Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10574926 | Journal of Inorganic Biochemistry | 2005 | 8 Pages |
Abstract
The mechanism of activation thioamide-pyridine anti-tuberculosis prodrugs is poorly described in the literature. It has recently been shown that ethionamide, an important component of second-line therapy for the treatment of multi-drug-resistant tuberculosis, is activated through an enzymatic electron transfer (ET) reaction. In an attempt to shed light on the activation of thioamide drugs, we have mimicked a redox process involving the thionicotinamide (thio) ligand, investigating its reactivity through coordination to the redox reversible [FeIII/II(CN)5(H2O)]2â/3â metal center. The reaction of the FeIII complex with thionicotinamide leads to the ligand conversion to the 3-cyanopyridine species coordinated to a FeII metal center. The rate constant, ket = 10 sâ1, was determined for this intra-molecular ET reaction. A kinetic study for the cross-reaction of thionicotinamide and [Fe(CN)6]3â was also carried out. The oxidation of thionicotinamide by [Fe(CN)6]3â leads to formation of mainly 3-cyanopyridine and [Fe(CN)6]4â with a ket = (5.38 ± 0.03) Mâ1 sâ1 at 25 °C, pH 12.0. The rate of this reaction is strongly dependent on pH due to an acid-base equilibrium related to the deprotonation of the R-SH functional group of the imidothiol form of thionicotinamide. The kinetic results reinforced the assignment of an intra-molecular mechanism for the ET reaction of [FeIII(CN)5(H2O)]2â and the thioamide ligand. These results can be valuable for the design of new thiocarbonyl-containing drugs against resistant strains of Mycobacterium tuberculosis by a self-activating mechanism.
Related Topics
Physical Sciences and Engineering
Chemistry
Inorganic Chemistry
Authors
Eduardo H.S. Sousa, Daniel L. Pontes, Izaura C.N. Diógenes, Luiz G.F. Lopes, Jaim S. Oliveira, Luiz A. Basso, Diógenes S. Santos, Ícaro S. Moreira,