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

• Published in: Drug development research Vol. 84; no. 1; pp. 45 - 61
• Main Authors: Dua, Tamanna, Mangal, Surabhi, Akshita, Goel, Harshdeep, Atri, Ankit K., Sharma, Purshotam, Harjai, Kusum, Singh, Vasundhara
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.02.2023
• Subjects: Anti-Bacterial Agents - chemistry; Antimicrobial resistance; Biofilms; Chemical synthesis; Cinnamaldehyde; Computer applications; Elastase; Eugenol; Evaluation; Ferulic acid; Guaiacol; Humans; Hybrids; Molecular docking; Molecular Docking Simulation; Perturbation; phytochemical; Phytochemicals; Phytochemicals - pharmacology; Pigmentation; Pseudomonas aeruginosa; Pyocyanin; quorum quenching; Quorum sensing; Vanillin; Venous Thromboembolism; Virulence; Virulence factors; Zingerone; Pseudomonas aeruginosa; quorum quenching; phytochemical
• ISSN: 0272-4391; 1098-2299
• DOI: 10.1002/ddr.22011

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.