Novel triclabendazole prodrug: A highly water soluble alternative for the treatment of fasciolosis

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• 作者：Miguel Flores-Ramos^a ; Froylá ; n Ibarra-Velarde^b ; Helgi Jung-Cook^a ; Alicia Herná ; ndez-Campos^a ; Yolanda Vera-Montenegro^b ; Rafael Castillo^a ; ^{rafaelc@unam.mx}
• 关键词：Triclabendazole ; Fasciola hepatica ; Prodrug ; Benzimidazole ; Phosphonooxymethyl ; Fasciolicidal activity
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：27
• 期：3
• 页码：616-619
• 全文大小：490 K
• 卷排序：27

文摘

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 26 h) 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 = 13.6 s) to liberate the precursor compound. An aqueous solution of MFR-5 administered intramuscularly to sheep at concentrations of 4, 6 and 8 mg/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.