Synthesis and antimicrobial activity of sulphamethoxazole-based ureas and imidazolidine-2,4,5-triones |
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Authors: | Martin Krátký Jana Mandíková František Trejtnar Vladimír Buchta Jiřina Stolaříková Jarmila Vinšová |
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Institution: | 1.Department of Inorganic and Organic Chemistry, Faculty of Pharmacy,Charles University in Prague,Hradec Králové,Czech Republic;2.Department of Pharmacology and Toxicology, Faculty of Pharmacy,Charles University in Prague,Hradec Králové,Czech Republic;3.Department of Biological and Medical Sciences, Faculty of Pharmacy,Charles University in Prague,Hradec Králové,Czech Republic;4.Department of Clinical Microbiology, Faculty of Medicine and University Hospital,Charles University in Prague,Hradec Králové,Czech Republic;5.Laboratory for Mycobacterial Diagnostics and Tuberculosis,Regional Institute of Public Health in Ostrava,Ostrava,Czech Republic |
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Abstract: | Progression of drug resistance among bacterial and fungal pathogens justifies the development of novel antimicrobial agents. Thus, a series of novel sulphamethoxazole-based ureas and imidazolidine-2,4,5-triones have been designed and synthesised. The urea derivatives were obtained by the reaction of sulphamethoxazole and isocyanates, and their cyclisation to imidazolidine-2,4,5-triones was performed via oxalyl chloride. All synthesised derivatives were evaluated in vitro to determine their activity against gram-positive and gram-negative bacteria, fungi, Mycobacterium tuberculosis, and atypical mycobacteria and their cytotoxicity. The growth of mycobacteria was inhibited within the range of 4–1000 µM and M. tuberculosis was the least-susceptible strain. 4-(3-Heptylureido)-N-(5-methylisoxazol-3-yl)benzenesulphonamide was identified as the most promising compound because it exhibited the highest activity against atypical mycobacteria at minimum inhibitory concentrations, from 4 µM, and with acceptable toxicity (selectivity indices for M. avium and M. kansasii higher than 16 and 62.5, respectively). Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, were inhibited at concentrations starting from 125 µM, whereas the investigated derivatives exhibited almost no antifungal potency and activity against gram-negative species. |
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