Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina.
Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA.
Bioorg Med Chem. 2019 Aug 15;27(16):3663-3673. doi: 10.1016/j.bmc.2019.07.004. Epub 2019 Jul 4.
As an extension of our project aimed at the search for new chemotherapeutic agents against Chagas disease and toxoplasmosis, several 1,1-bisphosphonates were designed, synthesized and biologically evaluated against Trypanosoma cruzi and Toxoplasma gondii, the etiologic agents of these diseases, respectively. In particular, and based on the antiparasitic activity exhibited by 2-alkylaminoethyl-1,1-bisphosphonates targeting farnesyl diphosphate synthase, a series of linear 2-alkylaminomethyl-1,1-bisphosphonic acids (compounds 21-33), that is, the position of the amino group was one carbon closer to the gem-phosphonate moiety, were evaluated as growth inhibitors against the clinically more relevant dividing form (amastigotes) of T. cruzi. Although all of these compounds resulted to be devoid of antiparasitic activity, these results were valuable for a rigorous SAR study. In addition, unexpectedly, the synthetic designed 2-cycloalkylaminoethyl-1,1-bisphosphonic acids 47-49 were free of antiparasitic activity. Moreover, long chain sulfur-containing 1,1-bisphosphonic acids, such as compounds 54-56, 59, turned out to be nanomolar growth inhibitors of tachyzoites of T. gondii. As many bisphosphonate-containing molecules are FDA-approved drugs for the treatment of bone resorption disorders, their potential nontoxicity makes them good candidates to control American trypanosomiasis and toxoplasmosis.
作为我们旨在寻找治疗恰加斯病和弓形体病的新化疗药物项目的延伸，我们设计、合成了几种 1,1-双膦酸盐，并对分别导致这些疾病的病原体克氏锥虫和刚地弓形虫进行了生物评价。特别是，基于针对法呢基二磷酸合酶的 2-烷氨基乙基-1,1-双膦酸盐表现出的抗寄生虫活性，我们评估了一系列线性 2-烷氨基甲基-1,1-双膦酸（化合物 21-33）作为生长抑制剂，针对克氏锥虫的临床相关性更强的分裂形式（无鞭毛体）。尽管所有这些化合物均没有表现出抗寄生虫活性，但这些结果对于严格的 SAR 研究具有重要价值。此外，出乎意料的是，合成设计的 2-环烷基氨基乙基-1,1-双膦酸 47-49 没有抗寄生虫活性。此外，长链含硫 1,1-双膦酸，如化合物 54-56、59，对刚地弓形虫的速殖子表现出纳摩尔级别的生长抑制作用。由于许多含双膦酸盐的分子是美国食品和药物管理局批准用于治疗骨质吸收紊乱的药物，它们的潜在非毒性使它们成为控制美洲锥虫病和弓形体病的良好候选药物。
