Medicinal Chemistry of Antitubercular Agents

1. Anti-tubercular Agents
Dr. Somdutt Mujwar
(Associate Professor)
M.M. College of Pharmacy,
Maharishi Markandeshwar (Deemed to be University)
Mullana, Ambala- Haryana, India
Mobile: +91-9827813303

2. Tuberculosis
 Mycobacterium tuberculosis is the causative agent that is responsible for
the tubercular infection which is mainly spread by coughing and
sneezing.
 Tuberculosis is a chronic granulomatous disease in which the alveolar
mucosa is primarily affected.
 Symptoms may include fever, night sweats, weakness, cough, chest pain,
shortness of breath, etc.

3.  A total of 1.5 million people died from TB in 2020.
 Worldwide, TB is the 13th leading cause of death and the second leading
infectious killer after COVID-19.
 Tuberculosis is declared as a Global Health Emergency by the WHO.
 Multidrug-resistant TB (MDR-TB) remains a public health crisis and a
health security threat.
 By 2022, US$ 13 billion is needed annually for TB prevention, diagnosis,
treatment and care to achieve the global target agreed at the UN high
level-meeting on TB in 2018.

4. Pathogenesis

5. Classification
Anti-tubercular Drugs
I. Synthetic Antitubercular Drugs II. Antitubercular Antibiotics Drugs
 Isoniazid
 Ethambutol
 Ethionamide
 Pyrazinamide,
 Para amino salicylic acid.
 Rifampicin
 Rifabutin
 Streptomycin
 Capreomycin sulphate
 Cycloserine

6. Classification
I. First Line
Antitubercular Drugs
II. Second Line
Antitubercular Drugs
III. Newer Antitubercular
Drugs
 Isoniazid
 Rifampicin
 Ethambutol
 Pyrazinamide
 Streptomycin
 Thioacetazone
 Para amino salicylic acid
(PAS)
 Ethionamide
 Cycloserine
 Kanamycin
 Amikacin
 Capreomycin
 Ciprofloxacin
 Ofloxacin
 Clarithromycin
 Azithromycin
 Rifabutin

7. I. Synthetic Antitubercular Drugs
1. Isoniazid
 Isoniazid is a prodrug which is activated by an enzyme catalase
peroxidase to its active metabolite which targets the bacterial inhA gene
which encodes Fatty Acid Synthase enzyme required for the synthesis of
Mycolic Acid.
 Isoniazid resistance by the pathogen is developed by mutation of catalase
peroxide enzyme and inhA gene.

8. • Isoniazid shows bacteriostatic effect on slowly dividing or resting bacilli,
while bactericidal action for actively dividing Mycobacterium
tuberculosis bacteria.
Chemical Synthesis

9. 2. Ethambutol
• It is a white crystalline powder which is freely soluble in water.
• It is a bacteriostatic in nature and it suppresses the growth of the most of the
tubercular bacteria those are resisted to isoniazid and streptomycin
• It interferes mycolic acid synthesis by inhibiting arabinosyl transferase enzyme.
3. Ethionamide
• It also interferes with the redox system of the tubercular bacteria.
• Its active metabolite interferes the mycolic acid synthesis by targeting inhA gene.
• Associated adverse effects are nausea, vomiting, mental disturbance, etc.

10. 4. Pyrazinamide
• Bactericidal in nature both intracellularly as well as inflammation site.
• Interferes mycolic acid synthesis by targeting fatty acid synthase-I gene.
• Associated adverse effects are hepatotoxicity, hyperuricemia, rashes, fever, etc.
5. Para amino salicylic acid
• It inhibits fatty acid synthesis of tubercular bacteria.
• Associated adverse effects are rashes, fever, liver dysfunction, and epigastric pain.

11. Chemical Synthesis

12. II. Antitubercular Antibiotics Drugs
1. Rifampicin (Rifampin)
 Bactericidal for extracellular, intracellular as well as slow dividing
mycobacterium.
 It interferes with the bacterial RNA synthesis by inhibiting DNA
Dependent RNA Polymerase enzyme.
 Resistance is developed by mutation in “rpoB gene” which encodes for β-
subunit of RNA polymerase enzyme
2. Rifabutin
 Rifabutin is a rifamycin antibiotic that is similar in structure and activity
to rifampin.
 It is typically only used in those who cannot tolerate rifampin such as
people with HIV/AIDS on antiretrovirals.

13. 3. Streptomycin
 Bactericidal to the extracellular bacilli.
 Inhibits protein synthesis by binding to 30S subunit of ribosome.
 Common toxicities associated with the streptomycins are
cytotoxicity, nephrotoxicity, renal function disorder, etc.
4. Cycloserine
 Cycloserine is supposed to exert its antibacterial action by
preventing the synthesis of cross linking peptides in the formation
of bacterial cell wall.
 It occurs as a white to pale yellow crystalline material that is highly
soluble in water.

14. Thank you!!!