Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.
Faculty of Science and Technology, Department of Basic and Applied Chemistry, University of Central Punjab, Lahore, Pakistan.
PLoS One. 2023 Jun 2;18(6):e0286684. doi: 10.1371/journal.pone.0286684. eCollection 2023.
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.
脲酶是一种已知的治疗药物靶点，可用于治疗幽门螺杆菌感染，因为它在胃黏膜中的定居和生长中起作用。在这项研究中，我们设计了一系列带有咪唑并[2,1-b]噻唑骨架的新型磺酸盐和磺胺酸盐，它们对脲酶表现出很强的抑制活性。最有效的化合物 2c 对脲酶的抑制作用，IC50 值为 2.94±0.05 μM，比硫脲阳性对照物（IC50=22.3±0.031 μM）强 8 倍。酶动力学研究表明，化合物 2c 是脲酶的竞争性抑制剂。对脲酶活性部位最有效的抑制剂进行分子建模研究表明，它们与不同的氨基酸残基有多种结合相互作用。对开发的化合物进行针对 H. pylori 的表型筛选，结果表明，与阳性对照物乙酰羟肟酸相比，这些化合物具有很高的活性（1a、1d、1h、2d 和 2f）。进一步研究了这些化合物对 AGS 胃细胞系和大肠杆菌的选择性。对最有前途的衍生物（1a、1d、1h、2d 和 2f）在 Caco-2 细胞系中的渗透性进行了研究。结果表明，化合物 1d 是一种潜在的先导药物候选物，因为它对脲酶的抑制作用，IC50 值为 3.09±0.07 μM，对 H. pylori 的 MIC 值为 0.031±0.011 mM，对 AGS 的选择性指数（SI）为 6.05。有趣的是，化合物 1d 对脲酶阴性的大肠杆菌没有活性，并且在 Caco-2 细胞中的渗透性较低，这支持了该化合物在不产生全身作用的情况下用于胃肠道感染的潜在用途。
