Recent advances in medicinal chemistry on PqsR in Pseudomonas aeruginosa: Scaffold optimization, SAR insights, and natural product modulators.

Targeting Pseudomonas aeruginosa virulence has gained significant attention as a promising strategy to control its pathogenicity, lower the risk of resistance development and improve the effectiveness of current antibiotics. This virulence is controlled by an intricate quorum-sensing system, with PqsR serving as a key regulatory hub. PqsR has gained attention as a promising therapeutic target, with multiple studies reporting that its disruption markedly reduces virulence and impairs biofilm development. This review synthesizes findings from approximately twenty major medicinal chemistry studies published over the past five years to guide the rational design of next-generation PqsR antagonists targeting multidrug-resistant Pseudomonas aeruginosa. We summarize efforts that yielded forty-six inhibitors with IC50 values ranging from 0.005 μM to 32 μM, emphasizing scaffold development, SAR insights, and optimization strategies that significantly enhanced potency. Importantly, we also examine the pharmacokinetic properties of the most active analogues, identifying key liabilities that currently limit their translational potential. Additionally, we discuss emerging natural products as promising PqsR inhibitors, offering structural diversity and multi-target activity that can inspire broad-spectrum anti-virulence agent design. Finally, we outline future optimization strategies to enhance the potency and drug-like properties of scaffolds with moderate potency, thereby expanding the landscape of viable PqsR-targeted therapeutics.