1. The document discusses the structure-activity relationships and mechanisms of action of various sulfonamides and sulfones used as antibacterial agents. 2. Key structural features required for antibacterial activity are identified as the sulphanilamide skeleton with amino- and sulphonyl-groups in the para position of the benzene ring. 3. Various sulfonamides discussed include sulfamethoxazole, sulfisoxazole, sulfapyridine, sulfadiazine, mafenide acetate, sulfasalazine, trimethoprim and dapsone. Their mechanisms, uses, and syntheses are described.

1. MEDICINAL
CHEMISTRY-III

2. SULPHONAMIDES
AND SULFONES
Raj K. Prasad (Gold Medalist)
M. Pharm. (Pharmaceutical Chemistry)

3. · In 1935, Trefouel performed a
structure–activity study on the
sulfonamide azo dyes and concluded that
the azo linkage was reductively cleaved to
release the active antibacterial product,
sulfanilamide.
Raj K. Prasad

4. STRUCTURE–
ACTIVITY
RELATIONSHIPS
(SAR) OF
SULFONAMIDES
Raj K. Prasad

5. 1. Sulphanilamide skeleton is the minimum
structural requirement for antibacterial activity.
2. The amino- and sulphonyl-groups on the
benzene ring are essential and should be in 1 and
4 position.
3. The N-4 amino group could be modified to be
prodrugs, which are converted to free amino
function in vivo. Eg. Phthalyl sulphathiazole
prodrug of sulphathiazole
Raj K. Prasad

6. Replacement of benzene
ring by other ring systems
or the introduction of
additional substituents on
it decreases or abolishes
its activity.
Exchange of the –SO2NH
group by –CONH reduces
the activity.
Raj K. Prasad

7. MOA
Raj K. Prasad

8. SULFAMETHIZOLE
· It is generally used for acute,
uncomplicated infections of the
urinary tract that are caused by
sensitive organisms.
Raj K. Prasad

9. SULFISOXAZOLE
OR
SULFAFURAZOLE
 It pKa value (5.0) almost very close to
that of PABA (i.e., 6.5).
 The acetyl derivative is tasteless
and, therefore, suitable for oral
administration, especially in liquid
preparations.
 it is a prodrug for sulfisoxazole.
Raj K. Prasad

10. Uses
It finds favour in the treatment of
various urinary-tract infections.
Sulfisoxazole Diolamine is used for
instillation of drops or ointment in
the eye for the local treatment of
susceptible infections.
Raj K. Prasad

11. SULPH
AMETH
AZINE
 Because it is more soluble in acid urine than sulfamerazine
is, the possibility of kidney damage from use of the drug is
decreased.
Uses
• This drug is used for pneumococcal, staphylococcal,
and streptococcal infections as well as for sepsis,
gonorrhea, and other infectious diseases
Raj K. Prasad

12. SULFACETAMIDE
• It is used for treating pneumonia, purulent tracheobronchitis,
urinary tract infections, gonorrheal diseases of the eyes in
newborns and adults.
• It also used in the treatment of bacterial infections of urinary tract.
Raj K. Prasad

13. SYNTHESIS
Raj K. Prasad

14. SULPHAPYRIDINE
It is a long-lasting drug.
Several cases of kidney
damage have resulted from
acetylsulfapyridine crystals
deposited in the kidneys. It
also causes severe nausea
in most patients.
Sulfapyridine is acetylated
and hydroxylated in the liver,
followed by conjugation with
glucuronic acid and, for 5-
ASA, acetylation in the
intestinal mucosal wall and
the liver.
Uses
Due of its toxicity, it is used
only for dermatitis
herpetiformis.
Raj K. Prasad

15. Sulfamethoxazole
 It only about 70% of it binds with proteins in the plasma after oral
administration, and it diffuses mostly to tissues and tissue fluids.
 It does not require frequent administration and is also the drug of
choice for many systemic infections.
 It is the preferred compound for combining with trimethoprim
because the t½ of both is similar. However, a high fraction is
acetylated, which is relatively insoluble—crystalluria can occur.
Raj K. Prasad

16. SYNTHESIS
Raj K. Prasad

17. SULPHADIAZINE
 It is readily soluble in dilute mineral acids and
bases. Its pKa is 6.3.
 Sulfadiazine sodium is administered as a 5% solution
in sterile water intravenously for patients requiring
an immediately high blood level of the sulfonamide.
Raj K. Prasad

18. · The Silver salt of this drug is only slightly
soluble and does not penetrate the cell wall but
acts on the external cell structure. Studies using
radioactive silver have shown essentially no
absorption into body fluids.
 This drug is not recommended for
urinary tract infections because of its low
solubility and certain nephrotoxicity.
 It is used in the form of silver salts
(sulfadiazine silver) as an external
antibacterial agent, primarily for treating
burns.
 It is believed that the presence of the
silver ion in the molecule facilitates
increased antimicrobial and wound-
healing action. It slowly releases silver
ions which appear to be largely
responsible for the antimicrobial action.
Raj K. Prasad

19. MAFENIDE
ACETATE
· Mafenide is a homologue of the sulfanilamide
molecule. It is not a true sulfanilamide -type compound,
as it is not inhibited by PABA.
· Its antibacterial action involves a mechanism that
differs from that of true sulfanilamide- type compounds.
· It is not effective orally.
Raj K. Prasad

20. SULFASALAZINE
• Sulfasalazine is a prodrug that is not active in its
ingested form; it hydrolysed in the body to m-
aminosalicylic acid and sulfapyridine.
• The drug is excreted through the kidneys and is
detectable colorimetrically in the urine, producing an
orange-yellow color when the urine is alkaline and no
color when the urine is acid.
• 5-Aminosalicylic acid, like acetylsalicylic acid, is an
inhibitor of prostaglandin biosynthesis and is known to
have therapeutic effect.
Raj K. Prasad

21. Raj K. Prasad

22. TRIMETHOPRIM
Uses
• Trimethoprim has a broad spectrum of
antimicrobial activity. It is 20–100 times more
active than sulfamethoxazole with respect to most
bacterial forms.
• Trimethoprim as a single agent is used only for
the treatment of uncomplicated urinary tract
infections.
Raj K. Prasad

23. SYNTHESIS
Raj K. Prasad

24. Raj K. Prasad

25. COTRIMOXAZOLE
(SULFAMETHOXAZO
LE–TRIMETHOPRIM)
(5:1)
Raj K. Prasad

26. DAPSONE (4,4’-diaminodiphenylsulfone) or
DDS
· Dapsone is used in the treatment of both
lepromatous and tuberculoid types of leprosy.
Dapsone is used widely for all forms of leprosy,
often in combination with clofazimine and rifampin.
Raj K. Prasad

27. SYNTHESIS
Raj K. Prasad

28. THANK YOU
Raj K. Prasad