Description of sulfonamides with their nomenclature, classification mode of action, structure activity relationship, adverse effects and uses

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

4. -unicellular eukaryotic
-No photosynthesis
-Responsible for diseases- Malaria,
Chagas’ disease, leishmaniasis,
amoebic dysentry, African sleeping
sickness
4

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

8. Microorganisms release waste
material during metabolism
Reaction from the host
to these metabolites
PATHOGENICITY
8

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

14. Bacteria
14

15. Typical infections
Organism Gram Infections
S. aureus Positive Skin & tissue infections,
septicemia, endocarditis, 25% of
hospital infections
Streptococcus Positive Sore throat, upper respiratory
tract infections, pneuminia
E. coli Negative Urinary tract & wound
infections, common in GIT and
after surgery, 25% of hospital
infections
Proteus Negative Urinary Tract Infections
Salmonella Negative Food poisoning, typhoid
15

16. Organism Gram Infections
Shigella Negative Dysentery
Enterobacter Negative Urinary Tract Infections,
Respiratory Tract Infections,
septicemia
Pseudomonas
aeruginosa
Negative Infections after burns and in
compromised persons like
cancer etc, chest infections
Haemophilus
influenzae
Negative Chest and ear infections,
meningitis
Bacteroides fragilis Negative Septicemia following surgery
16

17. 17

18. History
herbs
soyabean curd
wine
myrrh
inorganic salts
honey
18

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

23. 1945
•Bacitracin
1947
•Chloramphenicol
1948
•Chlortetracycline
23

24. 1952
• Microlides
1955
• Cepholosporins
1952
• Isoniazid
• Antitubercular
1962
• Nalidixic acid
1987
• Ciprofloxacin
24

25. Bacterial cell
25

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

31. 31

32. Mechanism of Antibacterial Action
• Inhibition of cell metabolism (eg. sulfonamides)
• Inhibition of bacterial cell wall synthesis (eg
Penicillins)
• Interaction with plasma membrane(eg.
Polymyxins)
• Disruption of protein synthesis (eg
Aminoglycosides)
• Inhibition of nucleic acid transcription &
replication (eg. Nalidixic acid)
32

33. 33
Mechanism of Antimicrobial Action

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

35. Prontosil
35
H2N N
NH2
N S
NH2
O
O
H2N S
NH2
O
O
Metabolism
Prontosil
Sulfanilamide

36. 36
R1
HN S
NHR2
O
O
Sulfonamide analogues
Saved
Winston Churchill’s
life during Second
World War

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

40. Based on pharmacological activity
• Antibacterial agents
eg. Sulfacetamide, Sulfadiazine, Sulfisoxazole
• Oral hypoglycemic agents
eg. Tolbutamide
• Diuretics
eg. Furosemide, Chlorthalidone, Bumetanide
40

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

46. 46
N
H
N
N
N
H
H2N
O
NH
Dihydropteroic acid
C
NH
O
OH
OH
O
O
Dihydrofolic acid
N
H
H
N
N
N
H
H2N
O
NH C
NH
O
OH
OH
O
O
Tetrahydrofolic acid
Folate
Reductase
Important for DNA synthesis

47. 47

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

54. Crystalluria & pKa
54
S
O
O
NH2H2N
-H
S
O
O
NHH2N S
O
O
NHH2N
10.4pH 1 6 14
Water insoluble
unionized form
Highly water soluble
ionized form

55. Adverse effects
• GIT- nausea, vomitting, anorexia, diarrhoea,
hepatitis
• UT- Oligouria, crystalluria
• Nervous system- headache, dizziness, confusion,
mental depression, peripheral neuritis, optic
neuritis
• Haemopetic system- leucopenia,
thromocytopenia, agranulocytosis
• Hypersensitivity reactions- eruptions, fever,
vascular lesions, serum sickness, jaundice, sore
throat, Steven-Johnson syndrome
55

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

64. 64
H2N S
H
N
O
O
Sulfamethizole
N
N
S
4-amino-N-(5-methyl-1,3,4-thiadiazol
-2-yl)benzenesulfonamide
Half life- 2.5 hr
Used in UTI
H2N S
H
N
O
O
Sulfisoxazole
N
O
4-amino-N-(3,4-dimethylisoxazol-5-yl)benzenesulfonamide
Half life- 6 hr
Used in UTI
(Gram -ve)

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

66. 66
H2N S
H
N
O
O
NN
Sulfachlorpyridazine
4-amino-N-(6-chloropyridazin-3-yl)benzenesulfonamide
Cl
Half life- 8 hr
H2N S
H
N
O
O
Sulfamethoxazole
N
O
4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide
Half life- 11 hr

67. 67
H2N S
H
N
O
O
Sulfasomizole
N
S
4-amino-N-(3-methylisothiazol-5-yl)benzenesulfonamide
H2N S
H
N
O
O
NN
Sulfamethoxypyridazine
4-amino-N-(6-methoxypyridazin-3-yl)benzenesulfonamide
O

68. 68
H2N S
H
N
O
O N
N
Sulfamethoxydiazine
4-amino-N-(5-methoxypyrimidin-2-yl)benzenesulfonamide
O
H2N S
H
N
O
O N
N
Sulfadimethoxine
4-amino-N-(2,6-dimethoxypyrimidin-4-yl)benzenesulfonamide
O
O

69. 69
H2N S
H
N
O
O
Sulfaphenazole
N
N
4-amino-N-(1-phenyl-1H-pyrazol-5-yl)benzenesulfonamide
H2N S
H
N
O
O N
N
Sulfalene
4-amino-N-(3-methoxypyrazin-2-yl)benzenesulfonamide
O

70. 70
H2N S
H
N
O
O N
N
Sulformethoxine
4-amino-N-(5,6-diethylpyrimidin-4-yl)benzenesulfonamide
Sulfadoxine
H2N S NH
O
O
N
4-amino-N-(2,3-dimethoxypyridin-4-yl)benzenesulfonamide
O O

71. 71
HO
Sulfasalazine
HO
O
2-hydroxy-5-((4-(N-pyridin-2-ylsulfamoyl)phenyl)diazenyl)benzoic acid
N N S NH
O
O
N
Prodrug
Poorly absorbable
Break down to m-aminosalicylic acid & sulfapyridine

72. Mixed sulfonamides
• Synergistic antibacterial action
• Prevention of crystalluria
• Trisulfapyrimidine (sulfadiazine, sulfamerazine
& sulfamethazine)
• Sulfadoxine & pyrimethamine- used in
chloroquine resistant malaria
72

73. Topical sulfonamides
• Sulfacetamide sodium- ophthalmic infections
• Sulfisoxazole Diolamine
• Triple sulfa (sulfabenzamide, sulfacetamide,
sulfathiazole)- used for vaginitis
73

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

78. 78
N
N
O
O
O
NH2
NH2
5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine
TRIMETHOPRIM

79. Synthesis of Sulfamethoxazole
79
NH2 NHCOCH3
NHCOCH3
SO2Cl
CH3COOH
(CH3CO)2O
HSO3Cl
Aniline Acetanilide
p-acetamidobenzene
sulfonyl chloride
Step-I

80. 80
NHCOCH3
SO2Cl
+ N
O
NH2
H3C
H2N S
H
N
O
O
Sulfamethoxazole
N
O(i) Pyridine / 1 hr
(ii) HCl / H2O reflux
Step-II
3-amino-5-methylisoxazole