Tabor Wojciech, Katsogiannou Aikaterini, Karta Danai, Andrianopoulou Evgenia, Berlicki Łukasz, Vassiliou Stamatia, Grabowiecka Agnieszka
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Zografou, 15771 Athens, Greece.
ACS Omega. 2023 Jul 28;8(31):28783-28796. doi: 10.1021/acsomega.3c03702. eCollection 2023 Aug 8.
A series of 32 thiourea-based urease inhibitors were synthesized and evaluated against native bacterial enzyme and whole cells of and strains. The proposed inhibitors represented structurally diverse thiosemicarbazones and thiocarbohydrazones, benzyl-substituted thiazolyl thioureas, 1-pyrazole-1-carbothioamides, and dihydropirimidine-2(1)-thiones. Kinetic characteristics with purified enzyme determined low micromolar inhibitors within each structural group. ()-2-(1-Phenylethylidene)hydrazine-1-carbothioamide ( = 0.39 ± 0.01 μM), ()-2-(4-methylbenzylidene)hydrazine-1-carbothioamide ( = 0.99 ± 0.04 μM), and '-((1,2)-1,3-diphenylallylidene)hydrazinecarbothiohydrazide ( = 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 PCM 543 (e.g., IC = 304 ± 14 μM for 1-benzyl-3-(4-(4-hydroxyphenyl)thiazol-2-yl)thiourea ) is a valuable achievement, as urease is recognized as a major virulence factor of this urinary tract pathogen.
合成了一系列32种基于硫脲的脲酶抑制剂，并针对天然细菌酶以及金黄色葡萄球菌和大肠杆菌菌株的全细胞进行了评估。所提出的抑制剂包括结构多样的硫代氨基脲和硫代碳酰肼、苄基取代的噻唑基硫脲、1-吡唑-1-碳硫酰胺以及二氢嘧啶-2(1)-硫酮。用纯化的脲酶测定的动力学特征表明每个结构组内都有低微摩尔浓度的抑制剂。(-)-2-(1-苯基亚乙基)肼-1-碳硫酰胺（Ki = 0.39 ± 0.01 μM）、(-)-2-(4-甲基亚苄基)肼-1-碳硫酰胺（Ki = 0.99 ± 0.04 μM）和' - ((1,2)-1,3-二苯基烯丙基亚苄基)肼碳硫酰肼（Ki = 2.23 ± 0.19 μM）被用于建模研究，这些研究揭示了活性位点镍离子的硫离子配位以及酰胺基团与Asp363和Ala366羰基部分侧链之间的氢键。全细胞研究证明了这些化合物在革兰氏阳性和革兰氏阴性微生物中的活性。在奇异变形杆菌PCM 543中观察到的脲解控制（例如，1-苄基-3-(4-(4-羟基苯基)噻唑-2-基)硫脲的IC50 = 304 ± 14 μM）是一项有价值的成果，因为脲酶被认为是这种尿路病原体的主要毒力因子。
