Novel Vanillin-based hybrids inhibit quorum sensing and silences phenotypical expressions in Pseudomonas aeruginosa

In this study, we report the chemical synthesis, computational analysis, and anti-virulent studies of five Vanillin-based hybrids employing phytochemicals. Vanillin (V) is known to have substantial anti-quorum sensing activity against the gram-negative pathogen Pseudomonas aeruginosa. Therefore, with the aim to further enhance the potency of Vanillin, it was chemically conjugated via a triazole (T) linker with five phytochemicals- Zingerone (Z), Eugenol (E), Guaiacol (G), Cinnamaldehyde (C), and Ferulic acid (F) to form the hybrids named as VTZ (1), VTE (2), VTG (3), VTC (4), and VTF (5), respectively. Molecular docking studies revealed the strong binding affinity of the designed hybrids with quorum-sensing receptors (LasR, Rh1R, and PqsR). The synthesized hybrids were also evaluated for anti-quorum sensing activities to examine the efficacy against P. aeruginosa bacterial strains PAO1. The hybrids VTE (2), VTG (3), and VTC (4) displayed improved anti-quorum activity relative to Vanillin. Furthermore, the attenuation of virulence factors of P. aeruginosa (Las-A protease, Las-B elastase, pyocyanin pigmentation, and motility) in the presence of VTE (2), VTG (3), and VTC (4) further authenticated the anti-virulent activity of the hybrids. The new design strategy of the phytochemical-phytochemical scaffolds and their biological evaluation provides a proof of concept for the simultaneous perturbation of well-established anti-virulent targets. This appears to be highly promising and effective strategy to ameliorate the enigma of antimicrobial resistance.