Anti-tubercular Drugs

Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis.

It primarily affects the lungs but can also impact other parts of the body, including the kidneys,
spine, and brain. TB is transmitted through airborne droplets when an infected person coughs,
sneezes, or speaks. Depending upon the site of infection, the disease can be categorized as follows
 Pulmonary tuberculosis (respiratory tract).
 Genitourinary tuberculosis (genitourinary tract)
 Tuberculous meningitis (nervous system).
 Miliary tuberculosis (a widespread infection)
Drugs used in the treatment of tuberculosis can be divided into two major categories
1. First-line drugs: Isoniazid, streptomycin, rifampicin, ethambutol, and pyrazinamide
2. Second-line drugs: Ethionamide, p-amino salicylic acid, ofloxacin, ciprofloxacin,
cycloserine, amikacin, kanamycin, viomycin, and capreomycin.

The majority of the patients with tuberculosis are treated with first-line drugs and shows excellent
results with a 6-month course of treatment. For the first 2 months, isoniazid, rifampicin, and
pyrazinamide are given, followed by isoniazid and rifampicin for the remaining 4 months. Second-
line drugs are used mainly to treat multidrug resistant M. tuberculosis infections
First-Line Drugs:
Ethambutol:
Ethambutol hydrochloride is a white crystalline powder, soluble in water and in alcohol.
It is not recommended for use as a single drug, but used in combinations with other anti-
tubercular drugs in the chemotherapy of pulmonary tuberculosis.
Mechanism of Action:
Its primary mechanism of action involves inhibiting the synthesis of the bacterial cell wall. By
inhibiting arabinosyl transferases, ethambutol disrupts the incorporation of arabinose into
arabinogalactan. This leads to an incomplete and defective cell wall structure.

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Therapeutic Applications:
 Used as part of a combination therapy for active tuberculosis infections. It is typically
administered alongside other anti-TB drugs such as INH, RIF, and pyrazinamide.
 In cases where the TB bacteria are resistant to first-line drugs, ethambutol may still be
effective and is included in the regimen for multidrug-resistant TB (MDR-TB).
 Ethambutol is also used to treat infections caused by the Mycobacterium avium complex
and kansasi
Synthesis:

Structure Activity Relationship:

1. The presence of two amino groups are essential for activity.
2. If OH groups are replaced by OCH3 or OC2H5 the compound remains active.
3. If OH groups are replaced by aromatic system (phenyl or pyridine) the compound becomes
inactive.
4. The change or replacement of amino moities by other acetyl ,butyl or nitrosyl moities
antimacobacterial activity will be lost.
5. Increase in size of N substituent results in loss of activity.
6. The dextro compound is 200-500 times more active as compared to meso.
Dose: The administered dose is 15–25 mg/kg once a day; low doses for new cases, and high doses
for use in patients who have had previous antitubercular therapy.
Isonicotinic acid hydrazide (Isoniazid):
Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the
mycobacterium is slow-growing.
Mechanism of Action:
It works by inhibiting the synthesis of mycolic acids, which are essential components of the bacterial
cell wall in Mycobacterium tuberculosis. Isoniazid is a prodrug, meaning it requires activation within
the bacterial cell. The activation is carried out by the enzyme catalase-peroxidase (KatG), which
converts isoniazid into its active form. Once activated, isoniazid binds to the NADH cofactor, forming
a complex that inhibits the enoyl-acyl carrier protein reductase (InhA). This inhibition prevents the
synthesis of mycolic acids, leading to the disruption of the bacterial cell wall and ultimately the death
of the bacteria.

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Synthesis:

4-Picoline on oxidation with potassium permanganate gives isonicotinic acid, which is converted
to ethyl ester by reaction with ethanol in presence of acid. Ester-amide interchange takes place by
reaction with hydrazine hydrate and affords INH.
Structure Activity Relationship:

1. Pyridine ring, if replaced with piperidine then the compound is less active than the original.
2. Hydrazide linkage when converted into hydrazone, a series of active compounds are
produced. Later it was found that in the body Hydrazones were converted again into
isoniazid.
3. If hydrazide is shifted to position no. 2 or 3 instead of 4, then the compound is less active.
4. If hydrazide group is replaced totally by alkyl or aryl, then the compound remains active
but less than isoniazid.
5. Outside ring, INH contains two nitrogen atoms (hydrazine), when an alkyl group is
introduced at N1 then the compound becomes inactive. When any alkyl group is introduced
at N2 then a series of active compounds are obtained but these are less active.
Dose: For the prophylaxis in case of adults is 5 mg/kg, with a maximum of 300 mg. For children:
10–20 mg/kg daily. Combination therapy Isoniazid, Rifampin and Pyrazinamide for 2 months
followed by Isoniazid (15 mg/kg orally) with. Rifampin (10 mg/kg upto 600 mg per dose)
twice/week for 4 months. For the prophylaxis in case of adults 5 mg/kg, with a maximum of 300
mg.

M. Awais Fareed Pharm D IUB (2019-24)

Rifampicin

Rifampicin is the most active agent in clinical use for the treatment of tuberculosis. It is used only
in combination with other anti-tubercular drugs, and it is ordinarily not recommended for the
treatment of other bacterial infections when alternative antibacterial agents are available
Mechanism of Action:
It is an antibiotic obtained from Streptomyces mediterranei. Rifampicin inhibits DNA-dependent
RNA polymerase of mycobacteria by forming a stable drug enzyme complex, leading to
suppression of initiation of chain formation in RNA synthesis and acts as a bactericidal drug.

Pyrazinamide
It is used to treat tuberculosis and meningitis. The drug should be used with great caution in
patients with hyperuricaemia or gout.
Mechanism of Action:
 Pyrazinamide is a prodrug that requires conversion to its active form, pyrazinoic acid
(POA), by the enzyme pyrazinamidase, which is produced by Mycobacterium
tuberculosis.Pyrazinoic acid accumulates inside the mycobacterial cells and disrupts their
membrane potential and energy production.
 Pyrazinamide is particularly effective in the acidic environment found within
macrophages, where the TB bacteria often reside. The acidic conditions enhance the
conversion of pyrazinamide to pyrazinoic acid, increasing its bactericidal activity.
 Pyrazinoic acid may inhibit fatty acid synthase I (FAS I) in Mycobacterium tuberculosis,
which is involved in the synthesis of fatty acids necessary for the bacterial cell membrane.
This inhibition further compromises the integrity and functionality of the cell membrane.

M. Awais Fareed Pharm D IUB (2019-24)

Synthesis:

Thermal decarboxylation of 2, 3-pyrazinedicarboxylic acid gives rise to the formation of the

corresponding monocarboxylic acid derivative as an intermediate by the loss of one mole of CO2.
The resulting product upon careful esterification with methanol followed by controlled aminolysis
produces the desired pyrazinamide.
Dose: Daily administered dose is 20–35 mg/kg in 3–4 equally spaced doses and maximum is 3 g
daily
Structure Activity Relationship:
1. When pyrazine ring is replaced with alternate heterocyclic ring e.g. pyridine or pyrimidine,
the compound becomes less active.
2. Pyrazine ring is mono-substituted while di-substituted derivatives are less active.
3. These were the initial findings because later on due to QSAR two disubstituted derivatives
were introduced – which were active.
 5-chloro, N-isobutyl pyrazinamide
 5 chloro, N- 2 methyl decyl pyrazinami

Dose: Daily administered dose is 20–35 mg/kg in 3–4 equally spaced doses and maximum is 3 g
daily
Cycloserine
It is an ‘Antibiotic’ (anti-mycobacterial drug) duly obtained from S. orchidaceus. It is a chemical
analogue of D-alanine.
Mechanism of Action:
It belongs to the second-line tuberculostatic drug and acts as an inhibitor of cell-wall synthesis by
blocking the incorporation of alananine to peptidoglycan during cell wall synthesis.
Therapeutic Applications:
 Cycloserine is frequently used for the adequate treatment of multidrug-resistant
tuberculosis along with certain other primary drugs.
 Its application for the control and management of acute UTIs caused by susceptible
microorganisms.

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Synthesis:

Structure Activity Relationship:

1. It contains keto group add at position 3 which is essential for activity.
2. Amino group add at position 4 which is essential for activity.
3. It's ring system is also called oxazolidine. it is obtained naturally as d-isomer
Ethionamide:
Ethionamide is an antibiotic used in the treatment of tuberculosis (TB), particularly in cases of
multidrug-resistant TB (MDR-TB).
Mechanism of Action:
Ethionamide is activated by the mycobacterial enzyme EthA. It inhibits InhA, an enzyme crucial
for mycolic acid synthesis. Inhibition of mycolic acid synthesis leads to a weakened cell wall and
bactericidal effect.

Synthesis:

M. Awais Fareed Pharm D IUB (2019-24)

Structure Activity Relationship:
1. In vitro, it is less active but in vivo more active because of increased lipophilicity due to
C2H5.
2. Pyridine ring if replaced with piperidine, then the compound is less active than original.
3. If ethyl group is shifted to position no. 3 or 5 instead of 2, then the compound is less
active.
4. No substitution can be made on position 4, it will result in termination of therapeutical
activity.

References
 Lectures by Dr. Mohsin Abbas Khan
 Textbook of Medicinal Chemistry—V. Alagarsamy.
 Medicinal Chemistry— Ashutosh Kar.
 Medicinal Chemistry—D. Sri Ram

M. Awais Fareed Pharm D IUB (2019-24)