Exploration of Thiourea-Based Scaffolds for the Construction of Bacterial Ureases Inhibitors

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High Resolution Image Download MS PowerPoint Slide A series of 32 thiourea-based urease inhibitors were synthesized and evaluated against native bacterial enzyme and whole cells of Sporosarcina pasteurii and Proteus mirabilis strains. The proposed inhibitors represented structurally diverse thiosemicarbazones and thiocarbohydrazones, benzyl-substituted thiazolyl thioureas, 1 H -pyrazole-1-carbothioamides, and dihydropirimidine-2(1 H )-thiones. Kinetic characteristics with purified S. pasteurii enzyme determined low micromolar inhibitors within each structural group. ( E )-2-(1-Phenylethylidene)hydrazine-1-carbothioamide 19 ( K i = 0.39 ± 0.01 μM), ( E )-2-(4-methylbenzylidene)hydrazine-1-carbothioamide 16 ( K i = 0.99 ± 0.04 μM), and N ′-((1 E,2 E )-1,3-diphenylallylidene)hydrazinecarbothiohydrazide 29 ( K i = 2.23 ± 0.19 μM) were used in modeling studies that revealed sulfur ion coordination of the active site nickel ion and hydrogen bonds between the amide group and the side chain of Asp363 and Ala366 carbonyl moiety. Whole-cell studies proved the activity of compounds in Gram-positive and Gram-negative microorganisms. Ureolysis control observed in P. mirabilis PCM 543 (e.g., IC 50 = 304 ± 14 μM for 1-benzyl-3-(4-(4-hydroxyphenyl)thiazol-2-yl)thiourea 52 ) is a valuable achievement, as urease is recognized as a major virulence factor of this urinary tract pathogen.

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