PDF(Pubmed)
Abstract：
Metronidazole (MTZ) is the most common drug used against Trichomonas vaginalis (T. vaginalis) infections; however, treatment failures and high rates of recurrence of trichomoniasis have been reported, suggesting the presence of resistance in T. vaginalis to MTZ. Therefore, research into new therapeutic options against T. vaginalis infections has become increasingly urgent. This study investigated the trichomonacidal activity of a series of five imidazole carbamate compounds (AGR-1, AGR-2, AGR-3, AGR-4, and AGR-5) through in vitro susceptibility assays to determine the IC50 value of each compound. All five compounds demonstrated potent trichomonacidal activity, with IC50 values in the nanomolar range and AGR-2 being the most potent (IC50 400 nM). To gain insight into molecular events related to AGR-induced cell death in T. vaginalis, we analyzed the expression profiles of some metabolic genes in the trophozoites exposed to AGR compounds and MTZ. It was found that both AGR and MTZ compounds reduced the expression of the glycolytic genes (CK, PFK, TPI, and ENOL) and genes involved in metabolism (G6PD, TKT, TALDO, NADHOX, ACT, and TUB), suggesting that disturbing these key metabolic genes alters the survival of the T. vaginalis parasite and that they probably share a similar mechanism of action. Additionally, the compounds showed low cytotoxicity in the Caco-2 and HT29 cell lines, and the results of the ADMET analysis indicated that these compounds have pharmacokinetic properties similar to those of MTZ. The findings offer significant insights that can serve as a basis for future in vivo studies of the compounds as a potential new treatment against T. vaginalis.
摘要：
甲硝唑（MTZ）是针对阴道毛滴虫的最常见药物（T。阴道)感染；然而，已经报道了滴虫的治疗失败和高复发率，提示阴道毛虫对MTZ存在抗性。因此,针对阴道毛虫感染的新治疗选择的研究变得越来越紧迫。本研究通过体外药敏试验研究了5种咪唑氨基甲酸酯化合物（AGR-1、AGR-2、AGR-3、AGR-4和AGR-5）的滴虫活性，以确定各化合物的IC50值。所有五个化合物都显示出有效的滴虫活性，IC50值在纳摩尔范围内,AGR-2是最有效的(IC50为400nM)。为了深入了解与AGR诱导的阴道毛虫细胞死亡相关的分子事件，我们分析了暴露于AGR化合物和MTZ的滋养体中一些代谢基因的表达谱。发现AGR和MTZ化合物均降低了糖酵解基因的表达（CK，PFK,TPI,和ENOL)和参与代谢的基因(G6PD，TKT,TALDO,NADHOX,ACT,和浴缸），这表明干扰这些关键代谢基因会改变阴道毛虫的存活，并且它们可能具有相似的作用机制。此外,这些化合物在Caco-2和HT29细胞系中显示出低的细胞毒性，ADMET分析结果表明这些化合物具有与MTZ相似的药代动力学性质。这些发现提供了重要的见解，可以作为该化合物作为针对阴道毛虫的潜在新疗法的未来体内研究的基础。
