ABSTRACT
BACKGROUND: Chagas disease, caused by the parasite Trypanosoma cruzi, represents a worldwide epidemiological, economic, and social problem. In the last decades, the trans-sialidase enzyme of Trypanosoma cruzi has been considered an attractive target for the development of new agents with potential trypanocidal activity. OBJECTIVE: In this work, the aim was to find new potential non-sugar trans-sialidase inhibitors using benzoic acid as a scaffold. METHODS: A structure-based virtual screening of the ZINC15 database was carried out. Additionally, the enzyme and trypanocidal activity of the selected compounds was determined. RESULTS: The results of this work detected 487 compounds derived from benzoic acid as potential transsialidase inhibitors with a more promising binding energy value (< -7.7 kcal/mol) than the known inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA). In particular, two lead compounds, V1 and V2, turned out to be promising trans-sialidase inhibitors. Even though the trypanocidal activity displayed was low, these compounds showed trans-sialidase inhibition values of 87.6% and 29.6%, respectively. CONCLUSION: Structure-based virtual screening using a molecular docking approach is a useful method for the identification of new trans-sialidase inhibitors.
Subject(s)
Benzoic Acid/chemistry , Benzoic Acid/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Neuraminidase/antagonists & inhibitors , Trypanosoma cruzi/enzymology , Benzoic Acid/metabolism , Drug Evaluation, Preclinical , Enzyme Inhibitors/metabolism , Molecular Docking Simulation , Neuraminidase/chemistry , Neuraminidase/metabolism , Protein Conformation , Thermodynamics , Trypanosoma cruzi/drug effects , User-Computer InterfaceABSTRACT
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.