Abstract
In previous studies we reported a novel series of organometallic compounds, Ru(II) complexed with clotrimazole, displaying potent trypanosomatid activity with unnoticeable toxicity toward normal mammalian cells. In view of the promising activity of Ru-clotrimazole complexes against Leishmania major (L. major), the present work sought to investigate the anti-leishmanial activity of the AM162 complex in the murine model of cutaneous leishmaniasis. In addition, to facilitate the design of new therapeutic strategies against this disease, we investigated the mode of action of two Ru-clotrimazole complexes in L. major promastigotes. Overall, we demonstrate that AM162 significantly reduced the lesion size in mice exposed to L. major infection. In addition, Ru-clotrimazole compounds are able to induce a mitochondrial dependent apoptotic-like death in the extracellular form of the parasite based on labeling of DNA fragments, mitochondrial depolarization, cell cycle alteration profile and plasma membrane phospholipid externalization. Our findings reveal a promising efficacy of the Ru-clotrimazole AM162 complex for the treatment of cutaneous leishmaniasis, as well as pro-apoptotic activity and thus guarantees further evaluation in pre-clinical studies.