Sulfonamides

(Sulfa drugs)

By
Dr. Hazem Abd El-Hady Ali, Ph.D
Lecturer of Pharmaceutical Chemistry
Discovery
Prontosil:

H2N SO2NH 2
In vivo (bacteria) Sulfanilamide
H2N N N SO2NH 2 +
reductive
cleavage H2N NH 2
NH 2
Prontosil
NH 2

Originally, sulfonamides were synthesized in Germany as azodyes. In an

attempt to expand on earlier ideas of using dyes as antimicrobial agents, a
man by the name of Gerhrard Domagk of Bayern Company in 1930

It is inactive in vitro but in vivo → sulfanilamide (active form) by reductive cleavage
This led to discovery of the first synthetic antibacterial agent
Sulfonamide = Aniline substituted sulfonamides (Sulfanilamides)
Chemistry of sulfonamide: they are classified as

1. Aniline-substituted sulfonamides (sulfanilamides)

2. Prodrugs that give active sulfanilamides (Prontosil)
3. Non-aniline sulfonamide derivatives (Mafenide ) (Sulfamylon)

NH 2

SO2NH 2

Mafenide
Physicochemical properties of sulfa drugs

1- Amphoteric characters:
React as acid & base

O O O
H OH
H3N S NHR H2N S NHR H2N S NR
H
O O O
Resonance stabilized

The deprotonated form (in -OH medium) is more stable due to resonance stabilization
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2-pKa
 The antibacterial activity of sulfonamides is related to pKa.
 Maximal activity would be found in those having a pKa value between 6.0 and 7.5,
since at physiological pH there must be a 1:1 ratio of the dissociated and
undissociated form. This will attain that sulfonamides penetrate the cell wall as un
dissociated molecule and act in ionized form.
3- Protein binding
 Sulfonamides bind differently to plasma proteins.
 For activity, toxicity, metabolism and glomerular filtration, the non bound part is the
significant.
4- Solubility of sulfa drugs
All sulfonamides are insoluble in water except the sodium salts, on the other hand all
sulfonamides are soluble in alkali except sulfaguanidine.

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 SAR
H2N SO2NHR

Change in A
A B C
 Free (N4) NH2 group is essential for activity.
 Removal of NH2 → inactive compounds.
 Replacement of NH2 by another group (e.g. alkyl, alkoxy etc.,)→ abolishes the
activity.
 Shifting NH2 gp to m- or o-position inactive compounds.
 Replacement of NH2 with NO2, NHOH, azo ► prodrugs which upon reduction or
hydrolysis in vivo ► free NH2 (e.g. intestinal sulfa) still retain its activity.
 N4 is best to be N-acyl “prodrug” this will help in;
1. Mask the bitter taste (can be used orally as syrup).
2. Hydrolyzed in vivo to give free active compound.

 Substitution on NH2 by hydrolysable group (e.g. succinyl) produces compound

which active in vivo
 H2N SO2NHR

A B C
Change in B

1. Phenyl group is essential; replacement with naphthalene, anthracene, pyridine or

by another heterocyclic rings or saturation to cyclohexyl → inactive compounds.
2. Substitution on benzene ring by halogen or any other group ► loss of activity.

Change in C

1. SO2NH- group must be directly attached to benzene ring & must be in the 4
position of aniline.
2. SO2NH- group may be free or monosubstituted
3. R should be electron withdrawing group ► ↑ acidity ►↓pKa ► ↑ionization ► ↑activity

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 Mode of action

 The sulfonamides are structural analogs of PABA that competitively inhibit the action
of dihydropteroate synthase (as they compete with PABA at the active site of the
enzyme), preventing the addition of PABA to pteridine diphosphate → inhibit
biosynthesis of DHF and blocking the net biosynthesis of folate coenzymes → inhibit
biosynthesis of thymidine required for DNA .

 This action arrests bacterial growth and cell division → bacteriostatic action
O O
H2N H2N S NR
O O
H-bond H-bond
Ionic bond Ionic bond

van der Waals van der Waals

Humans required folic acid as an essential growth factor and are unable to
synthesize folate from its components, so they get it from food intake.

At physiological pH, folic acid exists as a dianion, which can not cross the
bacterial cell wall by passive diffusion. For this reason these bacteria have to
synthesize folic acid de novo from PABA, and consequently, this process is
inhibited by sulfonamides, producing a bacteriostatic effect. i.e. Sulfonamides
act as a metabolite antagonist.

Dihydropteroate synthase - bacterial enzyme

1. Not present in human cells
2. Important in the biosynthesis of the tetrahydrofolate cofactor
3. Cofactor is crucial to pyrimidine and DNA biosynthesis
4. Crucial to cell growth and division
 Crystallurea & PKa

Sulphonamides and their acetyl derivatives are sparingly soluble in water & excreted
almost in urine → precipitation in kidney → crystalluria

1 6 10.4 14
PKa PKa (drug)-PH(urine)=log [unionized]/[ionized]
pH of
urine
PKa of SO2NH2 group = 10.4
pH of urine is ~ 6 and decrease in bacterial infection which lead to precipitation
of sulfonamides in kidney → sever renal damage
How to solve this problem???
we have to increase ionized concentration by:
1) Increasing urine flow (drinking water)
2) Increasing pH of the urine (by using oral sodium bicarbonate)
3) Preparing derivatives with lower PKa (by N1-subistitution with electron withdrawing
group) (which will not precipitate in at pH 6)
1) Mixing different sulfonamides to achieve the total dose
 Classes of sulfonamides
1- Systemic sulfonamides: [Oral / Absorbable]
A- Short-acting sulfonamides

They are rapidly absorbed & rapidly excreted

Their t1/2 vary from 4 - 7 hours
 B- Intermediate-acting sulfonamides

 Absorption & excretion is slower than the short-acting

 Their t1/2 range from 10-12 hours.
 C- Long-acting sulfonamides

 They are rapidly absorbed & slowly excreted,

 their t1/2 are 35-40 hours.
 They should be used only under extraordinary circumstances.
 Sulfamethoxypyridazine & sulfadimethoxine.
 Sulfonamides for urinary tract infections

 Used for UTI, because they are rapidly absorbed but slowly excreted by the
kidney and thus reach high concentration in UT.
 e.g.: sulfadiazine, sulfaisoxazole, sulfafurazole,, sulfacetamide.
 2- Intestinal sulfonamides; [oral / Non absorbable]
 They are prodrugs designed to be poorly absorbed in large intestine → N4
protecting group cleavage → free sulfonamide[active].
 Used in treatment of intestinal infections, ulcerative colitis, reduction bowel
flora.
Sulfasalazine

Used in treatment of ulcerative colitis (Crohn’s disease)

3- Topical sulfonamides

A- Ophthalmic sulfonamides

NH 2

Sulphacetamide Sodium (Ocusul)®

Na
SO2NCOCH 3

 Highly Water soluble at physiological PH of 7.4

 Uses: in conjunctivitis, superficial ocular infections, trachoma
 B- Topical sulfonamides for burn therapy and infected wounds

 The salt does not penetrate the cell wall but acts on the external cell structure
 Resistance to sulfonamides

Resistance of m.o. to sulfonamide drugs is by:

• The organism develop an alternative pathway for synthesis of folic acid.
• The bacterial cell wall becomes more permeable to folic acid.
• Increase PABA synthesis by m.o. to overcome inhibition of dihydropteroate
synthetase.
 Combination of trimethoprim & sulfa drugs (Co-trimoxazole) (septazole, sutrim),
aim to prevent resistance of bacteria to sulfa drugs.
 This combination has synergistic effect.
NH 2
4 OCH 3
3 N
5
Trimethoprim
H2N 2 N OCH 3
1
OCH 3

2,4-Diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine
M.O.A: inhibits dihydrofolate reductase enzyme,
Combination of sulfonamides with Dihydrofolate reductase inhibitors

Trimethoprim + sulfonamide ►synergistic inhibition

 The combination is used for oral treatment of UTI, Shigellosis, otitis
media and traveler diarrhea
 Trimethoprim has 10,000 fold diference in affinity for bacterial and mammalian
dihydrofolic acid reductase in vivo