Novel Antitrypanosomal Agents Based on Palladium Nitrofurylthiosemicarbazone Complexes:  DNA and Redox Metabolism as Potential Therapeutic Targets

Abstract

In the search for new therapeutic tools against American Trypanosomiasis palladium complexes with bioactive nitrofuran-containing thiosemicarbazones as ligands were obtained. Sixteen novel palladium (II) complexes with the formulas [PdCl2(HL)] and [Pd(L)2] were synthesized, and the crystal structure of [Pd(5-nitrofuryl-3-acroleine thiosemicarbazone)2] x 3DMSO was solved by X-ray diffraction methods. Most complexes showed higher in vitro growth inhibition activity against Trypanosoma cruzi than the standard drug Nifurtimox. In most cases, the activity of the ligand was maintained or even increased as a result of palladium complexation. In addition, the complexes' mode of antitrypanosomal action was investigated. Although the complexes showed strong DNA binding, all data strongly suggest that the main trypanocidal mechanism of action is the production of oxidative stress as a result of their bioreduction and extensive redox cycling. Moreover, the complexes were found to be irreversible inhibitors of trypanothione reductase.

Ruthenium(II) phosphine/diimine/picolinate complexes: Inorganic compounds as agents against tuberculosis

“…Complexes were tested for their DNA interaction ability using native calf thymus DNA (CT DNA) (Type I) by a modification of a previously reported procedure [40,41]. CT DNA (50 mg) was dissolved in water (30 mL) (overnight).…”

High Throughput Screening against the Peroxidase Cascade of African Trypanosomes Identifies Antiparasitic Compounds That Inactivate Tryparedoxin

“…The dithiol is kept reduced by NADPH and the flavoenzyme trypanothione reductase (TR), the system replacing the glutathione/glutathione reductase couple of the mammalian host (4). TR is the most thoroughly studied enzyme of the trypanothione metabolism, and a large number of inhibitors has been identified (5)(6)(7)(8)(9). Tpx is a distant member of the thioredoxin (Trx) protein family.…”

Antiprotozoal Activity of the Cyclopalladated Complexes AgainstLeishmania amazonensisandTrypanosoma cruzi

“…Other mechanism of action by palladium complexes 58 described that "the production of oxidative stress as a result of their bioreduction and extensive redox cycling", as well as the interaction with DNA. 21,56 Studies on the mechanism of action of cyclopalladated complexes 1-4 against both L. amazonensis and T. cruzi are underway, and so are the tests with other T. cruzi strains, due to genetic variability, to determine if our compounds may be following the similar mechanisms of action reported in the literature.…”