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(2)O)](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 degrees 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(2)O)](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.