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

Abstract

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, 1H-pyrazole-1-carbothioamides, and dihydropirimidine-2(1H)-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′-((1E,2E)-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.

Fabrication of Substituent-Regulated Two-Dimensional Copper-Based Coordination Polymers as Urease Inhibitors

“…Compared to other types of UIs, the two UIs demonstrate excellent urease inhibitory activities, as shown in Table . UI-1 and UI-2 show superior urease inhibitory activities when compared to the thiourea, coumarin-based hiosemicarbazones, and barbituric acid derivatives indicated as UIs, − which is due to the impact of both bis-pyridine-bis-amide ligand and copper ion where containing in the structures. The 3-bbpa ligand has two pyridinamide groups that can generate stronger contacts with active sites of urease as well as urease is inhibited by copper ions in and of itself.…”