Isoniazid (INH)*
- BP-S-6-Medicinal Chemistry III
- Mar 28
- 1 min read
Chemical Structure / Formula of Isoniazid
Formula: C6H7N3O
Structure: Pyridine ring with a hydrazide (-CONHNH₂) group.
Mechanism of Action
Prodrug that is activated by KatG enzyme (catalase-peroxidase) in Mycobacterium tuberculosis.
Once activated, it forms isonicotinoyl radical, which inhibits:
1. Enoyl-acyl carrier protein reductase (InhA) → prevents mycolic acid synthesis (essential for the mycobacterial cell wall).
2. Dihydrofolate reductase → interferes with nucleic acid synthesis.
Uses
First-line treatment for tuberculosis (TB).
Used alone for latent TB infection (LTBI).
Combined with rifampicin, ethambutol, and pyrazinamide for active TB.
Side Effects
Hepatotoxicity (elevated liver enzymes, hepatitis).
Peripheral neuropathy (due to pyridoxine deficiency – prevented by vitamin B6 supplementation).
Neurotoxicity (seizures, ataxia, dizziness).
Hemolysis in G6PD-deficient patients.
Drug-induced lupus (rare).
Structure-Activity Relationship (SAR) of Isoniazid
Structural Feature | SAR Insight |
Isonicotinic acid hydrazide core | Essential for activity. Modifications to the hydrazide group generally reduce or eliminate activity. |
Hydrazide (-CONHNH₂) group | Important for activation by the bacterial catalase-peroxidase enzyme (KatG). Oxidation is necessary for its prodrug activation. |
Free –NH₂ group | Critical for forming the isonicotinoyl radical that inhibits InhA (mycolic acid synthesis enzyme). |
Substitutions on pyridine ring | Generally, reduce antitubercular activity. |
Electron-donating groups | Usually decrease activity by altering binding or red |
Synthesis of Isoniazid
