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1
Sulfonamides
• In1930s, Domagk took Ehlrich's ideas (Bayer’s plan) of
using dyes as antimicrobial agents and expanded it to
azodyes and came up with Prontosil.
• His idea was that these dyes would work like Gram
stains, taken up by bacteria but not mammalian cells.
NH2N
N S
O
O
NH2
NH2
Prontosil
2
Sulfonamides
• It showed a remarkable activity against streptococcal
infections.
• But when he tried it on isolated bacterial cells, it showed
no activity?
• Later, he found out that prontosil is not active by itself,
but that it is metabolized by reductases to give the active
form of the sulfonamide.
• Thus came up with the principle of prodrugs in medicine.
• Sulfanilamide was synthesized in 1908 but never tested
for antibacterial activity.
4
MOA• They are synthetic compounds that get their specificity
from depletion of folic acid stores in bacterial cells.
• Mammalian cells are unaffected since they obtain their
folic acid from diet.
• Folic acid is important as a one carbon source in many
essential biochemical pathways.
• Its biosynthesis involves the synthesis of dihydropteroic
acid from pteridine and para-Aminobenzoic acid (PABA),
a step catalyzed by dihydropteroate synthase (DHPS).
• Several steps ensue resulting in the formation of
dihydrofolic acid, that is finally reduced to tetrahydrofolic
acid by dihydrofolate reductase (DHFR)
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MOAN
N
N
HN
CH2O
OH
H2N
P
O
O-
O P
O
O-
O-
CH2N
O
OH
PABA
DHPS
N
N
N
HN
OH
H2N
HN COOH
N
N
N
HN
OH
H2N
HN CO Glu
DHFR NADPH
N
N
NH
HN
OH
H2N
HN CO Glu
Pteridine
-PPi
Dihydropteroic acid
Tetrahydrofolic acid
Dihydrofolic acid
6
MOA
• In most bacterial species Sulfonamides are competitive
inhibitors of DHPS, an enzyme present exclusively in
bacterial cells.
• Sulfonamides are incorporated in place of PABA in the
enzyme active site leading to faulty products
• In both cases, the resulting low Folic acid pool will have
many damaging effects including failure in biosynthesis
of purine and thymylidate nucleotides (as Folic acid
supplies carbons during their biosynthesis) and
eventually inhibiting DNA synthesis.
7
MOA
• They are bacteriostatic in nature and have a broad
spectrum, but show poor activity against Pseudomonas,
enterococci and anaerobes.
• They are slow to act, since several generations are
needed before appreciable depletion of folate pool and
inhibition of growth.
8
General Characteristics
• The activity of sulfonamides depends on their
lipophilicity, which determines:
– ability to get inside the bacterial cell.
– their ionization at physiological pH.
• They have to be ionized to resemble PABA, to be better
incorporated into the active site of the enzyme and to
cause its inhibition.
• Their main use has been in the treatment of acute,
uncomplicated UTI, particularly those caused by
Escherichia coli.
9
Combination Therapy
• It has been suggested that a combination of a
sulfonamide with trimethoprim (dihydrofolate reductase
inhibitors) will have a synergistic effect since they act on
successive steps in the same biochemical pathway.
• If the bacteria would overcome one inhibited enzymatic
step, it would be extremely unlikely that it can pass the
second.
• In addition it is highly unlikely that resistance to both
drugs would arise.
10
Combination Therapy
• A fixed ratio (1:5) of these agents is used in UTI, otitis,
MRSA, bronchitis, and sometimes employed in typhoid.
• It has also found application in Pneumocystis carinii
Pneumonia (PCP) in AIDS patient, a condition that can
be fatal in such immuno-compromised patients.
11
SAR
• The amine and sulphonamide groups have to be para to
each other.
• The amine has to be unsubstituted.
• If the benzene ring is changed to any other ring, the
compound loses activity.
H2N S
O
NH2
O
12
SAR
• The amide is less active than the sulphonamide.
• Changes are allowed on the sulfonamide side:
– Monosubstitution on the sulfonamide may increase
activity (the compound still has one hydrogen to
donate and is capable for ionization) and modify
pharmacokinetic properties
– Disubstitution will abolish activity.
13
Pharmacokinetics
• They are well absorbed orally
• They are excreted in urine as the inactive acetylated
form.
• They diffuse freely throughout the body tissues and may
be detected in urine, saliva, sweat, bile, cerebrospinal,
peritoneal, ocular, synovial fluids, and in pleural.
• It crosses the placenta into the fetal circulation and low
concentrations have been detected in breast milk.
• Some Sulfonamides are not absorbed orally and are
used in GIT infections.
14
Toxicity
• Crystalluria, which can potentially lead to kidney
damage.
• The reason for this problem is that unsubstituted
sulfonamides will have low solubility around pH 6–7.
• Solutions:
– Increase urine flow (give plenty of fluids)
– Increase the pH of urine to around 10 using sodium
bicarbonate
– Use a combination of lower doses of sulfonamides
where each has its own solubility.
16
Sulfadiazine
• Sulfadiazine is readily absorbed.
• It is effective against susceptible organisms in bladder
infections, ear infections, or bronchitis.
H2N S
O
NH
O
Sulfadiazine
N
N
17
Sulfacetamide
• Sulfacetamide is used, in combinations, in preparations
for vaginal, eyes, and skin infections.
H2N S
O
NH
O
Sulfacetamide
CH3
O
18
Sulfamethizole
• Sulfamethizole is readily absorbed from the
gastrointestinal tract.
• It is a short-acting sulfonamide that is given by mouth in
the treatment of infections of the urinary tract, sometimes
in combination with other antibiotics.
H2N S
O
NH
O
Sulfamethizole
S
NN
CH3
19
Sulfamethoxazole
• Sulfametoxazole is readily absorbed from the
gastrointestinal tract.
• About 70% is bound to plasma proteins.
• Combination with trimethoprim due to similarity in t1l2
• (Chemotrim- Septazol- Entrim- Cortil- Co trimthoxazole- Sutrim)
H2N S
O
NH
O
Sulfamethoxazole
NO
CH3
20
Sulfadoxine
• Sulfadoxine has a half life of 4 - 9 days, and thus is a
long acting agent.
• It is used as a second line in the prophylaxis of
Pneumocystis carinii pneumonia (PCP) in AIDS patients,
and as an antimalarial agent.
H2N S
O
NH
O
Sulfadoxine
N
N
H3CO OCH3
21
Anti-Mycobacterials
• Mycobacterium are characterized by a complex cell
wall that is highly hydrophobic due to a high lipid content,
with a backbone made of mycolic acid, D-arabinose and
peptidoglycan
R1
R2
HO
COOH
Mycolic Acid
R1, R2: large fatty acid chains
CH3
H
OH
H OH
OH H
O
HO
D Aarabinose
22
Anti-Mycobacterials
• The cell wall shows low permeability, preventing many
antibiotics from being effective.
• It is identified as an acid fast Bacilli, where the cell wall
can be stained but not destained by acids.
23
TB
• Mycobacterium causes two major diseases, leprosy and
tuberculosis.
• It is estimated that one third to one half of the world
population is infected by Mycobacterium tuberculosis
and that 6% of all deaths worldwide is due to this
disease, making it the most deadly infectious bacterial
disease.
24
Isoniazid (INH) (Isocid forte)
• Synthetic agent used since 1950s.
• It is bactericidal against replicating bacteria, and
bacteriostatic against non-replicating bacteria.
• Its mechanism of action is still debated, but it is obvious
that it acts by inhibiting cell wall biosynthesis, since
bacteria treated with this agent lose their acid fast ability.
N
O NHNH2
Isoniazide
25
Isoniazid
• It is converted to isonicotinic acid and isonicotinamide in
bacterial cells via the action of a bacterial enzyme, katG.
N
O NHNH 2
Isoniazide (Nydrazid)
KatG
Catalase Peroxidase
N
O OH
N
O NH2
Isonicotinic Acid Isonicotinamide
26
Isoniazid
• It is proposed that the intermediates produced in this
reaction are reactive acylating species, which are
responsible for the antimicrobial activity.
N
O NHNH 2
Isoniazide (Nydrazid)
KatG
Catalase Peroxidase
N
O OH
N
O NH2
Isonicotinic Acid Isonicotinamide
N
O N NH
N
CO .
N
C
O O
O.
N
C
O O
OH
27
Isoniazid
• The acylating species are thought to interfere with
mycolic acid biosynthesis, possibly through acylating
NADH, a cofactor essential in the double bond reduction
during the elongation of the fatty acid side chain
N
H H
R
H3C
O
Acylating Species form
INH Oxidation
NADH
N
H
R
H3C
O
Acylated NADH
O
N
28
Isoniazid• This agent is orally absorbed, but food and antacids,
especially those containing aluminum, interfere with
absorption.
• Metabolism takes place via n-acetyl transferase that
yields inactive acetylated metabolites.
• Further metabolism will yield acetyl-hydrazide, which has
been implicated as a hepatotoxic compound.
N
O NHNH 2
N-Acyteylation
N
O NH NH C
O
CH3
NH2 NH C
O
CH3
Acetyl Hydrazide
(hepatotoxic)
29
Rifamycins
• Isolated from Streptomyces.
• Effective against a wide variety of bacteria, including
Mycobacterium, but cannot penetrate gram negative
cells.
• They inhibit bacterial RNA polymerase by binding to the
β-subunit of the enzyme, and block RNA synthesis.
• They are highly effective against rapidly dividing
Mycobacterium.
30
Rifamycins• They bind reversibly to RNA polymerase via three binding
points:
– Hydrophobic interaction between the naphthalene ring
and proteins in the enzyme via a π-π interaction.
– Hydrogen bonding between hydroxyl groups on C21
and C23 with RNA polymerase.
– Chelation with Zinc (which is present within the
enzyme) through the hydroxyl groups at C1 and C8.
31
Rifamycins
O
H3COCO
CH3
H3CO
NH
O
O
OH
N N N CH3
H3C
O
H3C
OH OH
OHOH
CH3 CH3 CH3
CH3
Naphthalene Ring (Hydrophobic interaction
with the enzyme
Hydroxyl Groups
(Hydrogen bonding
with the enzyme)
Hydroxyl Groups
(Chelation with zinc)
32
Rifampin
• Rifampicin, also known as rifampin
• Rifampin is semisynthetic agents that are used in combination with
INH.
• Common side effects include: often turns urine, sweat, and tears a
red or orange color.
• Part of the recommended treatment of active tuberculosis during
pregnancy.
• It works by stopping the making of RNA by bacteria.
O
H3COCO
CH3
H3CO
NH
O
O
OH
N N N CH3
H3C
O
H3C
OH OH
OHOH
CH3 CH3 CH3
CH3
Rifampin
33
Rifapentine
• Considered more active than rifampin, and has a longer
half-life resulting in a less frequent dose regimen.
• It differs in the 3-substitution, which is thought to be
responsible for cell entry, and thus this agent shows
better oral bioavailability.
O
H3COCO
CH3
H3CO
NH
O
O
OH
N N N
H3C
O
H3C
OH OH
OHOH
CH3 CH3 CH3
CH3
Rifapentine
34
Pyrazinamide
• A popular drug used in many combinations, but
unfortunately resistance develops very quickly.
• Its mechanism of action appears to involve its hydrolysis
to pyrazinoic acid via the bacterial enzyme pmcA.
N
N
NH2
O
Pyrazinamide
35
Pyrazinamide• The acid is believed to act as an anti-metabolite of
nicotinamide and interferes with NAD biosynthesis.
• It may also lower the pH inside the organism to a deadly
level.
• It is especially effective against semi-dormant
mycobacterium, and is used in combinations with INH and
rifampin.
• The major side effect is a dose-related hepatotoxicity
• Ricure- Rimstar (Isoniazid- Rifampicin- Pyrazinamide)
• Isorifa- Rifam plus- Rimactazid- Riozid (Isoniazid- Rifampicin)
36
Ethambutol
• Ethambutol is effective against other Mycobacterium
such as M. avium, seen in many HIV patients.
• It inhibits arabinosyl transferase, an enzyme important in
formation of the arabinogalactan portion of the
mycobacterium cell wall.
• It shows synergism with rifampin, possibly due to the cell
wall damage it causes.
C
C2H5
H
CH2OH
HN
NH
C
C2H5
CH2OH
H
Ethambutol
37
Dapsone
• Dapsone has the same mechanism of action and
properties of sulfonamides.
• It is specific to Mycobacterium.
• It is well absorbed but is not very soluble and causes GI
irritation.
• Use mainly to treat leprosy.
S
O
O
H2N NH2
4,4'-Diaminodiphenyl sulfone (Dapsone, DDS)
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