title: 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.affiliation: Departamento de Química Orgânica e Inorgânica, Universidade Federal de Ceará, Cx. Postal 12200, Campus do Pici s/n, Fortaleza CE 60455-760, Brazil.
authors.forename: Eduardo H S
authors.initials: EH
authors.lastname: Sousa
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Pontes
authors.forename: Izaura C N
authors.initials: IC
authors.lastname: Diógenes
authors.forename: Luiz G F
authors.initials: LG
authors.lastname: Lopes
authors.forename: Jaim S
authors.initials: JS
authors.lastname: Oliveira
authors.forename: Luiz A
authors.initials: LA
authors.lastname: Basso
authors.forename: Diógenes S
authors.initials: DS
authors.lastname: Santos
authors.forename: Icaro S
authors.initials: IS
authors.lastname: Moreira
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000378:metabolism; D001711:Biotransformation; D024901:Drug Resistance, Multiple, Bacterial; D004579:Electron Transport; D005290:Ferric Compounds / Q000737:chemistry* / Q000378:metabolism; D005296:Ferrous Compounds / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D005290:Ferric Compounds; D005296:Ferrous Compounds; D011355:Prodrugs; C121008:pentacyanoferrate (III); C058614:pentacyanoferrate (II); D009536:Niacinamide; C070820:thionicotinamide