Details

Autor(en) / Beteiligte

• Laborde, Julie
• Deraeve, Céline
• de Mesquita Vieira, Francisca Gilmara
• Sournia-Saquet, Alix
• Rechignat, Lionel
• Villela, Anne Drumond
• Abbadi, Bruno Lopes
• Macchi, Fernanda Souza
• Pissinate, Kenia
• Bizarro, Cristiano V.
• Machado, Pablo
• Basso, Luiz Augusto
• Pratviel, Geneviève
• de França Lopes, Luiz Gonzaga
• Sousa, Eduardo Henrique Silva
• Bernardes-Génisson, Vania

Titel

Synthesis and mechanistic investigation of iron(II) complexes of isoniazid and derivatives as a redox-mediated activation strategy for anti-tuberculosis therapy

Ist Teil von

• Journal of inorganic biochemistry, 2018-02, Vol.179, p.71-81

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (MTB) represents a major threat to global health. Isoniazid (INH) is a prodrug used in the first-line treatment of tuberculosis. It undergoes oxidation by a catalase-peroxidase KatG, leading to generation of an isonicotinoyl radical that reacts with NAD(H) forming the INH-NADH adduct as the active metabolite. A redox-mediated activation of isoniazid using an iron metal complex was previously proposed as a strategy to overcome isoniazid resistance due to KatG mutations. Here, we have prepared a series of iron metal complexes with isoniazid and analogues, containing alkyl substituents at the hydrazide moiety, and also with pyrazinamide derivatives. These complexes were activated by H2O2 and studied by ESR and LC-MS. For the first time, the formation of the oxidized INH-NAD adduct from the pentacyano(isoniazid)ferrate(II) complex was detected by LC-MS, supporting a redox-mediated activation, for which a mechanistic proposition is reported. ESR data showed all alkylated hydrazides, in contrast to non-substituted hydrazides, only generated alkyl-based radicals. The structural modifications did not improve minimal inhibitory concentration (MIC) against MTB in comparison to isoniazid iron complex, providing support to isonicotinoyl radical formation as a requirement for activity. Nonetheless, the pyrazinoic acid hydrazide iron complex showed redox-mediated activation using H2O2 with generation of a pyrazinoyl radical intermediate and production of pyrazinoic acid, which is in fact the active metabolite of pyrazinamide prodrug. Thereby, this strategy can also unveil new opportunities for activation of this type of drug. Complexation of the antitubercular prodrugs isoniazid and pyrazinamide with [FeII(CN)5]3- as a strategy to generate, through H2O2 activation, the corresponding active metabolites and overcome Mycobacterium tuberculosis resistance. [Display omitted] •Synthesis of isoniazid-FeII(CN)5 complex and analogues•Evidences for radical formation from hydrazide-based iron(II) compounds using H2O2•The isoniazid-FeII(CN)5 complex can be converted into the active metabolite of isoniazid.•Pyrazinehydrazide-FeII(CN)5 complex is able to generate pyrazinoic acid metabolite.