Unlocking new antimicrobial leads in the last decade: exploring quinolin-2-one based hybrids' synthesis, action, SAR, and challenges in tackling antimicrobial resistance.
TL;DR
Quinolin-2-one derivatives demonstrated considerable therapeutic promise as versatile antimicrobial scaffolds, but current studies revealed several limitations, including poor aqueous solubility, insufficient preclinical ADMET characterization, and limited in vivo validation.
Abstract
The rapid emergence of antimicrobial resistance (AMR) posed a major global health threat and created an urgent need for new broad-spectrum antimicrobial agents. The quinolin-2-one scaffold emerged as a privileged structural motif in medicinal chemistry because it exhibited promising activity against a wide range of bacterial and fungal pathogens. Continuous optimization of this scaffold remained essential to address the increasing burden of resistance. This review summarized recent advances in quinolin-2-one derivatives reported from 2015 to 2025. It systematically examined synthetic approaches and revealed a growing shift toward greener and more sustainable methodologies. The review also analyzed the structure-activity relationships that governed antimicrobial potency, integrated findings from biological evaluations, discussed proposed mechanisms of action, including inhibition of DNA topoisomerases and disruption of cell wall biosynthesis, and assessed the available toxicity data for the reported compounds. Advantages, disadvantages and future perspectives Quinolin-2-one derivatives demonstrated considerable therapeutic promise as versatile antimicrobial scaffolds. However, current studies revealed several limitations, including poor aqueous solubility, insufficient preclinical ADMET characterization, and limited in vivo validation. Future investigations should address these pharmacokinetic and toxicological limitations to support the rational design of next-generation quinolin-2-one hybrids and improve their potential for clinical translation.