New Ruthenium Complexes of Ketoconazole are Active against Leishmania major and Trypanosoma cruzi and Non-toxic to Human and Murine Normal Cells
Six new complexes ruthenium-ketoconazole (Ru-KTZ) complexes have been synthesized and characterized, including two coordination complexes [RuCl2(DMSO)3(KTZ)] (1) and [RuCl2(bipy)(DMSO)(KTZ)] (2), and four organometallic compounds [RuII(6-p-cymene)Cl2(KTZ)] (3), [RuII(6-p-cymene)(en)(KTZ)][BF4]2 (4), [RuII(6-p-cymene)(bipy)(KTZ)][BF4]2 (5), and [RuII(6-p-cymene)(acac)(KTZ)][BF4] (6). The crystal structure of (3) is reported. The in vitro activity of the new compounds against promastigotes and amastigotes of L. major and epimastigotes of T. cruzi was evaluated in comparison with uncomplexed ketoconazole and with control Ru complexes of similar structures but not containing ketoconazole. The cytotoxicity of the new metal complexes toward human fibroblasts and osteoblasts, as well as murine macrophages was also assessed. Complexation of KTZ to RuII in compounds 3-5 results in a marked enhancement of the activity and of the selectivity toward epimastigotes and intracellular amastigotes of L. major. Complexes 3-5 also showed an enhancement of the activity of KTZ against T. cruzi. The new compounds represent good leads for further studies toward new treatments for leishmaniasis and Chagas’ disease.