In Vitro and In Vivo Trypanocidal Effects of the Cyclopalladated Compound 7a, a Drug Candidate for Treatment of Chagas' Disease

Abstract

Chagas' disease, a neglected tropical infection, affects about 18 million people, and 100 million are at risk. The only drug available, benznidazole, is effective in the acute form and in the early chronic form, but its efficacy and tolerance are inversely related to the age of the patients. Side effects are frequent in elderly patients. The search for new drugs is thus warranted. In the present study we evaluated the in vitro and in vivo effect of a cyclopalladated compound (7a) against Trypanosoma cruzi, the agent of Chagas' disease. The 7a compound inhibits trypomastigote cell invasion, decreases intracellular amastigote proliferation, and is very effective as a trypanocidal drug in vivo, even at very low dosages. It was 340-fold more cytotoxic to parasites than to mammalian cells and was more effective than benznidazole in all in vitro and in vivo experiments. The 7a cyclopalladate complex exerts an apoptosis-like death in T. cruzi trypomastigote forms and causes mitochondrion disruption seen by electron microscopy.

Antiprotozoal Activity of the Cyclopalladated Complexes AgainstLeishmania amazonensisandTrypanosoma cruzi

“…Some authors 24 observed that cyclopalladated complex against T. cruzi reduced the parasitemia and mortality in vivo with very low and nontoxic doses, as well as inhibited amastigote intracellular proliferation, similar to observed for us in vitro in T. cruzi and L. amazonensis intracellular amastigote.…”

“…For palladium compounds, it was recently verified that a cyclopalladated complex showed a high selectivity index with trypanocidal activity in the treatment of Chagas disease. 24 Literature has reported a cyclopalladated compound with leishmanicidal activity 25 against L. amazonensis promastigote and amastigote forms; and the activity of some palladium(II) cyclometalated complexes 26 against T. cruzi and Leishmania, which indicate on preliminary data that the compounds inhibited the growth of intracellular amastigote forms.…”

Identification of a New Amide-Containing Thiazole as a Drug Candidate for Treatment of Chagas' Disease

“…Mammals can be infected by contaminated feces and urine of the insect vector with Trypanosoma cruzi, transfusion with infected blood, birth canal transmission, or oral transmission by contaminated food (2). Although excellent chemotherapeutic approaches have been described (3)(4)(5), nevertheless the pharmacology used to control this parasitic infection remains unsatisfactory. The current specific treatments are based on old and quite nonspecific drugs, benznidazole (Bnz; Radanil; Roche) and nifurtimox (Nfx; Bayer).…”

Cyclopalladated Compound 7a Induces Apoptosis- and Autophagy-Like Mechanisms in Paracoccidioides and Is a Candidate for Paracoccidioidomycosis Treatment

“…More importantly, the compound was not toxic to animals when 100 l of a 150-g/ml solution was administered for 5 sequential days (data not shown). Cyclopalladated 7a was effective in the treatment of murine melanoma (12) and human melanoma, colon, breast, and uterine cervix cancers; glioblastoma (13); leukemia (14); and Chagas disease (15). In tumor cells, cyclopalladated 7a causes anoikis and apoptosis by dissipating the mitochondrial membrane potential, thus activating effector caspases, causing chromatin condensation and DNA degradation (13,14).…”

“…In tumor cells, cyclopalladated 7a causes anoikis and apoptosis by dissipating the mitochondrial membrane potential, thus activating effector caspases, causing chromatin condensation and DNA degradation (13,14). In Trypanosoma cruzi, which causes Chagas disease, cyclopalladated 7a evokes an apoptosis-like cell death through mitochondrial disruption (15).…”