Isoniazid
[CAS# 54-85-3]

Identification

• Classification: API >> Synthetic anti-infective drugs >> Anti-tuberculosis leprosy
• Name: Isoniazid
• Synonyms: Isonicotinic acid hydrazide; INAH; Pyridine-4-carbohydrazide
• Molecular Formula: C₆H₇N₃O
• Molecular Weight: 137.14
• CAS Registry Number: 54-85-3
• EC Number: 200-214-6
• SMILES: C1=CN=CC=C1C(=O)NN

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*
• Melting point: 171 - 173 ºC (Expl.)
• Flash point: 190 ºC (Expl.)
• Solubility: DMSO 28.2 mg/mL, Water 28.2 mg/mL (Expl.)
• Index of refraction: 1.584 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315
• Precautionary Statements: P264-P270-P280-P301+P317-P302+P352-P321-P330-P332+P317-P362+P364-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Skin irritation	Skin Irrit.	2	H315
Reproductive toxicity	Repr.	1A	H360
Eye irritation	Eye Irrit.	2	H319
Specific target organ toxicity - single exposure	STOT SE	2	H371
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Specific target organ toxicity - single exposure	STOT SE	3	H335
Reproductive toxicity	Repr.	2	H361
Specific target organ toxicity - repeated exposure	STOT RE	2	H372
Germ cell mutagenicity	Muta.	2	H341
Acute toxicity	Acute Tox.	3	H301
Carcinogenicity	Carc.	2	H351

Discovory and Applicatios

Isoniazid is a synthetic antibacterial agent widely used as a first-line medication for the prevention and treatment of tuberculosis (TB). Chemically known as isonicotinic acid hydrazide, isoniazid has the molecular formula C₆H₇N₃O and consists of a hydrazide functional group attached to a pyridine ring. It was first synthesized in the early 20th century and introduced into clinical use in the 1950s, revolutionizing TB therapy due to its potent activity against Mycobacterium tuberculosis.

The discovery of isoniazid followed efforts to identify effective antimycobacterial compounds. Early studies revealed that isoniazid exhibited strong bactericidal activity against actively replicating tubercle bacilli by interfering with cell wall synthesis. It remains one of the cornerstone drugs in combination therapy regimens for tuberculosis, used alongside rifampicin, pyrazinamide, and ethambutol.

Isoniazid’s mechanism of action involves inhibition of the synthesis of mycolic acids, essential long-chain fatty acids forming a critical component of the mycobacterial cell wall. The drug is a prodrug activated by the bacterial enzyme catalase-peroxidase (encoded by the katG gene), which converts isoniazid into reactive species that target enzymes involved in mycolic acid biosynthesis, such as InhA. This selective toxicity underlies its effectiveness in killing Mycobacterium tuberculosis without significantly affecting human cells.

Clinically, isoniazid is administered orally and is well absorbed from the gastrointestinal tract. It distributes widely in body tissues and fluids, including cerebrospinal fluid, which is important for treating tuberculous meningitis. The drug undergoes hepatic metabolism primarily by acetylation, a process subject to genetic variability among individuals, resulting in “slow” and “fast” acetylator phenotypes that influence plasma levels and risk of side effects.

Adverse effects of isoniazid include hepatotoxicity, peripheral neuropathy, and hypersensitivity reactions. Hepatic injury is dose-dependent and more common in patients with preexisting liver disease or alcohol use. Peripheral neuropathy results from interference with vitamin B6 (pyridoxine) metabolism and is preventable with vitamin B6 supplementation during therapy. Regular monitoring of liver function tests is recommended during prolonged treatment.

Resistance to isoniazid arises primarily through mutations in the katG gene or alterations in the target enzyme InhA, which reduce activation or binding of the drug. The emergence of isoniazid-resistant Mycobacterium tuberculosis strains has necessitated the use of combination therapies and the development of new antitubercular drugs.

Analytically, isoniazid can be detected and quantified in pharmaceutical formulations and biological samples using techniques such as high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), and ultraviolet-visible (UV-Vis) spectroscopy. These methods support quality control, pharmacokinetic studies, and therapeutic drug monitoring.

In summary, isoniazid is a key antitubercular agent that acts by inhibiting mycolic acid synthesis after activation by bacterial enzymes. Its discovery and clinical use have been pivotal in the management of tuberculosis. Despite potential side effects and emerging resistance, isoniazid remains an essential component of TB treatment regimens worldwide.

References

1979. A study of intracellular iron metabolism using pyridoxal isonicotinoyl hydrazone and other synthetic chelating agents. Biochimica et Biophysica Acta (BBA) - General Subjects, 585(2).
DOI: 10.1016/0304-4165(79)90100-4

1979. On the Mechanism of the Antimycobacterial Activity of Isoniazid + Prothionamide + Dapsone (Isoprodian®). Chemotherapy, 25(5).
DOI: 10.1159/000237849

1979. Evaluation of various isoniazid slow releasing matrix preparations for intermittent chemotherapy of tuberculosis. Research communications in chemical pathology and pharmacology, 24(2).
URL: https://pubmed.ncbi.nlm.nih.gov/461989