Antitubercular Drugs

PHRM 304

Mycobacterium tuberculosis

• Main etiological agent of tuberculosis (TB)• 2nd leading infectious cause of death after

HIV• Can remain dormant for years• Most host never develop the disease• In 2007, 353,000 TB patient were found In

Bangladesh (6th in the world, WHO)

Mycobacterium tuberculosis

Antitubercular drugs

• Combined treatment of two or more drugs is used. Advantages:

• Prevents emergence of resistance• Additive effect: smaller dose is sufficient

First-line agents

• Isoniazid• Rifampicin• Pyrazinamide• Ethambutol• Streptomycin

Second-line agents

• Ethionamide, p-aminosalicylic acid, cycloserine, capreomycin, and kanamycin

• Active antibacterial agents, but they usually are less well tolerated or have a higher incidence of adverse effects

• Utilized in cases of resistance, retreatment, or intolerance to the first-line drugs

HYDRAZIDE AND DERIVATIVESFirst-line agent

Hydrazide

• N-N covalent bond• Four substituents• One acyl group Hydrazide

Isoniazid (INH)

• Isoniazid (INH) is a synthetic antibacterial agent• Considered to be the primary drug for

treatment

Isoniazid (INH)

1 2

1

Mechanism of action

• Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase enzyme that in M. tuberculosis is called KatG.

• Inhibiting the synthesis of mycolic acids, important constituents of the mycobacterial cell wall

• Most active drug for tuberculosis

Mechanism of action

• In the bacterium it is converted to isonicotinic acid, which is membrane impermeable, hence likely to accumulate intracellularly.

N

COHO

Active compounds (R1 and/or R2 = alkyl ; R3 = H)

Destroyed the activity (R1 and R2 = H/alkyl; R3 = alkyl)

Hydroxamic acid Amide

Iproniazid• Tuberculostatic• Psychostimulant• Hepatotoxic: no longer used

Isoniazid hydrazone

Synthesis: INH react with aldehyde and ketoneProdrug: Similar activityActivate in GI tract

Hydrazone

P-AMINOSALICYLIC ACIDSecond-line agent

p-aminosalicylic acid

• Commonly known as PAS• Used in combination of other TB drugs

p-aminosalicylic acid

• It was the second antibiotic found to be effective in the treatment of tuberculosis, after streptomycin.

• PAS is always used in combination with other anti-TB drugs.

p-aminosalicylic acid

• Its potency is less than that of the current five first-line drugs (isoniazid, rifampicin, ethambutol, pyrazinamide, and streptomycin) for treating tuberculosis, but it is still useful in the treatment of multidrug-resistant (MDR) tuberculosis.

-NH2•Replace with•Alkoxy, amides, hydroxy, 3o amine

-OH •Replace with•Amino, thiol

-COOH •Replace with•Alkyl ester, amides, nitrates

Structure variation results inactive or less active compounds:

Mechanism of action

• The mechanism of action is very similar to that of sulfonamides, which inhibit dihydropteroate synthase and thus the biosynthesis of folic acid.

• Structurally similar to PABA & sulfonamides.