Back to Search
Start Over
Molecular mechanism for the activation of the anti-tuberculosis drug isoniazid by Mn(III): First detection and unequivocal identification of the critical N-centered isoniazidyl radical and its exact location
- Source :
- Free Radical Biology and Medicine. 143:232-239
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Isoniazid (INH), the most-widely used anti-tuberculosis drug, has been shown to be activated by Mn(III) to produce the reactive carbon-centered isonicotinic acyl radical, which was considered to be responsible for its anti-tuberculosis activity. However, it is still not clear whether the previously-proposed N-centered isoniazidyl radical intermediate can be initially produced or not; and if so, what is its exact location on the hydrazine group, distal- or proximal-nitrogen? Through complementary applications of ESR spin-trapping and HPLC/MS methods, here we show that the characteristic and transient N-centered isoniazidyl radical intermediate can be detected and identified from INH activation uniquely by Mn(III)Acetate not by Mn(III) pyrophosphate. The exact location of the radical was found to be at the distal-nitrogen of the hydrazine group by 15N-isotope-labeling techniques via using 15N-labeled INH. Diisonicotinyl hydrazine was identified as a new reaction product from INH/Mn(III). Analogous results were observed with other hydrazides. This study represents the first detection and unequivocal identification of the initial N-centered isoniazidyl radical and its exact location. These findings should provide a new perspective on the molecular mechanism of INH activation, which may have broad biomedical and toxicological significance for future research for more efficient hydrazide anti-tuberculosis drugs.
- Subjects :
- 0301 basic medicine
Drug
Free Radicals
Stereochemistry
media_common.quotation_subject
Antitubercular Agents
Hydrazide
Biochemistry
Pyrophosphate
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Anti tuberculosis
Physiology (medical)
Isoniazid
medicine
Exact location
Hydrazine (antidepressant)
media_common
Manganese
Electron Spin Resonance Spectroscopy
030104 developmental biology
chemistry
Molecular mechanism
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 08915849
- Volume :
- 143
- Database :
- OpenAIRE
- Journal :
- Free Radical Biology and Medicine
- Accession number :
- edsair.doi.dedup.....d821e12bb76189868ec773ebcc1b3634