Bacterial infections, particularly hospital-acquired infections caused by Pseudomonas aeruginosa, have become a global threat with a high mortality rate. Gram-negative bacteria including P. aeruginosa employ N-acyl homoserine lactones (AHLs) as chemical signals to regulate the expression of pathogenic phenotypes through a mechanism called quorum sensing (QS). Recently, strategies targeting bacterial behaviour or QS have received great attention due to their ability to disarm rather than kill pathogenic bacteria, which lowers the evolutionary burden on bacteria and the risk of resistance development. In the present study, we report the design and synthesis of N-alkyl- and N-aryl 3,4 dichloro- and 3,4-dibromopyrrole-2-one derivatives through the reductive amination of mucochloric and mucobromic acid with aliphatic and aromatic amines. The quorum sensing inhibition (QSI) activity of the synthesized compounds was determined against a P. aeruginosa MH602 reporter strain. The phenolic compounds exhibited the best activity with 80% and 75% QSI at 250 µM and were comparable in activity to the positive control compound Fu-30. Computational docking studies performed using the LasR receptor protein of P. aeruginosa suggested the importance of hydrogen bonding and hydrophobic interactions for QSI.
We designed and synthesized 2‐phenylindole‐amide‐triazole and salicyclic acid‐triazole analogues and characterized using NMR, MS and elemental analysis. Furthermore, single crystal was developed for N‐(2‐Phenyl‐1H‐indol‐3‐yl)‐2‐(4‐propyl‐1H‐1,2,3‐triazol‐1‐yl)acetamide (7 a), 2‐(4‐(4‐(tert‐Butyl)phenyl)‐1H‐1,2,3‐triazol‐1‐yl)‐N‐(2‐phenyl‐1H‐indol‐3‐yl)acetamide (7 h) and 3‐(1‐(4‐Ethylphenyl)‐1H‐1,2,3‐triazol‐4‐yl)‐N‐(2‐phenyl‐1H‐indol‐3‐yl)propanamide (10 j). Final compounds were screened for in vitro quorum sensing inhibitory (QSI) activity against Pseudomonas aeruginosa. The QSI activity was determined in the LasR expressing P. aeruginosa MH602 reporter strain by measuring green fluorescent protein (GFP) production. 10 j, 4‐(1‐Heptyl‐1H‐1,2,3‐triazol‐4‐yl)‐N‐(2‐phenyl‐1H‐indol‐3‐yl)butanamide (11 b) and 4‐(1‐(4‐Bromophenyl)‐1H‐1,2,3‐triazol‐4‐yl)‐N‐(2‐phenyl‐1H‐indol‐3‐yl)butanamide (11 e) exhibited promising QSI activity with 60.82, 58.89 and 54.34% at 250 μM, respectively. 1,2,3‐Triazole based salicylic acid derivatives exhibited moderate to good activity and 2‐Hydroxy‐4‐(1‐phenyl‐1H‐1,2,3‐triazol‐4‐yl)benzoic acid (17 e) is the most promising QS inhibitor with 40.28% inhibition at 250 μM. These compounds were docked into the binding site of the LasR receptor protein to understand possible binding ligand‐protein interactions. The most active compounds were subjected to cytotoxicity assay and were found to be less cytotoxic against HEK 293 cell line at 100 μM.
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