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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
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 electr...
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Published in: | Journal of inorganic biochemistry 2005-02, Vol.99 (2), p.368-375 |
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Main Authors: | , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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. |
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ISSN: | 0162-0134 1873-3344 |
DOI: | 10.1016/j.jinorgbio.2004.10.004 |