González-Hernández Iliana, Palomares-Alonso Francisca, Becerril-Vega José, Melchor-Doncel de la Torre Silvia, Hernández-Luis Francisco, Rodriguez-Morales Sergio, Aguayo-Ortiz Rodrigo, Dominguez Laura, Rodríguez-Balderas César A, González-Maciel Angélica, Rojas-Tomé Irma Susana, Castro Nelly, Jung-Cook Helgi
Laboratorio de Neuropsicofarmacología, Instituto Nacional de Neurología y Neurocirugía.
Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México.
Chem Pharm Bull (Tokyo). 2019;67(12):1293-1300. doi: 10.1248/cpb.c19-00574.
Based on our previous research on cysticidal drugs, we report the synthesis and evaluation of three new benzimidazole derivatives. In these compounds, the amido group was used as a bioisosteric replacement of the ester group. The molecular docking on β-tubulin revealed that the derivatives interacted through hydrogen bonding with N165, E198 and V236. All compounds showed in vitro activity against Taenia crassiceps cysts. Among them, benzimidazole 3 was found to be the most potent of the series (EC 0.86 µM). This compound also exhibited the highest probability of binding and the lowest binding free energy score and was therefore selected for in vivo evaluation. Results indicated that the efficacy of compound 3 was comparable to that of the reference drug, albendazole (50.39 vs. 47.16% parasite reduction). Animals treated with compound 3 seemed to tolerate this benzimidazole well, with no changes in behavior, or food and water consumption. These findings are consistent with the in silico prediction results, which indicated low toxicity risks. The pharmacokinetic study showed that the half-life and mean residence time (6.06 and 11.9 h, respectively) were long after oral administration. Together, these results indicate that this new benzimidazole derivative represents a promising structure with cysticidal activity.
基于我们之前对杀囊药物的研究，我们报道了三种新型苯并咪唑衍生物的合成与评价。在这些化合物中，酰胺基被用作酯基的生物电子等排体替代物。对β-微管蛋白的分子对接显示，这些衍生物通过与N165、E198和V236形成氢键相互作用。所有化合物均表现出对肥胖带绦虫囊肿的体外活性。其中，苯并咪唑3被发现是该系列中最有效的（EC 0.86 µM）。该化合物还表现出最高的结合概率和最低的结合自由能分数，因此被选用于体内评价。结果表明，化合物3的疗效与参考药物阿苯达唑相当（寄生虫减少率分别为50.39%和47.16%）。用化合物3治疗的动物似乎对这种苯并咪唑耐受性良好，行为、食物和水的摄入量均无变化。这些发现与计算机预测结果一致，表明毒性风险较低。药代动力学研究表明，口服给药后半衰期和平均驻留时间较长（分别为6.06和11.9 小时）。总之，这些结果表明这种新型苯并咪唑衍生物代表了一种具有杀囊活性的有前景的结构。
