Lec.

9
Sulfonamides

- The sulfonamide antimicrobial drugs were the first effective

chemo- therapeutic agents that could be used systemically to
cure bacterial infections in humans.

- Their introduction led to a sharp decline in the morbidity

and mortality of infectious diseases.

4-Amino-N-substituted-benzene sulfonamide
 - Prontosil was the first sulfonamide synthesized in 1935
which produced in vivo antibacterial activity.

- It was found that this compound metabolized by

bacteria present in the small intestine to produce the
effective sulfonamide.

Mechanism of action
- Sulfonamides inhibit folate synthesis through inhibition of dihydro-
pteroate synthetase enzyme.

+ +

Dihydropteroate
Synthetase

O OH
O

OH
O N
H Dihydrofolic acid
N O
HN N
H

H2N N N Dihydrofolate
H
Reductase
O OH
O

OH
O N
H H
N O
HN N
H Tetrahydro folic acid
H2N N N
H
Cont.
The sulfonamide molecule is similar enough in structure to PABA
that the enzyme is fooled into accepting it into its active site.

- Once it is bound, the sulfonamide prevents PABA from binding.

- As a result, folic acid is no longer synthesized. Since folic acid is
essential to cell growth, the cell will stop dividing.

SAR of Sulfonamides
The synthesis of a large number of sulfonamide analogues led to
the following conclusions:

- The p -amino group (N4) is essential for activity and must be

unsubstituted .
-The only exception is when N-substituted with acyl (i.e. amides).
-The acylation of p -amine group will metabolized in the body to
regenerate the active compound, thus amides can be used as
sulfonamide prodrugs.
Cont.
- The aromatic ring and the sulfonamide functional group
are both required.

- The – SO2NH2 group must be directly linked to the

benzene ring.
-The aromatic ring must be para-substituted only.

- The sulfonamide nitrogen must be primary or

secondary.

- Substitution with N1 is the only possible site that can be

varied in sulfonamides which produce variable effects on
the antibacterial activity.

Crystalluria and the pKa

- Sulfanilamides and their metabolites (usually acetylated at N4) are
excreted almost entirely in the urine.
- The pKa of the sulfonamido group of sulfanilamide is 10.4, so the pH at
which the drug is 50% ionized is 10.4
- Because the urine is usually about pH 6 (and potentially lower during
bacterial infections), essentially all of the sulfanilamide is in the
relatively insoluble (non-ionized form) in the kidneys causing
crystalluria.
Cont.
- Early approaches to adjust the solubility of sulfanilamide in the urine
as in the following:

1- Greatly increasing the urine flow. During the early years of

sulfonamide use, patients taking the drugs were cautioned to “force
fluids.” The idea was that if the glomerular filtration rate could be
increased, there would be less opportunity for seed crystals to form in
the renal tubules.
2- Increasing the pH of the urine using oral sodium bicarbonate. The
closer the pH of the urine is to 10.4 (for sulfanilamide itself), the more
of the highly water-soluble salt form will be present.
3- Preparing derivatives of sulfanilamide that have lower pKa values,
closer to the pH of the urine. This approach has been taken with
virtually all sulfonamides in clinical use today.

Cont.
- The newer, semisynthetic sulfonamides possess lower pKa values
because of the electron-withdrawing properties of the heterocyclic rings
attached to N1 and also providing additional stability for the salt form.
Hence, the drugs donate a proton more easily, and the pKa values are
lowered.

- Various electron withdrawing groups were extensively investigated but

some of them found to be too toxic, poorly active, or both.

- In addition to the benefit beyond withdrawing groups against

crystalluria, the reduced pKa is closely related to the pKa of PABA which
augment the antibacterial activity of the resultant compound.
Cont.

Acidity Increases

Classes of Sulfonamides

Sulfonamides

Systemic Intestinal Ophthalmic Sulfonamides

Sulfonamides sulfonamides sulfonamides for burn therapy

Intermediate-
Short-acting Long-acting
acting
Sulfonamides sulfonamides
sulfonamides
 I. Systemic Sulfonamides
According to their duration of action they are
divided to:
- Short-acting Sulfonamides
- Intermediate-acting sulfonamides
- Long-acting sulfonamides

A) Short-acting Sulfonamides
• They are rapidly absorbed and rapidly excreted. Their half lives from 4-7 hours
and they are administered every 4 to 8 hours.
 B) Intermediate-acting
sulfonamides
• They are absorbed and excreted more slowly than short-acting.
• Their half lives range from 10 to 12 hours so they are given twice daily.

C) Long-acting sulfonamides

• They are rapidly absorbed but slowly excreted their half

lives are 35 to 40 hours.
 II. Intestinal sulfonamides
- Such compounds also known as sulfonamide prodrugs, for example
sulfasalazine.

❖ Sulfasalazine is mainly used for treatment of inflammatory bowel disease,

including ulcerative colitis and Crohn's disease. It is also effective in several types of
arthritis, particularly rheumatoid arthritis.
❖ Reductive metabolism by means of azoreductase enzyme converts the drug to
sulfapyridine and 5-aminosalicylic acid (anti-inflammatory) both components are
active.

Ophthalmic sulfonamides
• They are used in treatment of conjunctivitis and
other superficial ocular infections.
 IV. Sulfonamides for
Burn Therapy
• Mafenide is not a true sulfonilamide, it is not effective
systemically, but is particularly effective topically in the
treatment of burns or for healing infected wounds.

O
NH2
S
O
H2N

Mafenide
4-(Aminomethyl)benzenesulfonamide

cont.

• Silver sulfadiazine is used as effective topical

antimicrobial agents, especially against Pseudomonas
bacteria in burn therapy, where treatment failure with
other drugs may occur.
+
Ag
O -
N N
S
O N

H2 N
Silver sulfadiazine
- Sulfonamide drugs can be given in mixture form to give
synergism in activity and to reduce side effects, for example a
triple sulfa vaginal cream (sulfabenzamide, sulfacetamide,
and sulfathiazole) which is used for Gardnerella vaginalis
infections.

- Sulfonamides are used also in combination with other drugs, for

example Sulfamethoxazole and Trimethoprim.
- There is a synergistic effect obtained from such combination.
- When taken orally the tablet has a standard ratio of
5 : 1
40 mg of the sulfa and 8 mg trimethoprim.
- Both drugs are excreted in urine their half lives are about 8-10 hours.
 Antiprotozoal agents
-Protozoa are microscopic unicellular eukaryotes that have a
relatively complex internal structure and carry out complex
metabolic activities.
-Most species are free living, but some are parasitic on other
organisms. Infections range from asymptomatic to serious
disease. Life threatening conditions, depending on the species
and strain of the parasite and the resistance of the host.
- Protozoal diseases are highly prevalent in tropical Third
World countries, where they infect both human and animal
populations, causing suffering, death, and enormous
economic hardship. The most common protozoal diseases are
malaria, amebiasis, giardiasis, trichomoniasis, toxoplasmosis,
and, as a direct consequence of the AIDS epidemic, P. carinii
pneumonia (PCP).

Antiprotozoal Medications
1- Metronidazole:
- 2-Methyl-5-nitroimidazole-1-ethanol is the most useful of a
group of antiprotozoal nitroimidazole derivatives that have
been synthesized in various laboratories throughout the
world.

- It is particularly active against Gram-negative anaerobes,

such as Bacteroides and Fusobacterium spp. It is also effective
against Gram-positive anaerobic bacilli (e.g., Clostridium
spp.) and cocci (e.g., Peptococcus, Peptidostreptococcus
spp.).
Cont.
- Because of its bactericidal action, metronidazole has
become an important agent for the treatment of serious
infections (e.g., septicemia, pneumonia, peritonitis, pelvic
infections, abscesses, meningitis) caused by anaerobic
bacteria.

- It has been speculated that a reactive intermediate formed

in the microbial reduction of the 5-nitro group of Metro-
nidazole covalently binds to the DNA of the microorganism,
triggering inhibition of protein synthesis leading to lethal
effect. Potential reactive intermediates include the nitroso,
hydroxylamine, and amine.

Diloxanide furate
- It is the 2-furoate ester of 2,2-dichloro-4-hydroxy-N-methyl-
acetanilide. It was developed as a result of the discovery that
various α, α-dichloroacetamides possessed amebicidal
activity in vitro.
- Diloxanide itself and many of
its esters are also active, Non-
polar esters of diloxanide are
more potent than polar ones.

- Diloxanide furoate has been used in the treatment of

asymptomatic carriers of E. histolytica. Diloxanide furoate is a
white crystalline powder. It is administered orally as 500-mg
tablets.