PPH 308: MEDICINAL CHEMISTRY-II (Anti-tubercular Agents)

Presentation · January 2018
DOI: 10.13140/RG.2.2.21684.76165

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PPH 308: MEDICINAL CHEMISTRY – II Unit: IV: Anti-TB and anti-leprosy Drugs

Anti-TB and anti-leprosy Drugs: Synthesis of Isoniazid, Ethambutol, Pyrazinamide, Dapsone, clofazimine.

 Anti-tubercular Agents

 Tuberculosis (TB)

– Tuberculosis (TB) is an infectious disease usually caused by the bacterium Mycobacterium tuberculosis (MTB).
– Tuberculosis generally affects the lungs, but can also affect other parts of the body.
– Most infections do not have symptoms, in which case it is known as latent tuberculosis.
– Latent tuberculosis infection (LTBI) means a patient is infected with Mycobacterium tuberculosis, but the patient

does not have active tuberculosis.
– About 10% of latent infections progress to active disease which, if left untreated, kills about half of those infected.
– The classic symptoms of active TB are a chronic cough with blood-containing sputum, fever, night sweats,

and weight loss.
– Tuberculosis is spread through the air when people who have active TB in their lungs cough, spit, speak, or sneeze.

People with latent TB do not spread the disease.
– Active infection occurs more often in people with HIV/AIDS and in those who smoke.
– Diagnosis of active TB is based on chest X-rays, as well as microscopic examination and culture of body fluids.

Diagnosis of latent TB relies on the tuberculin skin test (TST) or blood tests.

 Mycobacterium

– Mycobacteria are designated as the transition forms existing between bacteria and fungi.
– The Greek prefix “myco” – means “fungus” alluding to the way mycobacteria have been observed to grow in a

mold-like fashion on the surface of cultures. It has a positive gram stain and a spirochete spine.
– Mycobacterium refers to a genus of acid-fast organisms.
– Mycobacteria are aerobic and non-motile bacteria.
– Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. This genus includes

pathogens known to cause serious diseases in mammals, including tuberculosis (Mycobacterium tuberculosis) and
leprosy (Mycobacterium leprae) in humans.

Note By:
 Robert Koch discovered the tuberculosis bacillus.
 Albert Calmette and Camille Guérin achieved the first genuine success in immunization against tuberculosis in

1906, using attenuated bovine-strain tuberculosis. It was called Bacille Calmette–Guérin (BCG). The BCG
vaccine was first used on humans in 1921 in France

Albert Calmette Camille Guérin Robert Heinrich Hermann Koch
Born: 12 July 1863 Nice, France Born: 22 December 1872 Poitiers Born: 11 December 1843 Clausthal
Died: 29 October 1933 (aged 70) Paris Died: 9 June 1961 (aged 88) Paris Died: 27 May 1910 (aged 66) Baden
Nationality: France Nationality: France Nationality: German
Known for Bacillus Calmette-Guérin Known for Bacillus Calmette-Guérin Known for Discovery bacteriology
antivenin antivenin Koch’s postulates of germ theory
Scientific career: Bacteriology Scientific career: Bacteriology Isolation of anthrax, tuberculosis and
Institutions Pasteur Institute Institutions Pasteur Institute cholera.

Nobel Prize in Medicine (1905)
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Lecturer Notes_Dr. S. Mondal_B. Pharm 6 Semester_GITAM (Deemed to be University) Page | 1
E-mail: [email protected]

PPH 308: MEDICINAL CHEMISTRY – II Unit: IV: Anti-TB and anti-leprosy Drugs

 Comparison between cell envelopes of mycobacteria and other bacteria

(a) The innermost layer of the mycobacterial cell envelope is composed of peptidoglycan and is lined by a layer of

arabinogalactan. The presence of mycolic acids covalently bound to arabinogalactan, aswell as the interaction of
glycolipids and lipoglycans with mycolic acids in the outer layer, confers high hydrophobicity to the
mycobacterial cell wall

(b) Gram-negative cell walls contain a thin peptidoglycan layer that lines the plasma membrane and an outer
membrane composed of lipopolysaccharides, responsible for their antigenic properties;

(c) The cell walls of Gram-positive bacteria are thick and mainly composed of a peptidoglycan layer adjacent to
the plasma membrane.

 Common infection sites of the tuberculosis
– Common infections of TB are lungs (primary site), brain, bone, liver, and kidney. The main symptoms are cough,

tachycardia, cyanosis and respiratory failure. Depending upon the site of infection, the disease can be categorized
as follows:
o Pulmonary tuberculosis (respiratory tract).
o Genitourinary tuberculosis (genitourinary tract).
o Tuberculous meningitis (nervous system).
o Miliary tuberculosis (a widespread infection).

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PPH 308: MEDICINAL CHEMISTRY – II Unit: IV: Anti-TB and anti-leprosy Drugs

 Drugs used in the treatment of tuberculosis
– 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.

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E-mail: [email protected]

PPH 308: MEDICINAL CHEMISTRY – II Unit: IV: Anti-TB and anti-leprosy Drugs

 Isoniazid

 Synthesis

 Mechanism of action:
– It causes a decreased synthesis of mycolic acid. Mycolic acid is a constituent of mycobacterial cell wall that is

thought to be responsible for the acid fastness of the bacteria.
– Isoniazid is a prodrug that is activated on the surface of M. tuberculosis by katG enzyme to isonicotinic acid.

Isonicotinic acid inhibits the bacterial cell wall mycolic acid, thereby making M. tuberculosis susceptible to
reactive oxygen radicals. Isoniazid may be bacteriostatic or bactericidal in action, depending on the concentration
of the drug attained at the site of infection and the susceptibility of the infecting organism. The drug is active
against susceptible bacteria only during bacterial cell division.

KatG is mycobacterial catalase (peroxidase),

AcpM is Acyl carrier protein,

KaSA is Beta ketoacyl carrier protein synthetase.

 The biotransformation of isoniazid

 Adverse Reactions:
– Peripheral neuropathy, elevated serum transaminases (SGOT; SGPT), bilirubinemia, bilirubinuria, jaundice,

hepatitis (may be fatal), nausea, vomiting, epigastric distress, pancreatitis, blood dyscrasias, hypersensitivity
reactions, hyperglycemia, pellagra, metabolic acidosis, rheumatic syndrome.

 Dose: Prophylaxis: 300 mg once daily. Active infection: 5 mg/kg daily; max 300 mg once daily.

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PPH 308: MEDICINAL CHEMISTRY – II Unit: IV: Anti-TB and anti-leprosy Drugs

 Ethambutol HCl

 Synthesis

 Mechanism of action
– It causes inhibition of mycobacterial arabinosyl transferases which is involved in polymerization reaction of

arabinoglycan, which is an essential component of mycobacterial cell wall.
– It is also thought to inhibit RNA synthesis.

 Pharmacokinetics
– It is well absorbed from the gut. It is well distributed throughout

the body. Peak level of 2-5 μg/ml is achieved in 2-4 hours. It can
cross the blood brain barrier when the meninges is inflamed. 20%
percent of the metabolites are excreted in feces and 50% is
excreted in urine.

 Therapeutic uses
– Ethambutol is found to be more effective against M. tuberculosis

and M. kansasii.
– It can be used for Tuberculous meningitis.

 Dosage
– Its usual dose is 15mg/kg/day.

 Adverse effects:
– It may cause fever and skin rashes.
– It may cause optic neuritis and reduction in visual acuity. It may

also cause a loss of red and green color discrimination.

Note By:
o Mycobacterium kansasii is a bacterium in the Mycobacterium family.
o The genus includes species known to cause serious diseases in mammals, including tuberculosis and leprosy, but

this species is generally not dangerous to healthy people.
o Gram-positive, non-motile, moderately-long too long and acid-fast rods.

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Lecturer Notes_Dr. S. Mondal_B. Pharm 6 Semester_GITAM (Deemed to be University) Page | 5
E-mail: [email protected]

PPH 308: MEDICINAL CHEMISTRY – II Unit: IV: Anti-TB and anti-leprosy Drugs

 Pyrazinamide

 Synthesis

 Mechanism of action
– Pyrazinamide diffuses into the granuloma of M. tuberculosis, where the tuberculosis enzyme pyrazinamidase

converts pyrazinamide to the active form pyrazinoic acid.
– Under acidic conditions of pH 5 to 6, the pyrazinoic acid that slowly leaks out converts to the protonated

conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate. The net effect is that more
pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH.

– Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase-I (FAS), which is required by the bacterium
to synthesize fatty acids.

– Pyrazinoic acid was proposed to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation process.

 Pharmacokinetics
– Pyrazinamide is well absorbed orally. It crosses inflamed meninges and is an essential part of the treatment of

tuberculous meningitis. It is metabolised by the liver and the metabolic products are excreted by the kidneys.
– The metabolic route constitutes of hydrolysis by hepatic microsomal pyrazinamidase into pyrazinoic acid, which

may be then, oxidized by xanthine oxidase to 5-hydroxy pyrazinoic acid. The later compound may appear free
either in the urine or as a conjugate with glycine.

 Dose: Daily administered dose is 20–35 mg/kg in 3–4 equally spaced doses and maximum is 3 g daily.

 Adverse effects
– The most common (approximately 1%) side effect of pyrazinamide is joint pains (arthralgia)
– The most dangerous side effect of pyrazinamide is hepatotoxicity.
– Other side effects include nausea and vomiting, anorexia, sideroblastic anemia, skin rash, urticaria, pruritus,

dysuria, interstitial nephritis, malaise; rarely porphyria, and fever.

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E-mail: [email protected]

PPH 308: MEDICINAL CHEMISTRY – II Unit: IV: Anti-TB and anti-leprosy Drugs

 Dapsone (DDS, Diaminodiphenyl sulphone)

 Synthesis

 Mechanism of action
– As an antibacterial, Dapsone inhibits bacterial synthesis of dihydrofolic acid, via competition with para-

aminobenzoate for the active site of dihydropteroate synthase.
– As an anti-inflammatory, Dapsone inhibits the enzyme myeloperoxidase. As part of the respiratory burst that

neutrophils use to kill bacteria

 Adverse effects
– The most prominent side-effects of this drug are dose-related hemolysis (which may lead to hemolytic anemia)

and methemoglobinemia.
– Toxic hepatitis and cholestatic jaundice.
– Other adverse effects include nausea, headache, and rash (which are common), and insomnia, psychosis, and

peripheral neuropathy.

 Dosage

– The dose as tablets is 25 or 100 mg. For adults the dose consumed is 50 mg per day orally. For lepromatous
leprosy, 100 mg Dapsone + 600 mg Rifampin and/or clofazimine 100 mg daily for at least 2 years followed by
Dapsone monotherapy. For borderline tuberculoid disease, Dapsone 100 mg daily + Rifampin 600 mg once
monthly for 6 months.

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PPH 308: MEDICINAL CHEMISTRY – II Unit: IV: Anti-TB and anti-leprosy Drugs

 Pharmacokinetics
– The major metabolic product of Dapsone results from N-acetylation in the liver by N-acetyltransferase.
– It also undergoes N-hydroxylation to hydroxylamine derivative. These metabolic reactions are catalyzed by

CYP3A4 isoforms.
– The urine consist of small amounts of Dapsone and the metabolites, that is, N-acetyldiamino-diphenyl sulphone

and N-hydroxy-diamino-diphenyl sulfone, as well as glucuronide and sulphate of each of these substances.

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Lecturer Notes_Dr. S. Mondal_B. Pharm 6 Semester_GITAM (Deemed to be University) Page | 8
E-mail: [email protected]

PPH 308: MEDICINAL CHEMISTRY – II Unit: IV: Anti-TB and anti-leprosy Drugs

 Clofazimine

 SAR of Clofazimine

 Mechanism of action
– Clofazimine works by binding to the guanine bases of bacterial DNA, thereby blocking the template function of the

DNA and inhibiting bacterial proliferation.
– It also increases activity of bacterial phospholipase A2, leading to release and accumulation of lysophospholipids,

which are toxic and inhibit bacterial proliferation.

 Adverse effects
– Clofazimine produces pink to brownish skin pigmentation in 75-100% of patients.
– Several patients have developed depression which in some cases resulted in suicide.
– Cases of icthyosis and skin dryness.
– 40-50% of patients develop gastrointestinal intolerance.

Note By: Ichthyosis is a family of rare genetic skin disorders characterized by dry, thickened, scaly skin.

 Dosage: The dose orally is 100 mg daily.

 Medical uses
– The primary use of clofazimine is for the treatment of leprosy.
– It has been used studied in combination with other antimycobacterial drugs to treat Mycobacterium avium

infections in people with HIV/AIDS and Mycobacterium avium paratuberculosis. Clofazimine also has a marked
anti-inflammatory effect.

– The drug is given as an alternative to people who cannot tolerate the effects of Dapsone for leprosy.

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E-mail: [email protected]

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