Medicinal chemistry of antitubercular agents

1. ANTI-TUBERCULAR
AGENTS

2. Tuberculosis
Tuberculosis (TB) is a chronic granulomatous disease and a major health problem especially in the
developing countries.
TB is a bacterial infection spread through inhaling tiny droplets from the coughs, sneezes or spits of an
infected person (lung infection).
It mainly affects lungs, but it can affect any part of the body, including abdomen, glands, bones and nervous
system.
TB is a potentially serious condition, but it can be cured if it's treated with the right antibiotics at the right
time.

3. Epidemiology
In 2019, an estimated 10 million people fell ill with TB worldwide; 5.6 million men, 3.2 million women and
1.2 million children.
TB is present in all countries and age groups. But TB is curable and preventable. A total of 1.4 million people
died from TB in 2019 (including 208000 people with HIV).
Worldwide, TB is one of the top 10 causes of death and leading cause from a single infectious agent (above
HIV/AIDS).
In 2019, the 30 high TB burden countries accounted for 87% of the new TB cases. Eight countries account
for two thirds of the total, with India leading the count, followed by Indonesia, China, the Philippines,
Pakistan, Nigeria, Bangladesh and South Africa.
Globally, TB incidence is falling at about 2% per year and between 2015 and 2019 the cumulative reduction
was 9%.

5. Two thirds were in eight countries:
India (26%)
Indonesia (8.5%)
China (8.4%)
Philippines (6%)
Pakistan (5.7%)
Nigeria (4.4%)
Bangladesh (3.6%)
South Africa (3.6%)

6. The three countries with the largest share of the global burden in 2019 were:
India (27%)
China (14%)
the Russian Federation (8%)
It is estimated that about 40% of the Indian population is infected with the TB bacteria, vast majority of
whom have latent TB rather than TB disease.

7. Total TB Cases Worldwide

8. TB Incidence in India: 2000-2019

9. TB Mortality in India: 2000-2019

10. Symptoms
TB may infect any part of the body, but most commonly occurs in lungs (known as pulmonary TB). Extra-
pulmonary TB occurs when tuberculosis develops outside of the lungs, although extra-pulmonary TB may
coexist with pulmonary TB.
General signs and symptoms include fever, chills, night sweats, loss of appetite, weight loss, and fatigue.
Significant nail clubbing may also occur.
Pulmonary TB
If a TB infection does become active, it most commonly involves the lungs (in about 90% of cases).
Symptoms may include chest pain and a prolonged cough producing sputum. About 25% of people may not
have any symptoms. Occasionally, people may cough up blood in small amounts, and in very rare cases,
infection may erode into the pulmonary artery, resulting in massive bleeding. TB may become a chronic
illness and cause extensive scarring in the upper lobes of lungs. The upper lung lobes are more frequently
affected by TB than the lower ones.

12. Extra-pulmonary TB
In 15-20% of active cases, the infection spreads outside the lungs, causing other kinds of TB. These are
collectively denoted as extra-pulmonary TB.
Extra-pulmonary TB occurs more commonly in people with a weakened immune system and young children.
In those with HIV, this occurs in more than 50% of cases.
Notable extra-pulmonary infection sites include the pleura (in tuberculous pleurisy), the central nervous
system (in tuberculous meningitis), the lymphatic system (in scrofula of the neck), the genitourinary system
(in urogenital TB), and the bones and joints (in Pott disease of the spine).
A potentially more serious, widespread form of TB is called disseminated TB, it is also known as miliary
tuberculosis.
Miliary TB currently makes up about 10% of the total extrapulmonary cases.

14. Etiology
TB is caused by a type of bacterium called Mycobacterium tuberculosis. It is spread when a person with
active TB disease in their lungs coughs or sneezes and someone else inhales the expelled droplets, which
contain TB bacteria.
Although, TB is spread in a similar way to a cold or flu, it is not as contagious. You would have to spend
prolonged periods (even several hours) in close contact with an infected person to catch the infection
yourself.
For example, TB infections usually spread between family members who live in the same house. It would be
highly unlikely for you to become infected by sitting next to an infected person on, for instance, a bus or
train.
Not everyone with TB is infectious. Children with TB or people with a TB infection that occurs outside lungs
(extra-pulmonary TB) do not spread the infection.

15. Latent and active TB
In most healthy people, the immune system has the ability to destroy the bacteria (mycobacterium) that cause
tuberculosis.
But in some cases, the bacteria infect the body (of healthy people) but do not cause any symptoms (latent
tuberculosis), or the infection begins to cause symptoms within weeks, months or even years (active
tuberculosis).
Up to 10% of people with latent tuberculosis (latent TB) eventually develop active tuberculosis (active TB)
years after the initial infection. This usually happens either within the first year or two years of the TB
infection, or when the immune system is weakened – for example, if someone is having chemotherapy for
treatment of cancer.

16. Anti-tubercular Agents
Anti-tubercular agents (anti-TB or antimycobacterial drugs) are the medicines used for the treatment of TB
infection.
First successful drug for treatment of TB was PAS (para-amino salicylic acid) developed by Lehman in 1943.
Dramatic success came when Waksman and Schutz discovered Streptomycin which has made remarkable
progress.
Followed by Thiacetazone by Domagk in 1946; in 1952 Isoniazid; Pyrazinamide by Kushner and colleagues
in 1952 and later on Rifampicin in 1957 by S. Margalith has totally changed the strategy in the
chemotherapy.
Ethambutol came in 1961 by Lederle -laboratories. Fluoroquinolones, newer macrolides and congener of
Rifampicin → Rifabutin are recent addition in antimycobacterial drugs.

17. Classification
Synthetic antitubercular agents
Isoniozid
N
O NH
NH2
Pyrazinamide
N
N
NH2
O
Ethionamide
N
CSNH2
CH2CH3
Para-amino salicylic acid
O OH
OH
NH2
Prothionamide
N
CSNH2
CH2CH2CH3
Thiacetazone
NHCOCH3
C
H N NH C NH2
S
Ethambutol
OH
N
H
N
H
O
H
Terizidone
N
N
NH
O
O
N
H
O
O

18. Anti-tubercular antibiotics
Rifampicin
OH
O
NH
N
N
N
O
OH
OH OH
O
O
O
O
O
H
O
Rifabutin
O
NH
O
OH
OH OH
O
O
O
O
O
H
O
NH
N
N

19. Cycloserine N
H
O
NH2
O
Streptomycin
O O
NH
OH
O
H
OH
O
O
H
O O
H
N
OH
N
NH2
N
H2
OH
NH2
NH2
O
H
Capreomycin sulphate
NH
N
H
NH
N
H
NH
O
N
H2
NH
O
N
H
NH
N
H
O
O
O NH2
NH2
O N
H
NH2
O
S
OH
OH
O
O

20. Kanamycin
O
O
NH2
O
H NH2
O
N
H2
O
H
OH
OH
O
OH
OH
N
H2
O
H
Amikacin
O
O
N
H
O
H NH2
O
N
H2
O
H
OH
OH
O
OH
N
H2
O
H
OH
O
OH

21. Fluoroquinolones
Ofloxacin
N
N
N
O
OH
O
F
O
Levofloxacin
N
N
N
O
OH
O
F
O
Moxifloxacin
N
O
OH
O
F
N
NH
H
H
Ciprofloxacin
N
N
N
H
O
OH
O
F

22. Mechanism of Action

24. ISONIAZID

25. RIFAMPIN

26. PYRAZINAMIDE

27. ETHAMBUTOL

28. Structure Activity Relationships
ISONIAZID

30. ETHAMBUTOL

32. PYRAZINAMIDE

33. REFAMPIN

36. FLUOROQUINOLONES

37. SYNTHESIS OF ANTITUBERCULAR DRUGS
Isoniazid
IUPAC Name: Pyridine-4-carbohydrazide
Synthesis: Isoniazid is prepared by first carrying out oxidation of 4-methylpyridine (picoline) to obtain iso-
nicotinic acid which upon esterification followed by heating with anhydrous hydrazine yields the desired
compound.
N
CH3
N
O OH
N
O O CH3
N
O NH
NH2
KMnO4
[O]
C2H5OH
H+
- H2O
Picoline Pyridine-4-carboxylic
acid
(Isonicotic acid)
Ethyl
pyridine-4-carboxylate
(Ethylisoniconate)
Isoniazid
(Isonicotinic
acid hydrazide)
NH2NH2
- C2H5OH

38. Uses:
Mycobacterium infections (it is recommended to be given with pyridoxine to avoid neuropathy in patients)
Latent tuberculosis (in patients with positive tuberculin skin test)
Prophylaxis against active TB in individuals who are in great risk as very young or immune-compromised
individuals

39. para-Amino salicylic acid
IUPAC Name: 4-Amino-2-hydroxybenzoic acid
Synthesis:
Method (1): This method involves reduction of 3-nitrophenol to 3-aminophenol which undergoes Kolbe
Schmidt reaction to yield the product para-aminosalicylic acid (4-amino-2-hydroxybenzoic acid).
OH
NO2
NH2
OH
O OH
OH
NH2
3-Nitro
phenol
3-Amino
phenol Para amino salicylic
acid
Sn/HCl
[H]
Kolbe Schmidt
reaction
CO2/K2CO3

40. Method (2): This method involves nitration of 2-amino benzoic acid to form 4-nitro-2-amino benzoic acid.
This compound is reacted with NaNO2 and HCl to give 2-hydroxy-4-nitro benzoic acid which is reduced to
form the desired product para-aminosalicylic acid (4-amino-2-hydroxybenzoic acid).
NH2
O OH O OH
OH
NH2
2-Amino
benzoic
acid
4-Nitro-2-amino
benzoic acid
Para amino salicylic
acid
HNO3
H2SO4
NH2
O OH
NO2
OH
O OH
NO2
2-Hydroxy-4-nitro
benzoic acid
Sn
HCl
[H]
NaNO2
HCl
Boiling
H2O
Uses: Specifically, it is used to treat active drug resistant tuberculosis together with other antituberculosis
medications. It has also been used in the treatment of inflammatory bowel disease (ulcerative colitis and
Crohn's disease).