Design,synthesis, and biological evaluation of 1‐ethyl‐3‐(thiazol‐2‐yl)urea derivatives as Escherichia coli DNA gyrase inhibitors |
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Authors: | Tihomir Toma?i? Michaela Baran?oková Nace Zidar Janez Ila? Päivi Tammela Danijel Kikelj |
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Affiliation: | 1. Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia;2. Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland |
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Abstract: | Discovery of novel DNA gyrase B inhibitors remains an attractive field in the search for new antibacterial drugs to overcome the known bacterial resistance mechanisms. In the present study, we designed and synthesized novel ethylurea derivatives of 4,5,6,7‐tetrahydrobenzo1,2‐d]thiazole‐2,6‐diamine, 2‐(2‐aminothiazol‐4‐yl)acetic acid, and benzo1,2‐d]thiazole‐2,6‐diamine and evaluated their Escherichia coli DNA gyrase inhibition. The most potent DNA gyrase inhibitors in the prepared library of compounds were benzo1,2‐d]thiazoles 32–34 , 36 , and 37 with IC50 values in the low micromolar range. The most promising inhibitors identified were evaluated against selected Gram‐positive and Gram‐negative bacterial strains. Compound 33 showed a MIC of 50 μM against an E. coli efflux pump‐defective strain, which suggests that efflux decreases the on‐target concentrations of these compounds. |
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Keywords: | antibacterial DNA gyrase ethylurea inhibitor thiazole |
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