Sulphonamides- Antibacterial- Medicinal Chemistry-Pharmacy- As Per PCI syllabus lecture Notes

1. SULPHONAMIDES
Dr. Akhil Nagar
RCP-IPER
Shirpur

2. ANTIBACTERIAL SULFONAMIDES
• The sulfonamide antimicrobial drugs were the first effective
chemotherapeutic agents that could be used systemically for
the cure of bacterial infections in humans.
• The development of a combination of trimethoprim and
sulfamethoxazole and the demonstration of its usefulness in the
treatment and prophylaxis of certain opportunistic
microbial infections led to resurgence in the use of some
sulfonamides.
• A series of azo dyes, each containing the sulfonamide
functional group.
• Sulfonamide azo dyes were included in the test series because
they were readily synthesized and possessed superior staining
properties.

3. • The Bayer pathologist–bacteriologist named Gerhard
Domagk began to study a brilliant red dye, later named
Prontosil.
• Prontosil was found to protect against, and cure,
streptococcal infections in mice
• Prontosil was inactive on bacterial cultures but
derivatives was potent inhibitors.
• Prontosil belongs to Domagk with Nobel Prize in
medicine and physiology in 1938.

4. • Structure–activity study on the sulfonamide azo dyes
concluded that the azo linkage was reductively cleaved to
release the active antibacterial product, sulfanilamide.
• All of these findings ushered in the modern era of
chemotherapy and the concept of the prodrug.
• The sulfonamides can be grouped into three classes on
the basis of their use: oral absorbable agents, systemic
distribution, oral nonabsorbable agents such as sulfasalazine,
and topical agents such as sodium sulfacetamide ophthalmic
drops.

5. Nomenclature of the Sulfonamides
Antibacterials that are aniline-substituted sulfonamides (the
“sulfanilamides”).
Prodrugs that react to generate active sulfanilamides
(i.e.,sulfasalazine).
Nonaniline sulfonamides (i.e., mafenide acetate).

6. • The single pKa usually given for sulfanilamides refers
to the loss of an amide proton.
Mechanism of Action of the Sulfonamides:
N5-formyltetrahydrofolic acid,
N5,N10-methylenetetrahydrofolic acid, and
N10-formyltetrahydrofolic acid are intermediates of several
biosynthetic pathways that compose the one-carbon pool in
animals, bacteria, and plants.

7. • A key reaction involving folate coenzymes is catalyzed by the
enzyme thymidylate synthase, which transfers a methyl group
from N5,N10-tetrahydrofolic acid to deoxyuridine
monophosphate to form deoxythymidine monophosphate, an
important precursor to DNA.
• Another key reaction is the generation of formyl groups for the
biosynthesis of formylmethionyl tRNA units, the primary
building blocks in protein synthesis.

8. • The sulfonamides are structural analogs of PABA that
competitively inhibit the action of dihydropteroate synthase,
preventing the addition of PABA to pteridine diphosphate
and blocking the net biosynthesis of folate coenzymes.
• This action arrests bacterial growth and cell division.

12. • The sulfonamide group, SO2NH2, tends to gain stability if
it loses a proton, because the resulting negative charge is
resonancestabilized.

13. Sulphamethizole,
Sulfisoxazole
Sulphapyridine

14. Sulphamethizine Sulfacetamide
Sulfamethoxaole

15. Sulphadiazine
Mefenide acetate
Sulfasalazine

16. Folate reductase inhibitors: Trimethoprim
Cotrimoxazole: Sulfamethoxaole and Trimethoprim
Sulfamethoxaole
Trimethoprim (5-[(3,4,5-trimethoxyphenyl)methyl]-2,4-pyrimidinediamine
4-Amino-N-(5-methyl-3-isoxazolyl)benzenesulfonamide;

17. • Pyrimidinediamineis closely related to several
antimalarials
• trimethoprim as a single agent is used only for the
treatment of uncomplicated urinary tract infections.
• The concern is that when used as a single agent,
bacteria now susceptible to trimethoprim will rapidly
develop resistance.
Sulfones: Dapsone
Diaminodiphenylsulfone;

18. The sulfones are primarily of interest as antibacterial agents,
They are less effective than the sulfonamides. PABA partially
antagonizes the action of many of the sulfones.
Further, infections that arise in patients being treated with
sulfones are cross-resistant to sulfonamides.
Several sulfones have proved useful in the treatment of leprosy.
Sulfones were introduced into the treatment of leprosy after it
was found that sodium glucosulfone was effective in
experimental tuberculosis in guinea pigs.

19. Four variations on this structure have given active
compounds:
1. Substitution on both the 4- and 4-amino functions
2. Monosubstitution on only one of the amino functions
3. Nuclear substitution on one of the benzenoid rings
4. Replacement of one of the phenyl rings with a heterocyclic
ring
• Dapsone (4,4-sulfonylbisbenzeneamine, 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.
• Dapsone is also the drug of choice for dermatitis
herpetiformis and is sometimes used with pyrimethamine for
treatment of malaria and with trimethoprim for PCP