Abstract
Quorum sensing is a communication system among bacteria to sense the proper time to express their virulence factors. Quorum sensing inhibition is a therapeutic strategy to block bacterial mechanisms of virulence. The aim of this study was to synthesize and evaluate new bioisosteres of N-acyl homoserine lactones as Quorum sensing inhibitors in Chromobacterium violaceum CV026 by quantifying the specific production of violacein. Five series of compounds with different heterocyclic scaffolds were synthesized in good yields: thiazoles, 16a–c, thiazolines 17a–c, benzimidazoles 18a–c, pyridines 19a–c and imidazolines 32a–c. All 15 compounds showed activity as Quorum sensing inhibitors except 16a. Compounds 16b, 17a–c, 18a, 18c, 19c and 32b exhibited activity at concentrations of 10 µM and 100 µM, highlighting the activity of benzimidazole 18a (IC50 = 36.67 µM) and 32b (IC50 = 85.03 µM). Pyridine 19c displayed the best quorum sensing inhibition activity (IC50 = 9.66 µM). Molecular docking simulations were conducted for all test compounds on the Chromobacterium violaceum CviR protein to gain insight into the process of quorum sensing inhibition. The in-silico data reveal that all 15 the compounds have higher affinity for the protein than the native AHL ligand (1). A strong correlation was found between the theoretical and experimental results.
Highlights
Quorum sensing (QS), a mechanism of cell-to-cell communication in bacteria and fungi, involves self-produced chemical signals called autoinducers that function as semiochemicals [1]
Molecular docking was carried out to provide insight into the non-bonding interactions of the test compounds with the CviR protein (PDB code: 3QP6)
Compounds 16a–c, 17a–c, 18a–c, 19a–c and 32a–c were synthesized in moderate to very good global yields, finding MW energy and ultrasound to be extremely useful for the corresponding reactions
Summary
Quorum sensing (QS), a mechanism of cell-to-cell communication in bacteria and fungi, involves self-produced chemical signals called autoinducers that function as semiochemicals [1]. Bacteria use this mechanism to communicate among themselves through the recognition and measurement of extracellular autoinducers, which accumulate in the local environment until reaching a certain level. At such a point, the bacterial population is sufficient to allow for group actions and signaling pathways are activated and specific genes (some related to virulence factors) are transcribed [2,3,4,5]. Once reaching a certain level, AHLs 1 promote specific gene expression
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