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

Wojciech Tabor; Aikaterini Katsogiannou; Danai Karta; Evgenia Andrianopoulou; Łukasz Berlicki; Stamatia Vassiliou; Agnieszka Grabowiecka

doi:10.1021/acsomega.3c03702

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

ACS Omega. 2023 Jul 28;8(31):28783-28796. doi: 10.1021/acsomega.3c03702. eCollection 2023 Aug 8.

Authors

Wojciech Tabor¹, Aikaterini Katsogiannou², Danai Karta², Evgenia Andrianopoulou², Łukasz Berlicki¹, Stamatia Vassiliou², Agnieszka Grabowiecka¹

Affiliations

¹ Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
² Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Zografou, 15771 Athens, Greece.

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., IC₅₀ = 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.