Novel Polyphenolic Hybrids Modulate Quorum Sensing Regulated Virulence in <i>Pseudomonas aeruginosa</i>

Abstract Naturally occurring substituted benzoic acids, known for their exceptional biological activity against Pseudomonas aeruginosa , were reacted with various aldehydes, aniline, and tert‐butyl isocyanide at 25 °C to give the desired hybrids with good to excellent yield in the range of 60–85 % and well characterized by 1 H NMR, 13 C NMR, HRMS, IR, and HPLC analysis. Molecular docking and simulation studies of compounds were conducted which predicted a high affinity towards quorum‐sensing (QS) receptors of P. aeruginosa . The polyphenolic hybrids were first screened for anti‐QS activity using the Agrobacterium tumefaciens NTL4 biosensor strain, followed by examining the antivirulence potential of selected hybrids against P. aeruginosa PAO1 in vitro . The highest degree of AHL (acyl homoserine lactone) inhibition in PAO1 was observed with the compound having a maximum number of phenolic groups. The hybrids in this investigation were also found to be non‐cytotoxic (biocompatible) towards HEK cells and may be further tested for their therapeutic efficacy against P. aeruginosa infections in vivo . It has been observed that the anti‐QS activity is directly proportional to the number of hydroxyl groups on the aromatic ring and one of the major contributing factors can be their chelating capacity as depicted by CAS shuttle assay.