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-[Ru(II)Cl2(
DMSO)3(KTZ)] (1) and cis-[Ru(II)Cl2(bipy)(
DMSO)(KTZ)] (2) (where
DMSO is
dimethyl sulfoxide and bipy is
2,2'-bipyridine)-and four
organometallic compounds-[Ru(II)(η(6)-
p-cymene)Cl2(KTZ)] (3), [Ru(II)(η(6)-
p-cymene)(en)(KTZ)][BF4]2 (4), [Ru(II)(η(6)-
p-cymene)(bipy)(KTZ)][BF4]2 (5), and [Ru(II)(η(6)-
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 Ru(II) 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.