Resolution and evaluation of 3-chlorophenyl-3-hydroxypropionylhydroxamic acid as antivirulence agent with excellent eradication efficacy in Helicobacter pylori infected mice

Publication date: 30 August 2018
Source:European Journal of Pharmaceutical Sciences, Volume 121
Author(s): Qi Liu, Wei-Wei Ni, Zhen Li, Cai-Fu Bai, Dan-Dan Tan, Chang-Jun Pu, Dong Zhou, Qing-Peng Tian, Ni Luo, Kai-Li Tan, Le Dai, Yuan Yan, Yong Pei, Xian-Hui Li, Zhu-Ping Xiao, Hai-Liang Zhu
The continuing emergence of drug-resistant Helicobacter pylori (HP) drives the ongoing need for the development of new and effective anti-HP drugs. Urease inhibitor has now gained strong interest as an alternative approach for HP infections. 3-Chlorophenyl-3-hydroxypropionylhydroxamic acid (CPH), a novel urease inhibitor identified in our group, shows impressive potency, which was optically separated for a further exploration. Here, we report in vitro/in vivo pharmacological evaluation of (±)-CPHs and the enantiomers. The raceme and the individual enantiomers significantly suppress gastritis at 32 mg/kg b.i.d dose with lower toxicity to mammalian cells (with CC50s ≥ 3.16 mM) and mice (LD50s ≥ 2338 mg/kg) than the clinically used agent acetohydroxamic acid. Furthermore, a significant increase of eradication of HP is observed for the combination of (±)-CPHs or the enantiomers with an antimicrobial. These studies revealed that CPH is a promising candidate for an alternative treatment of HP-dependent conditions by targeting virulence factor urease, and CPH may be used as a raceme.

Graphical abstract

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