In:
PLOS ONE, Public Library of Science (PLoS), Vol. 18, No. 6 ( 2023-6-2), p. e0286684-
Abstract:
Urease enzyme is a known therapeutic drug target for treatment of Helicobacter pylori infection due to its role in settlement and growth in gastric mucosa. In this study, we designed a new series of sulfonates and sulfamates bearing imidazo[2,1- b ]thiazole scaffold that exhibit a potent inhibitory activity of urease enzyme. The most potent compound 2c inhibited urease with an IC 50 value of 2.94 ± 0.05 μM, which is 8-fold more potent than the thiourea positive control (IC 50 = 22.3 ± 0.031 μM). Enzyme kinetics study showed that compound 2c is a competitive inhibitor of urease. Molecular modeling studies of the most potent inhibitors in the urease 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 , and 2f ) 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 against urease with an IC 50 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.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0286684
DOI:
10.1371/journal.pone.0286684.g001
DOI:
10.1371/journal.pone.0286684.g002
DOI:
10.1371/journal.pone.0286684.g003
DOI:
10.1371/journal.pone.0286684.g004
DOI:
10.1371/journal.pone.0286684.g005
DOI:
10.1371/journal.pone.0286684.g006
DOI:
10.1371/journal.pone.0286684.g007
DOI:
10.1371/journal.pone.0286684.g008
DOI:
10.1371/journal.pone.0286684.g009
DOI:
10.1371/journal.pone.0286684.g010
DOI:
10.1371/journal.pone.0286684.g011
DOI:
10.1371/journal.pone.0286684.g012
DOI:
10.1371/journal.pone.0286684.g013
DOI:
10.1371/journal.pone.0286684.g014
DOI:
10.1371/journal.pone.0286684.g015
DOI:
10.1371/journal.pone.0286684.t001
DOI:
10.1371/journal.pone.0286684.t002
DOI:
10.1371/journal.pone.0286684.t003
DOI:
10.1371/journal.pone.0286684.t004
DOI:
10.1371/journal.pone.0286684.t005
DOI:
10.1371/journal.pone.0286684.t006
DOI:
10.1371/journal.pone.0286684.t007
DOI:
10.1371/journal.pone.0286684.s001
DOI:
10.1371/journal.pone.0286684.s002
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2267670-3
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