Sulfonamides were the first systemic antibacterial agents and remain important today. They work by competitively inhibiting dihydropteroate synthetase, blocking the biosynthesis of folic acid in bacteria. Sulfonamides are structurally similar to para-aminobenzoic acid (PABA), differing by a sulfonamide group attached to the amine. Many individual sulfonamides are used, including sulfamethoxazole, sulfasalazine, silver sulfadiazine, dapsone and sulfapyridine. Sulfonamides are often combined with inhibitors of dihydrofolate reductase for enhanced antibacterial effects. Adverse effects can include crystalluria, r

1. SULPHONAMIDES
GUIDE:
Mrs. T. PRABHA
ASISSITANT PROFESSOR
DEPARTMENT OF PHARMACEUTICAL ANALYSIS
NANDHA COLLEGE OF PHARMACY
ERODE-52
AMEERA.N
III PHARM D
NANDHA COLLEGE OF PHARMACY
ERODE-52

2.  Sulfonamides derived from p-amino benzene sulfonamide.
 It is the first chemotherapeutic agents implied systematically for prevention of bacterial
infections.
HISTORY:
 Screening of ‘dyes’ for their actibacterial properties in 1920s.
 Sulfonamido-chrysidine-commonly known as “prontosil red” was the first one effective in
streptococcal infection in mice by Domagk.
 cured his daughter.
 1937-prontosil was broken down to release “sulfanilamide”-many sulfonamides were produced.

3. CHEMISTRY OF SULPHONAMIDES:
■ Recognised since 1932.
■ In clinical usage since 1935.
■ First compound found to be effective antibacterial agents in safe dose ranges.
■ Chemically,it is a molecule containing sulfonamide(sulfanilamide , SO2NH2) functional
group attached to an analine.
■ Structurally related to p-amino benzoic acid (PABA).
■ This group is also present in other non-antibacterial compound like sulphonureas ,
benzothiazids , furosemide , acetazolamide.

4. NOMENCLACTURE OF THE SULFONAMIDES:
■ Sulfonamides is a generic term that denotes 3 different cases:
1. Antibacterials that are analine-substituted sulfonamides (sulfanilamides)
2. Prodrug that react to generate active sulfanilamides(sulfasalazine)
3. Nonanaline sulfonamides (mefenide acetate)

5. SYNERGISM OF SULFONAMIDE AND FOLATE
REDUCTASE INHIBITORS:
■ If biosynthesis of bacterial folate coenzymes is blocked at more than one point in the
pathway , the result will be a synergistic antimicrobial effect.
■ This is beneficial because the microbe will not develop resistance as readily as it would
with a singly blocked pathway.
■ The synergistic approach is used widely in antibacterial therapy with the combination of
sulfamethoxazole and trimethoprim
■ In antimalarial therapy with pyrimethamine plus a sulfonamide or quinine
.

6. THE PROBLEM OF CRYSTALLURIA
■ Sulfonamides are mostly excreted in urine as acetylated metabolite.
■ They are relatively water insoluble mainly due to the formation of acetylated
metabolites.
■ The acetylated metabolite is non-ionizable under the PH conditions of the urine(~7) that
increase the possibility of precipitation and the formation of crystals in the urine.
How to minimize the possibility of crystalluria formation with
sulfonamides:
 Increase the urine flow.
 Increase the PH of the urine to increase the ionization of sulfonamides and the formation
of water soluble salts.

7. ■ Lowering the Pka of the sulfonamide group which will help to increase the ionization under the
acidic conditions . This can be done by adding electron withdrawing group on the sulfonamide
side chain.

8. CLASSIFICATION
c)Agents which are employed topically
■ Mefenide
■ Sodium sulfacetamide
■ Silver sulfadiazole
ON THE BASIS OF:
 PHARMACOKINETIC
PROPERTIES:
a)Agents which are rapidly absorbed and
excreted:
■ Sulfamethaxazole
■ Sulfisoxazole
■ Sulfapyridine
■ sulfadiazine
b)Agents which are poorly absorbed in
GIT (local):
■ Sulfasalazine
■ Phthalyl sulfathiazole

11. STRUCTURALACTIVITY RELATIONSHIP:
■ The amino and sulfonyl radicle on benzene ring are essential for the activity and should be in 1 ,4 position.
■ The 4 amino group should be modified to produce prodrug which are converted into 3-amino functional group
invivo.
eg: phthalyl sulfathiazole
succinyl sulfathiazole
■ Replacement of benzene ring by another ring system or the introduction of additional subsituent on benzene
ring will decrease the activity.
■ Exchange of sulfonyl group (-SO2NH2) by other group like SO2C6H4(-P-NH2) ,CONH2,
CONHR, COC6H4R, to retain the activity.

12. ■ Subsitution of hectrocyclic aromatic nuclei at 1st position yield highly potent compound.
■ 1st position disubsitution in general leads to inactive compound because one hydrogen is
needed for ionization.
■ The pi charge of first position activity greater the charge greater the activity.
■ The protein binding like arginine, histidine, lysine, on basic center of sulfonamide will
affect the activity,because protein binding appear to modulate the bioavailability of drug
and its t1/2.

13. MECHANISM OF ACTION OF SULFONAMIDES:

14. ■ Sulfonamides and sulfones in antibacterial agents act as a
competitive inhibitor for incoperation of PABA to form
dihydropteroic acid.
■ The 1st position substitution in sulphonamide compete for site on
enzyme surface reserved for glutamate residue.
■ It compete for linking of PABA glutamate with pteridine
derivative.
■ Trimethoprim is a structural analogue of dihydrofolic acid.It is a
selective competitive inhibitor of microbial folate reductase,the
enzyme that reduces dihydrofolate to tetrahydrofolate.
■ Simultaneous administration of sulphonamides and trimethoprim
block the pathway of synthesis of tetrahydrofolate and producing
synthetic antimicrobial effect.

15. SULFADIAZINE
STRUCTURE

17. SULFASALAZINE
STRUCTURE

18.  DOSE:
3-4g / day in divided doses.
 DOSAGE:
500 mg Tablet
 ADVERSE EFFECT:
Gastric distress , oligospermia , anorexia , headache .
 USES:
Used in the treatment of ulcerative colitis and inflammatory bowel disease.
STRUCTURE
SULFAMETHOXAZOLE

19. SYNTHESIS
DOSE:
Orally 2 g followed by 1 g 8 hour.
DOSAGE:
Oral 500mg or 1g tablet

20.  ADVERSE EFFECTS:
 mental/mood changes
 extreme drowsiness
 sweating
 fast heartbeat
 USES:
• Used in the treatment of bacterial infection.
• Used in lower urinary tract and systemic infections caused by E.coli and p.Mirabilis.
• Used in combination with trimethoprim is used in treatment of several infections
including AIDS.
• It is also used to prevent and treat a certain type of pneumonia.

21. SULFAMETHIZOLE
SYNTHESIS
STRUCTURE

22.  DOSE :
500-1000mg 3-4 times daily
 DOSAGE:
500 mg tablet
 USES:
Gram-Negative Bacterial infection
Gram-Positive Bacterial Infections.
Urinary Tract Infections.
SILVER SULFADIAZINE
STRUCTURE

23.  DOSAGE:
1% cream.
 USES:
Used to prevent skin infections after burns .
Used to treat infected leg ulcers or pressure sores.
SYNTHESIS

24. SULFACETAMIDE SODIUM
SYNTHESIS
STRUCTURE

25.  DOSAGE:
Ophthalmic solution : 10% , 15% , 30%
Ointment :10%.
 ADVERSE EFFECT:
Hypersensitivity reactions , myopia , burning conjunctivitis , corneal ulcers , irritation, stinging.
 USES:
Used to treat bacterial eye infection like conjuctivitis.
DAPSONE
STRUCTURE

26.  DOSE:
50 mg daily
 DOSAGE:
25mg and 100mg tablets
SYNTHESIS

27.  ADVERSE EFFECT:
unusually fast heartbeat, bluish lips/skin, chest pain, mental/mood changes,
muscle weakness, difficulty urinating.
 USES:
used to treat a certain type of skin disorder (dermatitis herpetiformis).
It is also used with other drugs to treat Hansen's disease.
.
SULFASOXAZOLE
STRUCTURE

28.  DOSE:
4-6g daily 2-3 divided doses
 DOSAGE:
500mg tablet
 ADVERSE EFFECT:
Stomach pain , dizziness , rashes , headache , diarrhea
 USES:
Used to treat a certain type of bowel diseases called ulcerative colitis.
SULPHAMETHAZINE
STRUCTURE

29.  DOSE:
3-4 g daily in divided dose
 DOSAGE:
500mg tablet
 ADVERSE EFFECT:
Gastric distress , headache , nausea , oligospermia , vomiting , anorexia.
 USES:
Used for treatment of bacterial infections causing bronchitis , prostatitis and urinary
tract infection.
Used for pneumococcal ,staphylococcal and streptococcal infections.
Used in sepsis , gonorrhea and other infectious disease.

30.  DOSE:
250mg-1g 4 times aday for dermatitis herpetiform.
 DOSAGE:
250mg capsule
 ADVERSE EFFECT:
Fever , crystalluria ,blood dyscariasis , thyroid function disturbances , hypersensitivity.
 USES:
Used for the treatment of dermatitis herpetiformis,pemphigoid,bullous and pyoderma
gangrenosum.
SULFAPYRIDINE
STRUCTURE

31.  DOSE:
5% solution of mefenide chloride or mefenide propionate for topical use.
 DOSAGE:
Mefenide actetate cream
 ADVERSE EFFECT:
Allergic reactions , bleeding or oozing of skin , metabolic acidosis.
 USES:
 Used alone or with combination with other medication to prevent or treat wound
infections.
Used in the treatment and cure of gas gangrene . Also effective against clostridium
welchii on topical application .
MEFENIDE ACETATE
STRUCTURE

32.  DOSE:
2g per day in equally divide dose
 DOSAGE:
500 mg tablet
 ADVERSE EFFECT:
Decreased appetite , stomach upset or stomach pain , aching of joints , headache , photosensitivity,
rashes.
 USES:
Used to treat certain type of bowel disease called ulcerative colitis.
Delayed –release tablets of sulfasalazine used to treat rheumatoid arthritis
SULFASALAZINE
STRUCTURE

33.  ADVERSE EFFECT:
Headache , loss of appetite , stomach upset , nausea and vomiting .
 USES:
Used as antileprotic drug .It is less potent than dapsone and is used when there is a
gastric intolerance of dapsone.
SOLAPSONE
STRUCTURE

34. MIXED SULFONAMIDES
 TRISULFAPYRIMIDINES,ORAL SUSPENSION:
The oral suspension of trisulfapyrimidne contains equal weight of sulfadiazine ,
sulfamerazine and sulfamethazine either with or without an agent to raise the PH of
urine.
 TRISULFAPYRIMIDINES,TABLET:
Trisulfapyrimidine tablet contain essentially equal quantities of sulfadiazine ,
sulfamerazine and sulfamethizine .
 SULFADOXINE AND PYRIMETHAMINE:
The mixture of sulfadoxine and pyrimethamine is used to treat of P.falciparum
malaria in patients in whom chloroquine resistance is suspected .
It is also used for malaria prophylaxis for travelers to areas where chloroquine-
resistant malaria is endemic.

35. REFERENCE:
■ TEXTBOOKOF MEDICINALCHEMISTRY BY V.ALAGARSAMY.
■ MEDICINALCHEMISTRY BY ASHUTOSH KAR
■ https://www.researchgate.net/publication/321938118_Sulfonamides.