National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, PR China.
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
Eur J Pharm Sci. 2018 Aug 30;121:293-300. doi: 10.1016/j.ejps.2018.05.029. Epub 2018 May 31.
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 CCs ≥ 3.16 mM) and mice (LDs ≥ 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.
幽门螺杆菌（HP）耐药性的持续出现推动了开发新的有效抗 HP 药物的持续需求。 脲酶抑制剂作为 HP 感染的替代方法已引起广泛关注。 我们小组鉴定的新型脲酶抑制剂 3-氯苯基-3-羟基丙酰羟肟酸（CPH）显示出令人印象深刻的效力，现已进行光学分离以进一步探索。 在这里，我们报告了（±）-CPHs 及其对映异构体的体外/体内药理学评价。 消旋体和单个对映异构体以 32mg/kg b.i.d 剂量显着抑制胃炎，对哺乳动物细胞（CCs≥3.16mM）和小鼠（LDs≥2338mg/kg）的毒性低于临床使用的试剂乙酰羟肟酸。 此外，（±）-CPHs 或其与抗菌药物的组合观察到对 HP 的根除有显着增加。 这些研究表明，CPH 是通过靶向毒力因子脲酶替代治疗 HP 相关疾病的有前途的候选药物，CPH 可作为外消旋体使用。
