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

Title:Synthesis and Structure-Activity Relationship Studies of N-monosubstituted Aroylthioureas as Urease Inhibitors

Volume: 17 Issue: 9

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*Hai-Liang Zhu*

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,China

• National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000,China

Keywords: N-monosubstituted aroylthioureas, Reversible urease inhibitor, Helicobacter pylori, Surface plasmon resonance, Molecular docking, cytotoxicity.

Abstract:

Background: Thiourea is a classical urease inhibitor which is usually used 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 thiourea 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 via surface plasmon resonance (SPR) and by nonlinear regression analysis based on the mixed type inhibition model derived from Michaelis-Menten kinetics.

Results: Compounds b2, b11, and b19 reversibly inhibited urease with a mixed mechanism, and showed excellent potency against both cell-free urease and urease in the 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 an IC₅₀ value of 0.060 ± 0.004μM against cell-free urease, which bound to urea binding site with a very low KD value (0.420±0.003nM) and a very long residence time (6.7 min). Compound b11 was also demonstrated to have very low cytotoxicity to mammalian cells.

Conclusion: The results revealed that N-monosubstituted aroylthioureas bound to 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 urease-containing pathogens.

Cite this article as:

Ni Wei-Wei , Fang Hai-Lian , Ye Ya-Xi , Li Wei-Yi , Liu Li , Fu Zi-Juan , Dawalamu , Zhu Wen-Yan , Li Ke , Li Fang , Zou Xia , Ouyang Hui , Xiao Zhu-Ping *, Zhu Hai-Liang *, Synthesis and Structure-Activity Relationship Studies of N-monosubstituted Aroylthioureas as Urease Inhibitors, Medicinal Chemistry 2021; 17 (9) . https://dx.doi.org/10.2174/1573406416999200818152440