Flores-Ramos Miguel, Ibarra-Velarde Froylán, Jung-Cook Helgi, Hernández-Campos Alicia, Vera-Montenegro Yolanda, Castillo Rafael
Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Av. Universidad 3000, CDMX, México 04510, Mexico.
Facultad de Medicina Veterinaria y Zootecnia, Departamento de Parasitología, Universidad Nacional Autónoma de México, Av. Universidad 3000, CDMX, México 04510, Mexico.
Bioorg Med Chem Lett. 2017 Feb 1;27(3):616-619. doi: 10.1016/j.bmcl.2016.12.004. Epub 2016 Dec 2.
In this work we present the synthesis, aqueous solubility and stability, hydrolysis by alkaline phosphatase, and in vivo fasciolicidal activity in sheep of a highly water soluble phosphate salt prodrug of triclabendazole (MFR-5). The aqueous solubility of MFR-5 at pH 7 was 88,000-fold that of triclabendazole. MFR-5 showed excellent aqueous stability (>95% after 26h) at pH 7, making it ideal for developing pharmaceutical compositions in the form of solutions that can easily be hydrolyzed by the enzyme alkaline phosphatase (t=13.6s) to liberate the precursor compound. An aqueous solution of MFR-5 administered intramuscularly to sheep at concentrations of 4, 6 and 8mg/kg presented a fasciolicidal efficiency of 96.5%, 98.4% and 99.2%, respectively. In the in vivo experiments, MFR-5 reduced 100% the excretion of eggs in all of the above concentrations.
在本研究中，我们展示了三氯苯达唑的一种高水溶性磷酸盐前药（MFR - 5）的合成、水溶性及稳定性、碱性磷酸酶催化的水解作用，以及其在绵羊体内的杀片形吸虫活性。MFR - 5在pH 7时的水溶性是三氯苯达唑的88,000倍。MFR - 5在pH 7时表现出优异的水稳定性（26小时后>95%），这使其非常适合开发能够被碱性磷酸酶轻易水解（t = 13.6秒）以释放前体化合物的溶液剂型药物组合物。以4、6和8mg/kg的浓度给绵羊肌肉注射MFR - 5水溶液，其杀片形吸虫效率分别为96.5%、98.4%和99.2%。在体内实验中，上述所有浓度的MFR - 5均使虫卵排泄减少了100%。
