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

A series of 32 thiourea-based urease inhibitors weresynthesizedand evaluated against native bacterial enzyme and whole cells of Sporosarcina pasteurii and Proteusmirabilis strains. The proposed inhibitors representedstructurally diverse thiosemicarbazones and thiocarbohydrazones, benzyl-substitutedthiazolyl thioureas, 1H-pyrazole-1-carbothioamides,and dihydropirimidine-2(1H)-thiones. Kinetic characteristicswith purified S. pasteurii enzyme determinedlow micromolar inhibitors within each structural group. (E)-2-(1-Phenylethylidene)hydrazine-1-carbothioamide 19 (K ( i ) = 0.39 & PLUSMN; 0.01 & mu;M), (E)-2-(4-methylbenzylidene)hydrazine-1-carbothioamide 16 (K ( i ) = 0.99 & PLUSMN; 0.04 & mu;M), and N & PRIME;-((1E,2E)-1,3-diphenylallylidene)hydrazinecarbothiohydrazide 29 (K ( i ) = 2.23 & PLUSMN; 0.19 & mu;M) were used in modeling studies that revealedsulfur ion coordination of the active site nickel ion and hydrogenbonds between the amide group and the side chain of Asp363 and Ala366carbonyl moiety. Whole-cell studies proved the activity of compoundsin Gram-positive and Gram-negative microorganisms. Ureolysis controlobserved in P. mirabilis PCM 543 (e.g.,IC50 = 304 & PLUSMN; 14 & mu;M for 1-benzyl-3-(4-(4-hydroxyphenyl)thiazol-2-yl)thiourea 52) is a valuable achievement, as urease is recognized asa major virulence factor of this urinary tract pathogen.