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Metal–drug synergy: new ruthenium(II) complexes of ketoconazole are highly active against Leishmania major and Trypanosoma cruzi and nontoxic to human or murine normal cells

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Abstract

In our ongoing search for new metal-based chemotherapeutic agents against leishmaniasis and Chagas disease, six new ruthenium–ketoconazole (KTZ) complexes have been synthesized and characterized, including two octahedral coordination complexes—cis,fac-[RuIICl2(DMSO)3(KTZ)] (1) and cis-[RuIICl2(bipy)(DMSO)(KTZ)] (2) (where DMSO is dimethyl sulfoxide and bipy is 2,2′-bipyridine)—and four organometallic compounds—[RuII(η6-p-cymene)Cl2(KTZ)] (3), [RuII(η6-p-cymene)(en)(KTZ)][BF4]2 (4), [RuII(η6-p-cymene)(bipy)(KTZ)][BF4]2 (5), and [RuII(η6-p-cymene)(acac)(KTZ)][BF4] (6) (where en is ethylenediamine and acac is acetylacetonate); the crystal structure of 3 is described. The central hypothesis of our work is that combining a bioactive compound such as KTZ and a metal in a single molecule results in a synergy that can translate into improved activity and/or selectivity against parasites. In agreement with this hypothesis, complexation of KTZ with RuII in compounds 3–5 produces a marked enhancement of the activity toward promastigotes and intracellular amastigotes of Leishmania major, when compared with uncomplexed KTZ, or with similar ruthenium compounds not containing KTZ. Importantly, the selective toxicity of compounds 3–5 toward the leishmania parasites, in relation to human fibroblasts and osteoblasts or murine macrophages, is also superior to the selective toxicities of the individual constituents of the drug. When tested against Trypanosoma cruzi epimastigotes, some of the organometallic complexes displayed activity and selectivity comparable to those of free KTZ. A dual-target mechanism is suggested to account for the antiparasitic properties of these complexes.

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Fig. 1
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Abbreviations

acac:

Acetylacetonate

bipy:

2,2′-Bipyridine

CTZ:

Clotrimazole

DMSO:

Dimethyl sulfoxide

en:

Ethylenediamine

KTZ:

Ketoconazole

LD50 :

Median lethal dose

SBI:

Sterol biosynthesis inhibitor

THF:

Tetrahydrofuran

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Acknowledgments

We thank the staff of the Cell Culture and High Throughput Screening (HTS, #20) Core Facility of the University of Texas at El Paso for services and facilities provided; this core facility is supported by NIMHD grant G12MD007592. We thank the BBRC for a small grant (NIMHD/G12MD007592) and the University of Texas URI for a grant (to R.A.M.). M.A.V. was supported by NIH-RISE (2R25GM069621-10). We also thank the NIH for support through grant 5SC1GM089558 (to R.A.S.-D.) and the National Science Foundation (CHE-0619638) for the acquisition of an X-ray diffractometer for Columbia University.

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Authors and Affiliations

  1. Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA

    Eva Iniguez, Miguel A. Vasquez, Joanna Olivas & Rosa A. Maldonado

  2. Chemistry Department, Brooklyn College and The Graduate Center, The City University of New York, 2900 Bedford Avenue, Brooklyn, NY, 11210, USA

    Antonio Sánchez & Roberto A. Sánchez-Delgado

  3. Chemistry Department, New York City College of Technology, The City University of New York, Brooklyn, NY, 11210, USA

    Alberto Martínez

  4. Department of Chemistry, Columbia University, 3000 Broadway, New York, NY, 10027, USA

    Aaron Sattler

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  1. Eva Iniguez
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Correspondence to Roberto A. Sánchez-Delgado or Rosa A. Maldonado.

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Iniguez, E., Sánchez, A., Vasquez, M.A. et al. Metal–drug synergy: new ruthenium(II) complexes of ketoconazole are highly active against Leishmania major and Trypanosoma cruzi and nontoxic to human or murine normal cells. J Biol Inorg Chem 18, 779–790 (2013). https://doi.org/10.1007/s00775-013-1024-2

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