Inhibition of urease results in Helicobacter pylori growth arrest in the stomach, promoting urease as promising targets for gastrointestinal ulcer therapy. Twenty hybrid derivatives of flavonoid scaffold and hydroxamic acid, β-hydroxy-β-phenylpropionylhydroxamic acids, were therefore synthesized and evaluated against H. pylori urease. Biological evaluation of these compounds showed improved urease inhibition exhibiting micromolar to mid-nanomolar IC50 values. Most importantly, 3-(3-chlorophenyl)-3-hydroxypropionyl-hydroxamic acid (6g) exhibited high potency with IC50 of 0.083±0.004 μM and Ki of 0.014±0.003 μM, indicating that 6g is an excellent candidate to develop novel antiulcer agent. A mixture of competitive and uncompetitive mechanism was putatively proposed to understand the inconsistency between the crystallographic and kinetic studies for the first time, which is supported by our molecular docking studies.

译文

:脲酶的抑制导致幽门螺杆菌在胃中的生长停滞,促进脲酶成为胃肠道溃疡治疗的有希望的靶标。因此,合成了黄酮类支架和异羟肟酸的二十种杂合衍生物,β-羟基-β-苯基丙酰基异羟肟酸,并针对幽门螺杆菌脲酶进行了评估。这些化合物的生物学评估表明,尿素酶抑制作用得到改善,表现出微摩尔至中纳摩尔级的IC50值。最重要的是,3-(3-氯苯基)-3-羟基丙酰基-异羟肟酸(6g)表现出很高的效力,IC50为0.083±0.004μM,Ki为0.014±0.003μM,表明6g是开发新型抗溃疡药的极佳候选药物。为了首次了解晶体学和动力学研究之间的矛盾,提出了一种竞争机制和非竞争机制的混合物,这是我们的分子对接研究所支持的。

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