•
Antimycobacterial
Agents
Mycobacteria: Mycobacterium tuberculosis =>
Tuberculosis
Mycobacterium leprae => Leprosy (Hansen’s
disease)
• Slow-growing and difficult to stain (acid-fast bacilli).
• Abnormally high lipid content (mycolic acid) of the cell
envelope.
• Treatment of mycobacterial infection complicated by:
– Intracellular location of mycobacteria - phagocytes
– Drug resistance
– Chronic nature of these diseases
• In tuberculosis, the bacilli reach the alveoli, ingested by
pulmonary macrophages, fibroblasts then enclose the
infection site leading to formation of granulomas or
tubercles, hence the name Tubercle Bacillus (T.B).
Diagram of cell wall
• Leprosy primarily affects the skin as chronic
granulomatous infection.
• Tuberculosis primarily affects the lung (pulmonary
tuberculosis) but infection may extend to brain, bones,
eyes and skin (extrapulmonary tuberculosis) especially in
HIV-infected patients.
Tuberculosis
Clinical picture of leprosy:
Antitubercular agents
• Based on history of discovery, sulfanilamide
then dapsone then streptomycin (a turning point)
then PAS then isoniazid then ethambutol then
rifampin.
• Due to multiple drug resistance, a combination
of two or three of these agents is usually used.
• Classification:
A) p-Aminosalicylic acid derivatives.
B) Pyridine carboxylic acid derivatives.
C) Miscellaneous agents.
COOH
p-Aminosalicylic acid (PAS):
OH
Mode of action
Two possible mechanisms:
NH
• Similar to the mode of action of sulfonamides: 2
Being structurally similar to PABA, it acts as a
competitive antagonist to PABA by inhibiting
COO the
dihydropteroate synthetase eventually inhibits
OH
biosynthesis of mycobacterial DNA.
• It chelates trace elements.
Ca
HN
Disadvantages:
O
– Gastrointestinal irritation.
– Short half life (short duration).
• To overcome these disadvantages:
– It should be formulated in enteric-coated dosage
form or an antacid (aluminum hydroxide) is
prescribed concurrently.
– Developing less GI irritaing and longer acting
2
++
Pyridinecarboxylic acid derivatives:
Isoniazid (INH):
O
NHNH2
• Isonicotinic acid hydrazide.
Synthesis:
O
OH
N
O
OEt
O
NHNH2
OH
EtOH / H2SO4
OH
NH2NH2
OH
N
N
N
N
Pyridoxine
Mode of action:
• Inhibition of the biosynthesis of mycolic acids (branched
long chain fatty acids) which are important components
of the cell wall of mycobacteria.
• Active only against dividing mycobacteria.
NOTES:
1) INH is the most active antitubercular agent rather than
any other synthetic or antibiotic.
2) the equation of the assay is as follows:
CONHNH2
N
+ 2Br2 + H2O
COOH
N2 + HBr +
N
3)Ftivazide is hydrazone results from reaction of INH with
benzaldehyde derivatives,
It is as active as INH but non toxic.
OCH3
CONHN C
H
Ftivazide
N
OH
Side effects of INH:
long-term therapy may result in fatal drug induced
hepatitis.
It causes peripheral neuritis as it results in pyridoxine
deficiency by acting as a pyridoxine antagonist therefore,
the concurrent administration of pyridoxine (vitamin B6)
prevents the occurrence of peripheral neuritis.
INH is metabolized by acetylation. Nearly half of the
population are fast acylators of INH and the other half are
slow acylators of INH. Slow acylators (including middle
easterns) are genetically deficient of N-acetyltransferase
and are more prone to the side effects of INH. S
NH2
Ethionamide:
Developed as a less toxic (5 times) analogue of INH.
Mode of action like INH.
Active only against dividing mycobacteria.
N
a
SAR:
H
O
N
H
b
N
H
c
Aromatic ring:
N
• If replaced by benzene, piperidine or thiazole 
loss of activity.
Hydrazide moiety:
• The -position is the best position for activity.
• Replacement of Ha with alkyl groups 
decreases activity.
• Replacement of Hb and/or Hc with small alkyl
groups  increases activity. large alkyl groups
decreases activity.
• Replacement of Hb and Hc with alkylidene 
Diazine derivatives ( pyrazinamide ).
NH2
N
O
N
Pyrazinamide
N
KMnO4
N
/ -CO2
N
N
quioxaline
benzopyrazine
Assay:
COOH
Pyrazinedioic acid
NH2
N
COOH
N
N
Kjeldahl method
COOH
N
CH3OH/HCl
COOEt
N
NH3
N
CONH2
N
O
N COONa
+ NaOH Boiling in AMMONIA
+ NH3 which is recieved in
N
distillation apparatus
N
boric acid to form ammborate which is titratrated by st HCl and methyl red indicator
Miscellaneous agents
Ethambutol (Etibi):
Mode of action:
•
Being structurally similar to cellular polyamines
(spermidine and spermine), it interferes with their
function (essential for integrity of nucleic acids).
H2N
N
H
NH2
Spermidine
•
It chelates divalent metals thus inhibiting essential
enzymes.
O
N
H
M
O
N
H
Synthesis of ethambutol:
HO
2
NH2
+ Cl
Cl
Base
- 2HCl
Antitubercular antibiotics:
Streptomycin
Cycloserine
Rifampin
Ethambutol
Antileprotic agents
A) Sulfones:
O
H2N
S
NH2
O
Dapsone:Di-(4-aminophenyl)sulphone.
• The drug of choice for the treatment of leprosy.
• In addition to the antileprotic effect, dapsone has also
antimalarial and antileshmanial activities.
Mode of action:
• Acts by a mechanism similar to sulfonamides.
Evidences:
• PABA partially antagonizes the action of sulfones.
• Cross resistance between sulfonamides and sulfones.
Disadvantage:
• Poor solubility
poor formulation
Dapsone prodrugs (soluble dapsone
analogs):
Solapsone:Tetrasodium salt of Bis[4-(3phenyl-1,3disulphopropylamino)phenyl]sulphone
O
SO3Na
HN
S
NaO3S
NH
O
SO3Na
NaO3S
Solapsone undergoes acidic hydrolysis in the
stomach to release dapsone which is the active
antileprotic drug.
Synthesis of Dapsone
2 Cl
NO2
Na2S
O2N
S
NO2
OXID
K2Cr2O7
Dapsone
RED
Zn / HCl
O2N
O
S
O
NO2
Synthesis of Solapsone
O
H2N
S
O
NH2
condensation with 2 cinnamaldehyde
H
C
H
C
O
S
O
N
CHO
N
4NaHSO3
SO3Na
NaO3S
HN
O
S
O
NaO3S
Solapsone
NH
SO3Na
SAR of sulphones ( dapsone):
1) of the six isomers of diaminodiphenylsulphones only 4,4- is the active
one.
2) additional substitution of phenyl ring cause loss of activity.
3)N-alkyl and N-acyl derivatives retain activity due to deacylation and
dealkylation in vivo.
4)replacement of aminophenyl group with alkyl or aryl or heterocyclic
group will cause loss in activity.
5)activity is exhibited by several mono and bis
Schiffs base of aromatic aldehydes and aldehyde-bisulphite complexes as
in glucosulphone, and glucosulphone has weak activity in vitro as no
hydrolysis which regenerate ACTIVE DAPSONE.
6) sulphone group is essential for activity.
B) Miscellaneous agents:
Clofazimine:N,10-bis-(4-chlorophenyl)-2,10-dihydro-2[1-methylethylamino]-3-phenazinamine
• A phenazine dye
• Binds preferntially to
mycobacterial DNA
• Teratogenic
Cl
Thiambutosine:
N
N
N
N
H
Cl
• A thiourea derivative
• N-(4-butoxyphenyl)-N- -(4dimethylaminophenyl)thiourea
BuO
N
S
N
H
Other agents used for leprosy:
• Isoniazid, ethionamide, rifampin
N
H
The American Medical Association
“AMA” states:
• Treatment of leprosy is difficult and
complex.
• A combination of dapsone / clofazimine
/ rifampin should be used.
• Therapy duration = 5 years – life time.