Abstract:
Urease enzyme is a known therapeutic drug target for treatment of Helicobacter pylori infection due to its role in settlement and growthing as tricmucosa. In this study,we designed a new series of sulfonates and sulfamates bearing imidazo[2,1-b]thiazole scaffold that exhibit apotent inhibitory activity of urease enzyme. The most potent compound 2c inhibited ureasewith an IC50 value of 2.94 ± 0.05 µM, which is 8-fold more potent than the thiourea positive control (IC50= 22.3 ± 0.031 µM). Enzyme kinetics study showed that compound 2c is acompetitive inhibitor of urease. Molecular modeling studies of the most potent inhibitors in theurease active site suggested multiple binding interactions with different amino acid residues. Phenotypic screening of the developed compounds against H. pylori delivered molecules of that possess high potency (1a,1d,1h,2d,and2f) in comparison to the positive control, acetohydroxamic acid. Additional studies to investigate the selectivity of these compounds against AGS gastric cell line and E. coli were performed. Permeability of the most promising derivatives (1a, 1d, 1h, 2d, and 2f) in Caco-2 cell line, was investigated. As a result, compound 1d presented itself as a lead drug candidate since it exhibited a promising inhibition againsturease with an IC50 of 3.09 ± 0.07 µM,MIC value against H. pylori of 0.031 ± 0.011 mM, and SI against AGS of 6.05. Interestingly, compound 1d did not show activity against urease-negative E. coli and exhibited a low permeability in Caco-2 cells which supports the potential use of this compound for GIT infection without systemic effect.
Page(s):
357-357
DOI:
DOI not available
Published:
Journal: Abstract Book on International Conference on Food and Applied Sciences (ICFAS-23) 3-5 August 23, Volume: 0, Issue: 0, Year: 2023