CHANDIGARH UNIVERSITY

UIPS

MEDICINAL CHEMISTRY -III(PHT-351)

ASSIGNMENT -3

SUBMITTED TO: MS. MANISHA BHATTI

SUBMITTED BY: SHIFFALI

BRANCH: BPHARMACY

SEMESTER:6

UID:17BPH1048
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.

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, as well 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).

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.


ISONIAZID
 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).
KaSA is beta ketoacyl carrier protein synthetase

-
- ADVERSE EFFECTS
- Peripheral neuropathy, elevated serum transaminases (SGOT; SGPT),
bilirubinaemia, bilirubinuria, jaundice, hepatitis (may be fatal), nausea,
vomiting, epigastric distress, pancreatitis, blood dyscrasias, hypersensitivity
reactions, hyperglycaemia, pellagra, metabolic acidosis, rheumatic syndrome.

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

 ETHAMBUTOL HCl

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.
 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 are inflamed. 20% percent of the metabolites are
excreted in faeces 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.

 Pyrazinamide

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
anaemia, skin rash, urticaria, pruritus, dysuria, interstitial nephritis, malaise;
rarely porphyria, and fever.
-

 STREPTOMYCIN
- Part of aminoglycosides antibiotic
- First clinically useful antitubercular drug, but less effective than INH or rifampin
- Acts only on extracellular bacilli –poor penetration into cel s - Doesn’t cross the
BBB, but penetrates tubercular cavities
MECHANISM OF ACTION
• Irreversible inhibitors of protein synthesis,
• Bactericidal
• Inside the cell, aminoglycosides bind to specific 30S-subunit ribosomal
proteins and inhibits protein synthesis
• Resistance
– Inactivation by adenylation, acetylation, or phosphorylation
– impaired entry into the cell
– receptor protein on the 30Sribosomal subunit- deleted or
altered as a result of amutation
PHARMACOKINETICS
• absorbed very poorly from the intact gastrointestinal tract

• intramuscular injection or usual y administered intravenously as a 30- to 60- minute

infusion

• Normal half-life - 2–3 hours, but in renal failure patient it reduces to 24-48 hrs

CLINICAL USES
• Treatment of infections resistant to other drugs

• Adults: 20–40 mg/kg/d daily for several weeks

– Followed by 1–1.5 g two or three times weekly for several months

• Other drugs are always given in combination to prevent emergence of resistance

• Non tuberculosis species of mycobacteria other than Mycobacterium avium complex

(MAC) and Mycobacterium kansasii are resistant

• Dose is reduced to half in hemodialysispatient

 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 haemolysis (which
may lead to haemolytic anaemia) 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.
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 catalysed by CYP3A4 isoforms.
- The urine consists of small amounts of Dapsone and the metabolites, that is,
Nacetyldiamino-diphenyl sulphone and N-hydroxy-diamino-diphenyl
sulfone, as well as glucuronide and sulphate of each of these substances.
 - 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.

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

REFERENCES
• Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, BlivenSizemore
E, Hackman J, Hamilton CD, Menzies D, Kerrigan A, Weis SE,
Weiner M, Wing D, Conde MB, Bozeman L, Horsburgh CR, Chaisson RE
(December 2011). "Three months of rifapentine and isoniazid for latent
tuberculosis infection". The New England Journal of Medicine. 365 (23):
2155–66. doi:10.1056/nejmoa1104875. PMID 22150035
• Pharmaceutical Chemistry II- V.N. Raje
• Text book of pharmaceutical organic chemistry- Mohammed ali
• Essential of medical pharmacology - K.D. Tripathi 6th edition