conserved binding interactions that explain the improved activity of optimized analogues. Overall, the collective evidence establishes coumarin as a highly adaptable scaffold for the development of next-generation antibacterial agents and highlights integrated structure-based design, dual-target inhibition, and comprehensive biological validation as key priorities for future medicinal chemistry research. Literature was collected from databases including PubMed, Scopus and Web of Science, covering studies published from 2016 to 2026.