In:
Medicinal Chemistry, Bentham Science Publishers Ltd., Vol. 17, No. 9 ( 2021-11), p. 1046-1059
Abstract:
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 thiou rea 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 IC 50 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 IC 50 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 IC 50 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.
Type of Medium:
Online Resource
ISSN:
1573-4064
DOI:
10.2174/1573406416999200818152440
Language:
English
Publisher:
Bentham Science Publishers Ltd.
Publication Date:
2021
SSG:
15,3
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