Design, Synthesis and Biological Evaluation of Triazole‐Containing 2‐Phenylindole and Salicylic Acid as Quorum Sensing Inhibitors Against Pseudomonas aeruginosa

Abstract

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.

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

“…7), named 4-(1-heptyl-1H-1,2,3triazol-4-yl)-N-(2-phenyl-1H-indol-3-yl)butanamide, was found to have promising quorum sensing inhibitory activity against P. aeruginosa MH602 of 60.82% at 250 μM among the synthesised 2-phenylindoleamide-triazoles. 97 SAR analysis showed that an ethyl group at position four of the aryl portion positively affected the activity, whereas other groups, such as the bromo (-Br) derivative, exhibited moderate activity.…”

The Molecular Architecture of Pseudomonas aeruginosa Quorum-Sensing Inhibitors

“…The indole-based AHL analogue 9 ( Figure 5 c) and salicylic acid (SA) ( Figure 5 c) can effectively inhibit the P. aeruginosa LasR. Accordingly, in 2018, Sekhar et al designed and synthesized some derivatives of 2-phenylindole-amide-triazole and salicylic acid-triazole; among the compounds, four ( 1 0a – c , 1 1 ) were found to have inhibitory activity ( Figure 5 c) [ 39 ]. Later, the same group developed 1 2a – d ( Figure 5 c) as novel inhibitors of LasR-dependent quorum sensing; these compounds exhibited quorum-sensing inhibitory activity without showing toxic effects on normal cells [ 40 ].…”

“…Studies reported that the indole derivatives 7-fluoroindole, 7-hydroxyindole, and 3-indolylacetonitrile ( Figure 18 a) were potent antivirulence compounds. They reduced the production of QS-regulated virulence factors in P. aeruginosa [ 39 ]. Benzimidazole derivatives 5,6-dimethyl 2-aminobenzimidazole 5 8 and two benzimidazolium salts 59a , 59b ( Figure 18 b) were found to have inhibition effects on the production of QS-regulated virulence factors and biofilm formation in P. aeruginosa [ 140 , 141 ].…”

Bacterial virulence factors: a target for heterocyclic compounds to combat bacterial resistance

“…In 2018, Srinivasarao et al 110 designed and synthesized 2-phenylindole-amide-triazole and salicyclic acid-triazole analogues (21a–c). These compounds were screened for in vitro quorum sensing inhibitory (QSI) activity against Pseudomonas aeruginosa .…”