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

Abstract

In our ongoing search for new metal-based chemotherapeutic agents against leishmaniasis and Chagas disease, six new ruthenium-ketoconazole (Ru-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), 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); the crystal structure of (3) is described. The central hypothesis of our work is that combining a bioactive compound like 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 to 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 Ru 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 those of the individual constituents of the drug. When tested against Trypanosoma cruzi epimastigotes, some of the organometallic complexes displayed an activity and selectivity comparable to that of free KTZ. A dual-target mechanism is suggested to account for the antiparasitic properties of these complexes.

Nitro/Nitrosyl-Ruthenium Complexes Are Potent and Selective Anti-Trypanosoma cruzi Agents Causing Autophagy and Necrotic Parasite Death

“…This enhanced activity can be explained by the gain in lipophilicity. This strategy has been performed to enhance the potency of ketoconazole, clotrimazole, benznidazole, risedronate, and quinolones (34)(35)(36)(37)(38)(39). Alternatively, metal complexes which are composed of ligands with unique chemical properties (redox and electrochemical behavior based on ligand reductions) exhibit anti-T. cruzi properties, possibly due to parasite membrane accumulation, in addition to effects on DNA and enzymes (40)(41)(42)(43).…”

Photoinduced Interactions of Supramolecular Ruthenium(II) Complexes with Plasmid DNA: Synthesis and Spectroscopic, Electrochemical, and DNA Photocleavage Studies

“…3-Methoxy-4-(hydroxyphenyl)diphenanthropyrromethane [(php) 2 Van]. In approximately 8 mL of acetic acid was dissolved 0.300 g (1.37 mmol) of php and 0.417 g (2.74 mmol) of 3-methoxy-4-hydroxybenzaldehyde (vanillin, van).…”

Importance of metal complexes for development of potential leishmanicidal agents

“…In the next work of the same group, binding KTZ to Ru II in single molecules were reported and resulted in desired metaledrug synergy that produced a marked enhancement of the activity towards promastigotes and intracellular amastigotes of L. major in vitro assay, when compared with KTZ, or with similar ruthenium compounds not containing KTZ, together with a low toxicity toward mammalian cells (human fibroblasts and osteoblasts or murine macrophages) [48]. [Ru II (h 6 -p-cymene 5 )Cl 2 (KTZ)], 27 was the most active complex against L. major promastigotes with LD 50 , Relative Activity (LD 50 and >150, respectively.…”