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寻找热带病的新化疗药物：钌-克霉唑配合物对利什曼原虫和克氏锥虫表现出高体外活性，对正常哺乳动物细胞的毒性低。

Searching for new chemotherapies for tropical diseases: ruthenium-clotrimazole complexes display high in vitro activity against Leishmania major and Trypanosoma cruzi and low toxicity toward normal mammalian cells.

机构信息

Chemistry Department, Brooklyn College and The Graduate Center, The City University of New York, Brooklyn, New York 11210, USA.

出版信息

J Med Chem. 2012 Apr 26;55(8):3867-77. doi: 10.1021/jm300070h. Epub 2012 Apr 9.

DOI:10.1021/jm300070h
PMID:22448965
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3375397/
Abstract

Eight new ruthenium complexes of clotrimazole (CTZ) with high antiparasitic activity have been synthesized, cis,fac-[Ru(II)Cl(2)(DMSO)(3)(CTZ)] (1), cis,cis,trans-[Ru(II)Cl(2)(DMSO)(2)(CTZ)(2)] (2), Na[Ru(III)Cl(4)(DMSO)(CTZ)] (3), Na[trans-Ru(III)Cl(4)(CTZ)(2)] (4), [Ru(II)(η(6)-p-cymene)Cl(2)(CTZ)] (5), [Ru(II)(η(6)-p-cymene)(bipy)(CTZ)]BF(4) (6), [Ru(II)(η(6)-p-cymene)(en)(CTZ)]BF(4) (7), and [Ru(II)(η(6)-p-cymene)(acac)(CTZ)][BF(4)] (8) (bipy = bipyridine; en = ethlylenediamine; acac = acetylacetonate). The crystal structures of compounds 4-8 are described. Complexes 1-8 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 (IC(70) = 29 nM), while complex 8 displayed some effect at a higher concentration (IC(40) = 1 μM).

摘要

已经合成了 8 种具有高抗寄生虫活性的克霉唑（CTZ）的新型钌配合物，顺式，面-[Ru（II）Cl2（DMSO）3（CTZ）]（1），顺式，顺式，反式-[Ru（II）Cl2（DMSO）2（CTZ）2]（2），Na[Ru（III）Cl4（DMSO）（CTZ）]（3），Na[trans-Ru（III）Cl4（CTZ）2]（4），[Ru（II）（η（6）-p- 环戊二烯基）Cl2（CTZ）]（5），[Ru（II）（η（6）-p-环戊二烯基）（bipy）（CTZ）][BF4]（2）（6），[Ru（II）（η（6）-p-环戊二烯基）（en）（CTZ）][BF4]（2）（7）和[Ru（II）（η（6）-p-环戊二烯基）（acac）（CTZ）][BF4]（8）（bipy =联吡啶；en =乙二胺；acac =乙酰丙酮）。描述了化合物 4-8 的晶体结构。配合物 1-8 对利什曼原虫的前鞭毛体和克氏锥虫的epimastigotes 具有活性。特别值得注意的是，配合物 5 将 CTZ 的活性提高了 110 倍和 58 倍，对人成骨细胞没有明显的毒性，导致纳米摩尔和低微摩尔致死剂量和治疗指数分别为 500 和 75。在利什曼原虫感染的腹腔鼠巨噬细胞的高内涵成像测定中，配合物 5 对细胞内无鞭毛体的增殖显示出显著的抑制作用（IC70 = 29 nM），而配合物 8 在较高浓度下显示出一些效果（IC40 = 1 μM）。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc6/3375397/fbc2795c73d2/nihms-369574-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc6/3375397/2089473225ae/nihms-369574-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc6/3375397/bce268df73b0/nihms-369574-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc6/3375397/99bf12035eee/nihms-369574-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc6/3375397/78d18414e138/nihms-369574-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc6/3375397/fbc2795c73d2/nihms-369574-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc6/3375397/2089473225ae/nihms-369574-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc6/3375397/56733cebc661/nihms-369574-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc6/3375397/e2bc6423f1c0/nihms-369574-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc6/3375397/bce268df73b0/nihms-369574-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc6/3375397/99bf12035eee/nihms-369574-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc6/3375397/78d18414e138/nihms-369574-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc6/3375397/fbc2795c73d2/nihms-369574-f0004.jpg

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