The document discusses antitubercular agents used to treat tuberculosis (TB). TB is caused by Mycobacterium tuberculosis and spreads through the respiratory system. It can spread through the bloodstream to other organs. Treatment has been hampered by multidrug-resistant TB strains. First-line agents include isoniazid, rifampin, and ethambutol. Second-line agents are used if resistance develops or for patient factors. Isoniazid works by inhibiting fatty acid synthesis, while rifampin inhibits bacterial DNA-dependent RNA polymerase. New antitubercular agents are needed due to increasing drug resistance.

1. ANTITUBERCULAR
AGENTS
Rajasekhar Reddy A
M.Pharm., (Ph.D.)
Assistant Professor
College of Pharmacy
K L E F deemed to be University
Medicinal Chemistry

2. Tuberculosis:
• Tuberculosis (TB) is a chronic infectious disease caused by various strains of
Mycobacterium especially Mycobacterium tuberculosis which is an acid fast aerobic
bacillus.
• It is transmitted via the respiratory route.
• It mainly affects the lungs but can spread through blood stream and lymphatic system to
the brain, bones, eyes and skin.
• Tuberculosis is the leading worldwide cause of mortality resulting from an infectious
bacterial agent.
• “Most alarming is the emergence of multidrug-resistant TB” (MDR-TB).

5. • Drug therapy for the treatment of TB has been greatly hampered by the development of
MDR-TB and the lack of new classes of drugs.
• In fact, no new drugs have been developed in the last 40 years.
• The only change in the treatment of TB has been the strategy of using direct observed
treatment (DOT), with an emphasis on patient-centered care.
• Additionally, whereas the course of treatment has been reduced, through the use of drug
combinations, to 6 months, patient compliance continues to be a serious problem, which in
turn may be associated with the development of bacterial resistance.
Drug Therapy:

6. • First line agents.
An effective bacterial agent, with an acceptable degree of toxicity.
ex. Isoniazid, Ethambutol, Rifampicin, Streptomycin, Pyrazinamide, Rifabutin.
• Second line agents.
For microbial resistance or patient related factors.
ex. Ethionamide, Aminosalicylic acid, Cycloserine, Amikacin, Capreomycin.
Classification:

7. First line agents:
Isoniazid
Ethambutol Rifampicin
Pyrazinamide
RifabutinStreptomycin
Bioisosteric Replacement

8. Second line agents:
Ethionamide
Aminosalicylic acid
Cycloserine
Amikacin
Capreomycin

9. Possible Targets:

10. MOA of Isoniazid:

11. MOA of Isoniazid:

12. • It generally is recognized that INH is a pro-drug that is activated through an oxidation reaction catalyzed by
an endogenous enzyme.
• This enzyme, katG, which exhibits catalase-peroxidase activity, converts INH to a reactive species capable
of acylation of an enzyme system found exclusively in M . tuberculosis.
• Reaction of INH with catalase-peroxidase results in formation of isonicotinaldehyde, isonicotinic acid, and
isonicotinamide, which can be accounted for through the reactive intermediate isonicotinoyl radical or
isonicotinic peroxide.
• The mycolic acids are important constituents of the mycobacterial cell wall in that they provide a
permeability barrier to hydrophilic solutes.
• The enzyme inhA, produced under the control of the inhA gene, is an NADH-dependent, enoyl reductase
protein thought to be involved in double-bond reduction during fatty acid elongation.
MOA of Isoniazid:

13. • Isoniazid specifically inhibits long-chain fatty acid synthesis (>26 carbon atoms).
• It should be noted that the mycolic acids are α-branched lipids having a “short” arm of 20 to 24
carbons and a “long” arm of 50 to 60 carbons.
• It has been proposed that INH is activated to an electrophilic species that acylates the four
position of the NADH.
• The acylated NADH is no longer capable of catalyzing the reduction of unsaturated fatty acids,
which are essential for the synthesis of the mycolic acids.
MOA of Isoniazid:

14. Rifampicin:
MOA

15. • The rifamycins inhibit bacterial DNA-dependent RNA polymerase (DDRP) by binding to the β-
subunit of the enzyme and are highly active against rapidly dividing intracellular and extracellular
bacilli.
• Rifampin is active against DDRP from both Gram-positive and Gram-negative bacteria, but
because of poor penetration of the cell wall of Gram-negative organisms by RIF, the drug has less
value in infections caused by such organisms.
• Inhibition of DDRP leads to blocking the initiation of chain formation in RNA synthesis.
• It has been suggested that the naphthalene ring of the rifamycins π-π bonds to an aromatic amino
acid ring in the DDRP protein.
• The DDRP is a metalloenzyme that contains two zinc atoms.
MOA of Rifampicins:

16. • It is further postulated that the oxygens at C-1 and C-8 of a rifamycin can chelate to a zinc atom,
which increases the binding to DDRP, and finally, the oxygens at C-21 and C-23 form strong
hydrogen bonds to the DDRP.
• The binding of the rifamycins to DDRP results in the inhibition of the RNA synthesis.
• Specifically, RIF has been shown to inhibit the elongation of full-length transcripts, but it has no
effect on transcription initiation.
• Resistance develops when a mutation occurs in the gene responsible for the β-subunit of the RNA
polymerase (rpoB gene), resulting in an inability of the antibiotic to readily bind to the RNA
polymerase
MOA of Rifampicins:

17. Synthesis of Drugs: