Electron transfer kinetics and mechanistic study of the thionicotinamide coordinated to the pentacyanoferrate(III)/(II) complexes: a model system for the in vitro activation of thioamides anti-tuberculosis drugs

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 [Fe III/II(CN) 5(H 2O)] 2−/3− metal center. The reaction of the Fe III complex with thionicotinamide leads to the ligand conversion to the 3-cyanopyridine species coordinated to a Fe II metal center. The rate constant, k et = 10 s −1, was determined for this intra-molecular ET reaction. A kinetic study for the cross-reaction of thionicotinamide and [Fe(CN) 6] 3− was also carried out. The oxidation of thionicotinamide by [Fe(CN) 6] 3− leads to formation of mainly 3-cyanopyridine and [Fe(CN) 6] 4− with a k et = (5.38 ± 0.03) M −1 s −1 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 [Fe III(CN) 5(H 2O)] 2− 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.