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Synthesis and Structure-Activity Relationshπip Studies of N-monosubstituted Aroylthioureas as Urease Inhibitors

Author(s):

Wei-Wei Ni, Hai-Lian Fang, Ya-Xi Ye, Wei-Yi Li, Li Liu, Zi-Juan Fu, Dawalamu, Wen-Yan Zhu, Ke Li, Fang Li, Xia Zou, Hui Ouyang, Zhu-Ping Xiao and Hai-Liang Zhu*   Pages 1 - 14 ( 14 )

Abstract:


Background: Thiourea is a classical urease inhibitor usually as a positive control, and many N,N'-disubstituted thioureas have been determined as urease inhibitors. However, due to steric hindrance, N,N'-disubstituted thiourea motif could not bind urease as thiourea. On the contrary, N-monosubstituted thioureas with a tiny thiourea motif could theoretically bind into the active pocket as thiourea.

Objective: A series of N-monosubstituted aroylthioureas were designed and synthesized for evaluation as urease inhibitors.

Methods: Urease inhibition was determined by the indophenol method and IC50 values were calculated using computerized linear regression analysis of quantal log dose-probit functions. The kinetic parameters were estimated viasurface plasmon resonance (SPR) and by nonlinear regression analysis based on the mixed type inhibition model derived from Michaelis-Menten kinetics.

Results: Compounds b2, b11and b19 reversibly inhibited urease with a mixed mechanism, and showed excellent potency against both cell-free urease and urease in intact cell, with IC50 values being 90-to 450-fold and 5-to 50-fold lower than the positive control acetohydroxamic acid, respectively. The most potent compound b11 showed IC50 value of 0.060 ±0.004μM against cell-free urease, which bound to urea binding site with a very low KDvalue (0.420±0.003nM) and a very long residence time (6.7 min). Compound b11was also demonstrated having very low cytotoxicity to mammalian cells.

Conclusion: These results revealed that N-monosubstituted aroylthioureas clearly bind the active site of urease as expected, and represent a new class of urease inhibitors for the development of potential therapeutics against infections caused by ure-ase-containing pathogens.

Keywords:

N-monosubstituted aroylthioureas, reversible urease inhibitor, Helicobacter pylori, surface plasmon resonance, molecular docking, cytotoxicity.

Affiliation:

National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000



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