Munguía Beatriz, Michelena Mauricio, Melian Elisa, Saldaña Jenny, Ures Ximena, Manta Eduardo, Domínguez Laura
Cátedra de Farmacología, Laboratorio de Experimentación Animal, Depto. CIENFAR, Facultad de Química, Universidad de la República (Udelar), Av. General Flores 2124, Montevideo, Uruguay.
Cátedra de Química Farmacéutica, Depto. DQO, Facultad de Química, Udelar, Av. General Flores 2124, Montevideo, Uruguay.
Exp Parasitol. 2015 Jun;153:75-80. doi: 10.1016/j.exppara.2015.03.013. Epub 2015 Mar 25.
In the search for new anthelmintics able to overcome the resistance problem against all available drugs in livestock, the synthesis of novel valerolactam-benzimidazole hybrid compounds was reported. This allowed us to obtain these in vitro and in vivo bioactive compounds using Nippostrongylus brasiliensis rat model by integrating physiology-based assays and ex vivo diffusion studies. In order to further study those novel hybrid molecules, Haemonchus contortus (a sheep gastrointestinal nematode of interest) and Mesocestoides vogae tetrathyridia (a useful system to study the efficacy of anthelmintic drugs against cestoda) were used as parasite models to compare the ex vivo patterns of diffusion and biotransformation of benzimidazoles and their valerolactam-benzimidazole hybrid derivatives. On average, a nine-fold higher intraparasitic concentration of compounds was found in M. vogae compared with H.contortus, with similarities regarding the order of entry of compounds, highlighting febendazole (FEB) and its hybrid compound 10, while valerolactam compound 2 practically did not penetrate the parasites. Interestingly, sulphoxidation drug metabolism was observed and measured, revealing percentages of oxidation of 8.2% and 14.5% for albendazole (ABZ) and febendazole respectively in M. vogae, while this effect was more relevant in H. contortus parasite. More importantly, significant differences were observed between anthelmintic-susceptible adult parasites (Hc S) and those from sheep farms (Hc U). In fact, the percentages of oxidation of FEB and the hybrid compound 8 were higher in Hc U (25.5%, 54.1%, respectively) than in Hc S (8.8%, 38.2%). Interestingly, sulphoxidation of hybrid compound 10 was neither observed in M. vogae nor in H. contortus parasites, suggesting that increased drug metabolism (oxidation reactions) could not be used by these parasites as a defense mechanism against this novel drug.
在寻找能够克服家畜对所有现有药物产生抗药性问题的新型驱虫药的过程中，有报道称合成了新型戊内酰胺 - 苯并咪唑杂化化合物。通过整合基于生理学的分析方法和体外扩散研究，我们利用巴西日圆线虫大鼠模型获得了这些具有体外和体内生物活性的化合物。为了进一步研究这些新型杂化分子，使用捻转血矛线虫（一种引起人们关注的绵羊胃肠道线虫）和伏氏中绦虫四膜虫（一种用于研究驱虫药对绦虫疗效的有用模型）作为寄生虫模型，比较苯并咪唑及其戊内酰胺 - 苯并咪唑杂化衍生物的体外扩散和生物转化模式。平均而言，与捻转血矛线虫相比，在伏氏中绦虫中发现化合物的寄生体内浓度高九倍，化合物进入顺序相似，突出显示了非班太尔（FEB）及其杂化化合物10，而戊内酰胺化合物2实际上未穿透寄生虫。有趣的是，观察并测量了硫氧化药物代谢，结果显示在伏氏中绦虫中，阿苯达唑（ABZ）和非班太尔的氧化百分比分别为8.2%和14.5%，而这种效应在捻转血矛线虫寄生虫中更为明显。更重要的是，在对驱虫药敏感的成年寄生虫（Hc S）和来自养羊场的寄生虫（Hc U）之间观察到了显著差异。事实上，非班太尔和杂化化合物8在Hc U中的氧化百分比（分别为25.5%、54.1%）高于Hc S（8.8%、38.2%）。有趣的是，在伏氏中绦虫和捻转血矛线虫寄生虫中均未观察到杂化化合物10的硫氧化，这表明增加的药物代谢（氧化反应）不能被这些寄生虫用作针对这种新药的防御机制。
