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.
Eur J Med Chem. 2013 Feb;60:431-40. doi: 10.1016/j.ejmech.2012.12.015. Epub 2012 Dec 20.
As part of our efforts aimed at searching for new antiparasitic agents, 2-alkylmercaptoethyl-1,1-bisphosphonate derivatives were synthesized and evaluated against Trypanosoma cruzi, the etiologic agent of Chagas disease, and Toxoplasma gondii, the responsible agent for toxoplasmosis. Many of these sulfur-containing bisphosphonates were potent inhibitors against the intracellular form of T. cruzi, the clinically more relevant replicative form of this parasite, and tachyzoites of T. gondii targeting T. cruzi or T. gondii farnesyl diphosphate synthases (FPPSs), which constitute valid targets for the chemotherapy of these parasitic diseases. Interestingly, long chain length sulfur-containing bisphosphonates emerged as relevant antiparasitic agents. Taking compounds 37, 38, and 39 as representative members of this class of drugs, they exhibited ED(50) values of 15.8 μM, 12.8 μM, and 22.4 μM, respectively, against amastigotes of T. cruzi. These cellular activities matched the inhibition of the enzymatic activity of the target enzyme (TcFPPS) having IC(50) values of 6.4 μM, 1.7 μM, and 0.097 μM, respectively. In addition, these compounds were potent anti-Toxoplasma agents. They had ED(50) values of 2.6 μM, 1.2 μM, and 1.8 μM, respectively, against T. gondii tachyzoites, while they exhibited a very potent inhibitory action against the target enzyme (TgFPPS) showing IC(50) values of 0.024 μM, 0.025 μM, and 0.021 μM, respectively. Bisphosphonates bearing a sulfoxide unit at C-3 were also potent anti-Toxoplasma agents, particularly those bearing long aliphatic chains such as 43-45, which were also potent antiproliferative drugs against tachyzoites of T. gondii. These compounds inhibited the enzymatic activity of the target enzyme (TgFPPS) at the very low nanomolar range. These bisphosphonic acids have very good prospective not only as lead drugs but also as potential chemotherapeutic agents.
作为寻找新抗寄生虫药物的努力的一部分，我们合成了 2-烷基巯基乙基-1,1-双膦酸酯衍生物，并对引起恰加斯病的克氏锥虫和引起弓形体病的弓形体进行了评价。这些含硫双膦酸盐中有许多是克氏锥虫的有效抑制剂，克氏锥虫是这种寄生虫的更具临床意义的复制形式，也是弓形体的速殖子，靶向克氏锥虫或弓形体法呢基二磷酸合酶（FPPS），这是这些寄生虫病化学治疗的有效靶点。有趣的是，长链含硫双膦酸盐成为有效的抗寄生虫药物。以化合物 37、38 和 39 作为该类药物的代表性成员，它们对克氏锥虫的无鞭毛体的 ED（50）值分别为 15.8 μM、12.8 μM 和 22.4 μM。这些细胞活性与靶酶（TcFPPS）的酶活性抑制相匹配，IC（50）值分别为 6.4 μM、1.7 μM 和 0.097 μM。此外，这些化合物是有效的抗弓形体药物。它们对弓形体速殖体的 ED（50）值分别为 2.6 μM、1.2 μM 和 1.8 μM，而对靶酶（TgFPPS）则表现出非常强的抑制作用，IC（50）值分别为 0.024 μM、0.025 μM 和 0.021 μM。在 C-3 位带有亚砜单元的双膦酸盐也是有效的抗弓形体药物，特别是那些带有长脂肪链的双膦酸盐，如 43-45，它们也是对弓形体速殖体有很强的抗增殖作用的药物。这些化合物在非常低的纳摩尔范围内抑制靶酶（TgFPPS）的酶活性。这些双膦酸具有很好的前景，不仅可以作为先导药物，也可以作为潜在的化疗药物。
