Isoniazid: Radical-induced oxidation and reduction chemistry

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Antimicrobial Research

Background:

• Isoniazid is a key drug against Mycobacterium tuberculosis, but its precise mechanism remains under investigation.
• Activation by catalase-peroxidase KatG is crucial for isoniazid's therapeutic effect.
• Previous studies suggested nitric oxide production, which requires further clarification.

Purpose of the Study:

• To elucidate the initial reaction pathways of isoniazid activation.
• To investigate the role of hydroxyl radical oxidation and solvated electron reduction in isoniazid's mechanism.
• To determine the formation of radical intermediates and assess nitric oxide production.

Main Methods:

• Temperature-dependent rate constant measurements for hydroxyl radical oxidation and solvated electron reduction.
• Electron paramagnetic resonance (EPR) spin-trap measurements.
• Transient absorption spectroscopy.

Main Results:

• Hydroxyl radical oxidation of isoniazid primarily occurs at the hydrazyl nitrogen, supporting isonicotinyl radical formation.
• Solvated electron reduction predominantly targets the pyridine ring.
• EPR studies found no evidence of nitric oxide production.
• Transient absorption spectra confirmed the initial formation of the isonicotinyl acyl radical.

Conclusions:

• The study clarifies isoniazid's radical intermediate formation during activation.
• It provides evidence against nitric oxide being a product of isoniazid-KatG interaction.
• The findings support the established mechanism involving the isonicotinyl acyl radical in isoniazid's antimycobacterial action.