Medicinal chemistry and Pharmacology

1. ISONIAZID
Waqas Ahmad
(waqasgulshan8@gmail.com)
Faculty of Pharmacy Gomal University
D.I.Khan Pakistan

2. CONTENTS
6
SIDE
EFFECTS
5
INDICATIONS
4
MECHANISM OF
ACTION
3
STRUCTURE
ACTIVITY
RELATIONSHIP
2
CHEMICAL
STRUCTURE
1
DESCRIPTION
AND
HISTORY
ISONIAZID

3. ISONIAZID
DESCRIPTION:
 It is synthetic anti- TB drug introduced in 1950
Chemically, it is isonicotinic acid derivative – combination
of isonicotinic acid and hydrazine (Hydrazide)
 Chemical formula: C6H7N3O
 It is a prodrug; in body in converted into electrophilic
species which inhibit the synthesis of mycolic acid
 It is effective against rapidly dividing MTB but less
effective against dormant and semi dormant MTB.
 Pregnancy category “C”

4. PHARMACOKINETICS:
 Absorption: orally 90 to 95 %
 Protein binding: 0 to 10 %
 Metabolism: Liver; CYP450: 2C19, 3A4 inhibitor
 Elimination half-life: 0.5–1.6h (fast acetylators), 2-5h (slow
acetylators)
 Excretion:urine (primarily), feces

5. CHEMISTRY:
 Isoniazid is a chemical synthetic molecule.
 It s pyridine derivative of nicotinamide OR it is a hydrazide of
nicotinic acid.
 CHEMICAL NAME:
 1. 4-pyridinecarboxyhydrazide 2. Isonicotinohydrazide
3. Isonicotinic acid hydrazide
 MOLECULAR FORMULA: C6H7N3O
 MELTING POINT: 170 – 173
 SOLUBILITY:
Soluble in water, alcohol
Slightly soluble in chloroform and ether.

6. SYNTHESIS OF ISONIAZID:
METHOD 1:
 Basic hydrolysis of 4-cyano pyridine converts cyano / nitrile
group to an amide- isonicotinamide.Which then reacts with
hydrazine to produce isoniazid.

7. SYNTHESIS
Method 2:
 Another method for the preparation of isoniazid is the
ammoxidation of the 4-methylpyridine.

8. SAR OF ISONIAZID:
 Pyridine ring, if replaced with piperidine then the biological
activity lost.
 Hydrazide linkage when converted into hydrazine derivatives, a
series of active compounds are produced.
 If hydrazide is shifted to position 2 or 3 instead of 4 then the
compound is less active.
 Carbonyl hydrazide at position no. 4 is essential for biological
activity.
 INH contains 2 nitrogen atoms, when alkyl group is introduced
then:
1. If N1= compound became inactive
2. If N2= active compounds but less than orignal

9.  Replacement of hydrazide group with another amide or ester
group results in loss of activity.
 Oxidation of pyridine nitrogen results in loss of activity.
 For anti-tubercular activity terminal nitrogen is must
 N2- alkyl derivative ( N2-isopropyl derivative) is essential for
anti- tubercular activity.
 Dialkyl derivative ( O=C-NH-NR2) show high activity.
 When isopropyl group is attached to terminal nitrogen, the
compound show similar activity as INH.

10. Mechanism of action:
 In small doses it is act as bacteriostatic and in large doses it is
bacteriocidal
 Mycolic acid is the essential component of mycobacterial cell
wall ,The drug (isoniazid) inhibit the synthesis of the Mycolic
acid and as a result the cell wall become thin and inhibit the
growth of bacteria.
 Mechanism :
 Isoniazid is a prodrug activated by mycobacterial catalase-
peroxidase (KatG)
 It targets the enzyme acyl carrier protein reductase (InhA) and
b-ketoacyl-ACP synthetase

11. •Under the influence of KatG gene, INH is
converted into;
1. Isonicotinic aldehyde
2. Isonicotinic acid
3. Isonicotinamide

12. • From these compounds, highly reactive
electrophile species such as isonicotinyl
radical and isonicotinyl peroxy radical are
formed

13.  These radical acylate NADPH dependent beta-ketoacyl carrier
protein reductase, involved in the elongation of mycolic acid. It
results in the inhibition of cell wall leading to cell death.
 This enzyme selectively acts on fatty acids( more than 26
carbon). Mycolic acid is a alpha branched fatty acids having
short arm of 20 – 24 and long arm of 26 – 50 carbon.

14. Therapeutic uses:
 It is the first line drug in the treatment of pulmonary tuberculosis.
 It is active against extracellular and intracellular organisms Used for
prophylaxis against TB in individuals who are at great risk as very
young or immunocompromised patients.
 Latent tuberculosis in patients with positive tubercullin test
 It is used in tuberculo meningitis
 It is also used in the treatment of acute leukemia.
Side effects:
 Peripheral neuritis, Optic neuritis,Allergic
reactions,Hepatotoxicity,Gastric upset,Haemolytic
anaemia,CNS toxicity,Thrombocytopenia,Agranulocytosis and
Fever.

15. Contraindications:
 Hepato compromised patients
 Peripheral neuropathy
 Severe ranal impairment
 Anaemia
 Hypersensitive patients
 DOSE OF INH: