Design and discovery of urease and Helicobacter pylori inhibitors based on benzofuran/benzothiophene-sulfonate and sulfamate scaffolds for the treatment of ureolytic bacterial infections.

Autor: Hashem O; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates., Zaib S; Department of Basic and Applied Chemistry, Faculty of Science and Technology, University of Central Punjab, Lahore 54590, Pakistan. Electronic address: sumera.zaib@ucp.edu.pk., Zaraei SO; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates., Javed H; Department of Basic and Applied Chemistry, Faculty of Science and Technology, University of Central Punjab, Lahore 54590, Pakistan., Kedia RA; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates., Anbar HS; Department of Pharmaceutical Sciences, Dubai Pharmacy College for Girls, Dubai 19099, United Arab Emirates. Electronic address: dr.hanan@dpc.edu., Khan I; Department of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom., Ravi A; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates., El-Gamal MI; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: drmelgamal2002@gmail.com., Khoder G; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates. Electronic address: gkhoder@sharjah.ac.ae.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2024 Jun; Vol. 271 (Pt 1), pp. 132502. Date of Electronic Publication: 2024 May 18.
DOI: 10.1016/j.ijbiomac.2024.132502
Abstrakt: A series of sulfonate and sulfamate derivatives bearing benzofuran or benzothiophene scaffold exhibited potent inhibitory effect on urease enzyme. Most of the derivatives exhibited significantly higher potency than thiourea, the standard inhibitor. Compound 1s was identified as the most potent urease inhibitor with an IC 50 value of 0.42 ± 0.08 μM, which is 53-fold more potent than thiourea, positive control (IC 50  = 22.3 ± 0.031 μM). The docking results further revealed the binding interactions towards the urease active site. Phenotypic screening revealed that compounds 1c, 1d, 1e, 1f, 1j, 1n, and 1t exhibit high potency against H. pylori with MIC values ranging from 0.00625 to 0.05 mM and IC 50 values ranging from 0.0031 to 0.0095 mM, much more potent than the positive control, acetohydroxamic acid (MIC and IC 50 values were 12.5 and 7.38 mM, respectively). Additional studies were performed to investigate the toxicity of these compounds against the gastric epithelial cell line (AGS) and their selectivity profile against E. coli, and five Lactobacillus species representative of the gut microflora. Permeability characteristics of the most promising derivatives were investigated in Caco-2 cell line. The results indicate that the compounds could be targeted in the GIT only without systemic side effects.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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