Searching for New Chemotherapies for Tropical Diseases: Ruthenium鈥揅lotrimazole Complexes Display High in Vitro Activity against Leishmania major and Trypanosoma cruzi and Low Toxicity to

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• 作者：Alberto Mart铆nez ; Teresia Carreon ; Eva Iniguez ; Atilio Anzellotti ; Antonio S谩nchez ; Marina Tyan ; Aaron Sattler ; Linda Herrera ; Rosa A. Maldonado ; Roberto A. S谩nchez-Delgado
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 26, 2012
• 年：2012
• 卷：55
• 期：8
• 页码：3867-3877
• 全文大小：442K
• 年卷期：v.55,no.8(April 26, 2012)
• ISSN：1520-4804

文摘

Eight new ruthenium complexes of clotrimazole (CTZ) with high antiparasitic activity have been synthesized, cis,fac-[Ru^IICl₂(DMSO)₃(CTZ)] (1), cis,cis,trans-[Ru^IICl₂(DMSO)₂(CTZ)₂] (2), Na[Ru^IIICl₄(DMSO)(CTZ)] (3), Na[trans-Ru^IIICl₄(CTZ)₂] (4), [Ru^II(畏⁶-p-cymene)Cl₂(CTZ)] (5), [Ru^II(畏⁶-p-cymene)(bipy)(CTZ)][BF₄]₂ (6), [Ru^II(畏⁶-p-cymene)(en)(CTZ)][BF₄]₂ (7), and [Ru^II(畏⁶-p-cymene)(acac)(CTZ)][BF₄] (8) (bipy = bipyridine; en = ethlylenediamine; acac = acetylacetonate). The crystal structures of compounds 4鈥?b>8 are described. Complexes 1鈥?b>8 are active against promastigotes of Leishmania major and epimastigotes of Trypanosoma cruzi. Most notably, complex 5 increases the activity of CTZ by factors of 110 and 58 against L. major and T. cruzi, with no appreciable toxicity to human osteoblasts, resulting in nanomolar and low micromolar lethal doses and therapeutic indexes of 500 and 75, respectively. In a high-content imaging assay on L. major-infected intraperitoneal mice macrophages, complex 5 showed significant inhibition on the proliferation of intracellular amastigotes (IC₇₀ = 29 nM), while complex 8 displayed some effect at a higher concentration (IC₄₀ = 1 渭M).