Synthesis of novel quinazolinone-based heterocyclic acetamides as P. aeruginosa PqsR inhibitors.

Antimicrobial resistance (AMR) has become a major global concern for public health and economics and there is an urgent need to develop novel classes of antimicrobial drugs. Quorum Sensing (QS) has emerged as a promising target to counter AMR in P. aeruginosa as it controls the virulence factors and biofilm formation, causing infections in host and resistance against antibiotics. Pseudomonas quinolone signal (PQS) is one of the major signalling systems that includes PQS and HHQ as autoinducers which binds to transcription regulator PqsR (MvfR). Targeting PqsR to inhibit QS signalling could be a promising way of combating antimicrobial resistance in addition to conventional antimicrobial treatments. In this study, we have designed and synthesized a series of novel quinazolinone-based heterocyclic acetamides as PqsR modulators. The most potent compound 10k exhibited promising PqsR modulation with 87% reduction of pqs signalling at 200 μM concentration. It also showed significant reduction of biofilm formation in P. aeruginosa PAO1 strain. Additionally, it showed reduction in pyocyanin production in PAO1 strain at 200 μM with low haemolytic toxicity. Finally, the molecular docking studies showed that it occupies the same binding pocket in the PqsR receptor ligand binding domain with binding poses closely resembling the binding poses of native ligand PQS. This study has highlighted the potential of these molecules to be used to develop potent PqsR inhibitors which will serve as a novel way to treat antimicrobial resistance and microbial virulence in P. aeruginosa.