Introduction, Synthesis and SAR of Anti-Tubercular Drugs

1. ANTI-TUBERCULAR
DRUGS
(Intro, synthesis, sar…)
DEPARTMENT OF PHARMACY
UNIVERSITY OF PESHAWAR

2. TUBERCULOSIS
 An infectious disease caused by the bacterium Mycobacterium tuberculosis.
 Commonly affect the lungs but can also affect other parts of the body.
 Symptoms include:
Chronic cough
Hemoptysis
Fever
Night sweats
Weight loss
 It is spread through air via cough, sneeze, speak or spit.

3. DRUGS
 1st line:
Isoniazid
Rifampicin
Ethambutol
Pyrazinamide
Streptomycin
 2nd line:
Para amino salicylic acid
Capreomycin
Ciprofloxacin
Cycloserine
Ethionamide
Amikacin
Rifabutin

4. TUBERCULOSIS
Recommended treatment of pulmonary T.B is 6 months of combination of drugs.
 Intensive phase (2 months):
Rifampicin
Isoniazid
Pyrazinamide
Ethambutol
 Continuation phase (4 months):
Isoniazid
Rifampin
Ethambutol (Optional)

5. ISONIAZID
 Also known as isonicotinylhydrazide, 4-
Pyridinecarboxylic acid hydrazide.
 Isoniazid was first made in the early
20th century but its activity against
tuberculosis was first reported in the
early 1950s and was marketed in 1952.
 It is on the World Health Organization's
List of Essential Medicines, a list of
medicines that constitute the bare
minimum for a basic health system.

6. BRANDS
 NYDRAZIDE (Wilshire)
 ISONIAZID (Unexo)
 FAIRZIDE (Ferro)

7. MECHANISM OF ACTION
 Inhibits synthesis of mycolic acid which
is an essential components of
mycobacterial cell wall
 Isoniazid is a prodrug that is activated
by KatG, the mycobacterial catalase-
peroxidase.
 The enzyme inhA, is an NADH-
dependent, enoyl (acyl carrier protein)
reductase protein thought to be involved
in double-bond reduction during fatty
acid elongation.
 Isoniazid has bactericidal effect.

8. SYNTHESIS
 Step 1:
 4-methyl pyridine is oxidized to obtain Iso-nicotinic acid.

9. SYNTHESIS
 Step 2:
 Iso-nicotinic acid upon heating with anhydrous hydrazine form Isoniazid

10. S.A.R
 Pyridine ring is essential for activity.
 Substitution of R-1, R-2 at N-2 leads to
variable activity.
 Addition of isopropyl group at position
R-2 results in loss of anti-tubercular
activity but exhibit psychomotor
stimulant activity, while acetyl isoniazid
is inactive.
 Any substitution (Alkyl) at R-3 results in
loss of activity
 INH is most active derivative.

11. SIDE EFFECT
The most frequent reactions are those affecting the nervous system and the liver.
 Peripheral neuropathy (Dose related)
Prophylaxis Pyridoxine:
Adult: 100-200mg/day orally for 3 weeks or 25 to 100 mg/day for prophylaxis.
 Elevated LFT’s
 Fatal hepatitis
 Aplastic anemia.
 Hypersensitivity reaction
 Dark urine

12. DOSING
 Active tuberculosis:
Oral
Adult: 5 mg/kg/day in combination with other drugs.
Children: 10-30mg/kg/day in 2 divided doses
 Prophylaxis:
Oral
Adult: 300mg once daily
Children: 10mg/kg/day
 SIDE EFFECT:
Peripheral neuritis (Pyridoxine):
Adult: 100-200mg/day orally for 3 weeks or 25 to 100 mg/day for prophylaxis.

13. RIFAMPICIN
 Also known as Rifampin.
 Rifampicin was discovered in 1957 and
first sold as a medication in 1971.
 It’s a semi-synthetic derivative of
Rifamycin B, a macrocyclic antibiotic
produced by Streptomyces mediteranei.
 It is on the World Health
Organization's List of Essential
Medicines.

14. BRANDS
 LEDERRIF (Pfizer)
 UNERIF (Unexo)
 RIFACIN (Pharmawise)

15. MECHANISM OF ACTION
 Rifampin has bactericidal effect.
 Rifampin binds to bacterial DNA-dependent RNA polymerase and thereby inhibits
initiation of RNA chain, hence protein synthesis.

16. SYNTHESIS
 Rifamycin B is obtained from the fermentation liquid of Streptomyces
mediterranei (Amycolatopsis rifamycinica).
 Rifampicin is then obtained by synthetically modifying Rifamycin B.

17. S.A.R
 Intact macro cyclic molecule is essential
for activity.
 Saturation of double bonds in macro
cyclic ring leads to slightly decreased
activity.
 Free hydroxyl (-OH) group present at C-
1, C-8, C-21, C-23 are essential for
activity.
 Substitution of hydroxyl group at C-8,
C-21, C-23 leads to loss of activity;
except C-1 from hydroxyl to carbonyl.

18. SAR
 Modification at the C-3, C-4 often yield
compounds with improved
physicochemical and P.K properties.

19. SIDE EFFECTS
 Hepatotoxicity
 Flu like symptoms
 Red and orange colored urine, saliva etc.
 Rash

20. DOSING
 Active Tuberculosis:
Oral or I/V:
10mg/kg OD (Max 600mg/day) for 6 months in combination with other drugs.
 Latent Tuberculosis:
Oral or I/V:
10mg/kg OD (Max 600mg/day) for 4 months.

21. PYRAZINAMIDE
 It is a close analog of isoniazid
 It is a pro-drug (Pyrazinoic acid).
 The drug is largely bacteriostatic, but
can be bactericidal on actively
replicating tuberculosis bacteria.
 It is on the World Health Organization's
List of Essential Medicines.

22. BRANDS
 PYRAZINAMIDE (Pfizer)
 PZA CIBA 500 (Novartis)
 PYRAZID (Schazoo zaka)

23. MECHANISM OF ACTION
 Susceptible organisms produce pyrazinamidase, which is responsible for conversion
of pyrazinamide (Prodrug) to Pyrazinoic acid (Active) intracellularly.
 The protonated Pyrazinoic acid can permeate the mycobacterial membrane to lower
the pH of the cytoplasm, hence disrupting basic chemical processes especially energy
production.

24. SYNTHESIS
 Step 1:
o-phenylenediamine when reacted with glyoxal; quinoxaline is formed.

25. SYNTHESIS
 Step 2:
Quinoxaline is then oxidized with potassium permanganate to form pyrazin-2,3-
dicarboxylic acid.

26. SYNTHESIS
 Step 3:
pyrazin-2,3-dicarboxylic acid is then decarboxylated by heating to get pyrazin-2-
carboxylic acid.

27. SYNTHESIS
 Step 4:
pyrazin-2-carboxylic acid is then esterified in presence of methanol and
hydrochloric acid to get acetyl ester of pyrazin-2-carboxylic acid.

28. SYNTHESIS
 Step 5:
acetyl ester of pyrazin-2-carboxylic acid is then treated with ammonia to get
pyrazinamide.

29. S.A.R
 The best side chain is amide.
 Another potential side chain is ester
which is activated by bacterial esterase.
 Nitrogen (Pyrazinoyl) at P-2 is essential
for maximum activity.
 Substitution of “N” with “C”
(Nicotinoyl) leads to decreased activity.
 Any other substitution in the ring will
lead to loss of activity.

30. SIDE EFFECTS
 Arthralgia, Myalgia
 Gout
 Hepatotoxicity (Dose related)
 Rash

31. DOSING
 Active Tuberculosis:
Oral:
15 to 30 mg/kg (Max 2g/day) OD in combination with other drugs.
 Latent Tuberculosis:
Oral:
15 to 20 mg/kg (Max 2g/day) OD for 2 months

32. ETHAMBUTOL
 Ethambutol was discovered in 1961.
 It possesses bacteriostatic action against
Mycobacterium tuberculosis.
 Its (+) enantiomer is used as it is more
effective.
 It is on the World Health Organization's
List of Essential Medicines.

33. BRANDS
 MYAMBUTOL (Pfizer)
 TUBERCURE (Lowitt)
 ABBUTOL (Abbott)

34. MECHANISM OF ACTION
 Ethambutol is bacteriostatic against actively growing TB bacilli.
 It disrupts arabinogalactan (Polymer) synthesis by inhibiting the enzyme arabinosyl
transferase leads to increased permeability of the cell wall.

35. SYNTHESIS
 Step 1:
Nitropropane undergoes hydroxymethylation when treated with Formaldehyde to
form 2-nitrobutanol.

36. SYNTHESIS
 Step 2:
2-nitrobutanol is then reduced in presence of Raney’s nickel and hydrogen to form
2-aminobutanol.

37. SYNTHESIS
 Step 3:
(+) 2-aminobutanol is then treated with 2-dichloroethane in presence of sodium
hydroxide gives Ethambutol

38. S.A.R
 Increase in ethylene diamine chain
length leads to loss of activity.
 Replacement of either of the amino
group leads to loss of activity.
 Removal of alcohol groups leads to loss
of activity.
 Substitution of hydroxyl groups with
methoxy, ethoxy retains activity but with
aromatic group (Phenyl, Pyridine) leads
to loss of activity.
 Increasing the size of N-substituent lead
to loss of activity.

39. SIDE EFFECTS
 Optic neuritis (C.I in children below 6 years)
 Red-green color blindness
 Peripheral neuropathy
 Hyperuricemia

40. DOSING
 Active Tuberculosis:
Oral:
15 mg/kg OD for 2 months in combination with other drugs.

41. BRANDS (Multi ingredient)
 MYRIN (Pfizer):
 Isoniazid, Rifampicin, Ethambutol
 MYRIN-P (Pfizer):
 Isoniazid, Rifampicin, Ethambutol, Pyrazinamide
 RIMACTAL-INH (Novartis):
 Isoniazid, Rifampicin
 RIFAPIN-H (Schazoo zaka):
 Isoniazid, Rifampicin

42. THANK YOU!