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Sulfonamides
1. SULFONAMIDES
DR. R. S. Chavan
PDEA’s Seth Govind Raghunath sable
College of Pharmacy, Saswad
1
2. MICROBIOLOGY
• Microorganisms
distributed in air, water, soil, the bodies of
living plants and animals and dead organic
matters
• Human body
Mild defense – secretion f endogenous fluids
Strong defense- inflammatory
immunological
2
3. -unicellular organisms (procaryotic)
-Cell contains cell wall, cytoplasmic
membrane , protoplasm, flagella,
capsule, fimbriae etc
-Diverse in nature
-Some can carry out photosynthesis
MICROORGANISMS
3
5. -Ultramicroscopic (0.1 μ to 0.3μ in
diameter)
- Parasitic
- Contains a nucleic acid core & a
protein coat
- Either RNA or DNA
- (smaller size, simpler chemical
composition, lack of metabolic
enzymes, lack of protein synthetic
machinery, & cell dependent
mechanism of multiplication)
5
6. -Eukaryotic
-Can carry out photosynthesis
-Some are unicellular
-Some are multicellular (no
cell differentiation)
-Blue green algae(prokaryotic ,
can carry out
photosynthesis)
6
7. -Multicellular eukaryotic (no cell
differentiation )
-No photosynthesis
-Different shapes and sizes
-Range (single cell yeast to giant
multicellular mushrooms)
-Can form long filaments of
interconnected cells called mycelia
-Cause athlete’s foot, ringworm,
aspergillosis, candidiasis,
histoplasmosis, pneumonia,
meningitis 7
9. • Virulence- measure of pathogenicity of
microorganism
• Infection- microorganism may gain entry to
tissues and release poisonous substance and
may alarm fatal reactions in the host
• Infection spread rapidly in subarachnoid space
• Enzymes present in microorganism contribute
largely in virulence
9
10. Drug resistance
• Major concern
• Due to prolonged or repeated therapy and low
dose suppressive antibacterial prophylaxis
• May be natural or acquired by mutation or
gene transfer
• Cross resistance
10
11. Mechanism of drug resistance
• Decreased drug diffusion due to altered cell
permeability
• Change in structure or function of drug susceptible
microbial enzymes
• Production of new enzymes causing inactivation of
drug
• Drug action terminated by formation of drug
antagonistic metabolites
• Alternate biochemical reactions
• Through mutagenic changes , alteration in receptor
affinity
11
12. Treatment of infections
• Early days
Carbolic , iodine and heavy metals like silver
nitrate, mercuric chloride were used
Need of more effective selective and safe
agents
Highly
toxic
Biochemical differences are
explored for selectivity
12
13. Bacterial Infections
• Major cause of death worldwide
• Development of drug resistance
• Staphylococcus aureus
Escheria coli
Tuberculosis due to AIDS
13
19. • Observed bacteria in
microscope in 1670
Van
Leeuwenhock
• Found bacterial strain
causing fermentation
Pasteur
• Used carbolic acid as an
antiseptic
Lister
19
20. • Identified microorganism responsible
for TB, cholera and typhoidKoch
• Vaccination studied
• Father of chemotherapy
• Principle of magic bulletPaul Ehrlich
20
21. 1910
Paul Ehrlich
Synthesized Salvarsan, first
synthetic antimicrobial agent
Useful in syphilis and
trypanosomiasis
1934
Proflaxine was synthesized
But found to be very toxic
As As
H2N
HO
NH2
OH
NH2N NH2
21
22. 1935
• Red dye Prontosil- sulphonamides
• Effective against systemic bacterial infections
(1928)
1940
• Penicillin (Florey & Chain)
• Toxic fungal metabolite which kills bacteria &
allow fungus to compete for nutrients
1944
• Streptomycin
• Aminoglycosides
22
26. Difference between animal cell &
bacterial cell
Bacterial cell Animal cell
Contains cell wall as well as cell
membrane . Cell wall is crucial for
survival
Contains only cell membrane
Cell does not have defined nucleus Does have
Cell is simple in structure relatively Cell contains variety of structures
called organelles
Biochemistry is different –
Eg. Need to synthesize essential
vitamins , thus need required
enzymes
Acquire vitamins from food
26
27. Bacterial cell wall
• Porous & permeable structure
• Encloses cytoplasmic membrane that act as
physicochemical barrier
• Cytoplasmic membrane-
- 5 to10 mμ thick,
-contains polymerizing enzymes involved in
formation of cell wall & other extracellular
subunits
- encloses protoplasm
27
28. • Function of cytoplasm
To synthesize enzymes & other proteins
necessary for functioning of bacterial cell
• Bacteria contains granules rich in
nucleoprotein, starch, stored glycogen, fat or
lipid
• No. of bacilli are motile due to flagellae
28
29. • Bacterial cell wall-
-composed of diaminopimelic acid, muramic
acid, teichoic acid, amino sugars, amino acids,
carbohydrates and lipids.
-plays fundamental role in life activities of cell
-In drastic situations, protection by spore
formation
29
30. Difference between Gram positive &
Gram negative bacteria
Gram positive Gram negative
Thick cell wall (20-40 nm)
Contains fewer amino acids
Lipid content is less
Thin cell wall (2-7 nm)
Contains more amino acids
Major constituent is
lipopolysaccharide, thus lipid
content is high
Cell wall is composed of
peptidoglycan (amino sugars &
amino acids)
Amino sugars- N-
acetylglucosamine, N-
acetylmuramic acid
Cell wall is more complex
30
34. Sulfonamides
• Antimetabolites
• Prontosil- prodrug
• Effective against Gram positive organisms
especially pneumococci & meningococci
• Sulfonamides (sulfa drugs) are superseded by
penicillin due to narrow range of activity,
toxicity and development of resistance .
34
37. Nomenclature & classification
• Sulfonamides
N1 substituted are clinically useful
• Sulfones
37
H2
4
N S N1
H2
O
O
H2N S
O
O
4,4'-diamonodiphenyl sulfone
NH2
38. Classification based on pharmacokinetics
1. Rapidly absorbed & rapidly excreted (systemic
sulfonamides) eg. Sulfamethoxazole,
Sulfisoxazole, Sulfapyridine, Sulfadiazine
2. Poorly absorbed in GIT
locally acting , used in bowel / colon surgery
eg. Sulfasalazine, phthalylsulfathiazole
3. Employed topically
used in burns eg. Mafenide sod sulfacetamide,
silver sulfadiazine
38
39. Based on chemical nature
• Agents with substituent on amino gr (N4)
prodrugs eg. Prontosil, Solucopticin
• Agents with substituent on amido gr (N1)
more common eg. Sulfadiazine, Sulfadimidine,
Sulfacetamide
• Agents with substituents both on amino gr (N4) and
amido gr (N1)
eg. Succinyl sulfathiazole, Phthalyl sulfathiazole
• Agents with no amino functional gr on benzene
nucleus
Non anilino sulfonamides eg. Mafenide
39
41. Based on duration of action
1. Long acting
half life > 24 hr, Hypersensitivity reaction
eg. Sulfamethoxypyridazine, Sulfamethoxydiazine,
Sulfadimethoxine
2. Intermediate acting
half life = 10 to 24 hr eg. Sulfasomizole, Sulfamethoxazole
3. Short acting
half life < 10 hr eg. Sulfamethizole, Sulfasomidine, Sulfaisoxazole
4. Ultra long acting
half life > 50 hr eg. Sulfalene, Sulfasalazine, Sulfamethopyrazine,
Sulfadoxine, Sulfadimethoxine, Sulfaclomide
(should not be used in renal insufficiency) 41
42. Mechanism of action
• Sulfonamides are competitive enzyme
inhibitors of dihyropteroate synthetase
• Blocks the biosynthesis of tetrahydrofolate
(THF) in bacterial cell
• Sulfonamides are bacteriostatic and not
bactericidal
• Not recommended for patients with
weakened immune system
42
43. • Inhibition is reversible (Bacteria synthesize
more PABA)
• Resistance may develop due to mutation or
decreased permeability of bacterial cell
membrane to sulfonamides
43
Mechanism of action
44. 44
Pteridine Diphosphate
Dihydropteroate ×
Tetrahydrofolate (THF)
Tetrahydrofolate is enzyme cofactor which
provides one carbon unit for synthesis of
pyrimidine nucleic acid bases required for
DNA synthesis
Dihydropteroate
synthetasePABASulfonamides
competes
with PABA
45. 45
N
H
N
N
NH2N
OH
O P O P OH
OHOH
O O
Pteridine Diphosphate
H2N COOH
PABA
Sulfonamides
N
H
N
N
NH2N
OH
NH
Dihydropteroic acid
COOH
48. Success of sulfa drugs
• Based on two metabolic differences between
mammalian & bacterial cells
1. Bacteria have susceptible enzyme
dihydropteroate synthetase which is not
found in humans (THF is obtained from
dietary folic acid)
2. Bacteria lack the transport protein which
carries folic acid across the membrane. It is
present in humans
48
49. SAR
• para amino group is essential for activity and
must be unsubstituted (R1=H) except when
R1=acyl (amides). These are prodrugs which
get metabolized to generate active compound
49
HN S
NHR2
O
O
O
H2N S
NHR2
O
O
-CH3COOH
50. SAR
• Aromatic ring & sulfonamide skeleton are
essential
• Sulfur atom should be directly linked to
benzene ring
• Aromatic ring must be para substituted only
• Sulfonamide nitrogen must be primary or
secondary
• R2 is only possible site that can be varied
50
H2
4
N S N1
H2
O
O
51. Variation in R2
• Large range of heterocyclic & aromatic
structures which affects the extent of protein
binding
• Also affect the solubility of sulfonamides
• Thus variation in R2 affect the
pharmacokinetics rather than mechanism of
action
51
52. SAR
• At N1, with the substituent imparting electron
rich character to SO2 group, bacteriostatic
activity increases and heterocyclic ring
substituent gives high potency.
• Active form is ionized. Maximum activity at pKa
6.6 to 7.4
52
H2N S NH2
O
O
H2N S NH
O
O
+ H
Unionized form Ionized form
53. Pharmacokinetics
• White crystalline , poorly soluble in water, sodium
salts (increase in water solubility)
• Absorbed in intestine
• Protein binding (acetylated deri – more protein
binding)
• Metabolism- acetylation & oxidation
• Acetylated metabolites- no activity, toxic & less water
soluble
• Excretion – in urine (free or glucuronide conjugates)
• Renal failure patients- Toxicity
53
56. • Effects on fetus & neonates- compete with
bilirubin for protein binding, thus increased
bilirubin conc
• Miscellaneous- conjuctivitis, porphyria,
anthralgia, pulmonary eosinophilia,
displacement of drugs due to protein binding
56
57. Bacterial Resistance
• Mutation
• Increased production of PABA
• Increased ability of bacterial cell to inactivate
sulfa drugs
• Production of sulfa drug antagonist
• Decreased bacterial permeability to sulfa
drugs
57
58. Applications of sulfonamides
Relatively common use in
• Pneumonia
• Treatment of urinary tract infections
• Eye lotions in conjunctivitis
• Burn therapy
• Treatment & prophylaxis of cerebral
toxoplasmosis
• Chloroquine resistant malarial
58
59. Less common infections
• Nocardiosis
• Meningococcal meningitis
Generally not useful in
• Treatment of infections of mucous membrane
• Treatment of Gut infections
• Vaginal infection
• Respiratory tract infections
• Rheumatic fever
• Streptococcal infection
59
60. 60
Toxic , not used
Half life- 9 hr
Toxic , not used
H2N S
H
N
O
O
N
Sulfapyridine
4-amino-N-(pyridin-2-yl)benzenesulfonamide
H2N S
H
N
O
O
Sulfathiazole
N
S
4-amino-N-(thiazol-2-yl)benzenesulfonamide
61. 61
Ophthalmological
use
Half life- 7 hr
H2N S
H
N
O
O
COCH3
Sulfacetamide
N-(4-aminophenylsulfonyl)acetamide
Used in meningitis
Half life – 17 hr
H2N S
H
N
O
O N
N
Sulfadiazine
4-amino-N-(pyrimidin-2-yl)benzenesulfonamide
62. 62
Used in GI infections
H2N S
H
N
O
O
C
Sulfaguanidine
NH
NH2
4-amino-N-carbamimidoylbenzenesulfonamide
H2N S
H
N
O
O N
N
Sulfamethazine (Sulfadimidine)
4-amino-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide
Less used
pKa- 7.2
63. 63
Used in GI infections
HN S
H
N
O
O
Succinylsulfathiazole
N
S
C
O
H2C
H2C C
O
OH
4-oxo-4-(4-(N-thiazol-2-ylsulfamoyl)phenylamino)butanoic acid
HN S
H
N
O
O
Phthalylsulfathiazole
N
S
C
O
C OH
O
2-(4-(N-thiazol-2-ylsulfamoyl)phenylcarbamoyl)benzoic acid
65. 65
H2N S N
O
O
Sulfisoxazole Acetyl
N
O
N-(4-aminophenylsulfonyl)-N-(3,4-dimethyl
isoxazol-5-yl)acetamide
O
Prodrug
H2N S
H
N
O
O
N
N
Sulfasomidine
4-amino-N-(2,6-dimethylpyrimidin-4-yl)benzenesulfonamide
74. Topical sulfonamides for burn therapy
• Mafenide Acetate (clostrodium welchii)
• Silver sulfadiazine (pseudomonas)
74
Mafenide Acetate
S NH
O
O
O
H2N
N-acetoxy-4-(aminomethyl)benzenesulfonamide
O
75. Sulfones
• Used in the treatment of leprosy
• Inhibit dihydropteroate synthetase
• Less effective than sulfonamides
• Development of resistance lead to multidrug
therapy (dapsone, rifampicin & clofazimine)
• Prototype- Dapsone
75
76. • Also used for dermititis herpitiformis
• Used with pyrimethamine for malaria
• Adverse effects – hemolytic anemia,
methaemoglobinemia, & toxic hepatitic
effects
76
S
O
O
H2N NH2
4,4'-sulfonyldianiline
Dapsone
77. Dihydrofolate reductase inhibitors
• Trimethoprim
• Orally active diaminopyrimidine
• Highly selective antibacterial & antimalarial
• Usually given in combination with
sulfamethoxazole (co-trimoxazole)
77