Design and synthesis of novel anti-urease imidazothiazole derivatives with promising antibacterial activity against Helicobacter pylori.

Autor: Shahin AI; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates., Zaib S; Faculty of Science and Technology, Department of Basic and Applied Chemistry, University of Central Punjab, Lahore, Pakistan., Zaraei SO; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates., Kedia RA; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates., Anbar HS; Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, United Arab Emirates., Younas MT; Faculty of Science and Technology, Department of Basic and Applied Chemistry, University of Central Punjab, Lahore, Pakistan., Al-Tel TH; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates., Khoder G; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.; Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates., El-Gamal MI; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates.; Faculty of Pharmacy, Department of Medicinal Chemistry, Mansoura University, Mansoura, Egypt.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2023 Jun 02; Vol. 18 (6), pp. e0286684. Date of Electronic Publication: 2023 Jun 02 (Print Publication: 2023).
DOI: 10.1371/journal.pone.0286684
Abstrakt: 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 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 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 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.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Shahin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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