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(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.

• 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, Icaro S Moreira
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 99 Issue 2 Pg. 368-75 (Feb 2005) ISSN: 0162-0134 [Print] United States
• PMID: 15621268 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antitubercular Agents
• Ferric Compounds
• Ferrous Compounds
• Prodrugs
• pentacyanoferrate (III)
• pentacyanoferrate (II)
• Niacinamide
• thionicotinamide

Topics

• Antitubercular Agents (chemistry, metabolism)
• Biotransformation
• Drug Resistance, Multiple, Bacterial
• Electron Transport
• Ferric Compounds (chemistry, metabolism)
• Ferrous Compounds (chemistry, metabolism)
• Humans
• In Vitro Techniques
• Kinetics
• Magnetic Resonance Spectroscopy
• Molecular Structure
• Mycobacterium tuberculosis (drug effects, metabolism)
• Niacinamide (analogs & derivatives, chemistry, metabolism)
• Oxidation-Reduction
• Prodrugs (chemistry, metabolism)
• Spectroscopy, Fourier Transform Infrared
• Tuberculosis, Multidrug-Resistant (drug therapy, microbiology)