The molecular modifications of “Sulfanilamide” have been resulted into about 10,000 compounds and only less than three-dozen of them have attained therapeutic significance.
The nitrogen of “Sulfanilamide” is designated as N1 and that of aniline as N4.
(A). ISOMERIC FORMS OF SULFANILAMIDE:
The ortho and meta isomers i.e. orthonilamide and metanilamide, as well as the corresponding isomers of N1-heterocyclic derivatives are antibacterially inactive both in vivo and in vitro.
Some metanilamides have been proved effective as antimalarials e.g.
2-metanilamide-5-chloropyrimide is 16-times more active against plasmodium gallinaceum than quinine or Sulfadiazine.
(B). SUBSTITUTION OF BENZENE RING:
In general, any substitution of the nucleus of the sulfanilamides leads to loss of activity.
This effect is related to mechanism of action, which requires a basic amino group that should be free to conjugate with sulfamyl group.
For example, 3-carboxyhydrazide is active only against staphylococcus and pneumococcus in vitro.
(C). REPLACEMENT OF THE BENZENE RING:
The benzene nucleus can’t be replace by 5 or 6-membered heterocyclics because the aralkylation with PTERIDYLMETHYL moiety, in the PABA utilization process, would occur at the ring nitrogen and not at the amino group if it is nest to a heterocyclic ring nitrogen e.g. 3-aza analog is inactive.
(D). DERIVATION OR REPLACEMENT OF –SO2
The antibacterial activity lies in –SO2 group and any addition or removal at –SO2 group or even –SO3 will result in total loss of antibacterial activity.
(E). DERIVATION OR REPLACEMENT OF 4-AMINO GROUP:
1. Amino group at position-4 is responsible for the anti-microbial activity of sulphonamides. Any permanent substitution at N4 results in loss of anti-microbial activity.
2. If alkyl or any other functional group is placed at N4 removing hydrogen, activity is lost.
3. Pro-drugs can be formed by attaching a functional group at N4, which, can be hydrolyzed in the body to resume free NH2 state again, necessary for anti-bacterial activity. N4 acetylation with dicarboxylic acids such as succinic acid or phthalic acid yields sulphonamides, which are not absorbed in small intestine but are hydrolyzed in large intestine to yield free active form of drug allowed to act locally.
Other examples are:
Sulfasalazine
N4-phthalylsulfathiazole
Mafenide
(F). N1 SUBSTITUTION DERIVATIVE:
Substituted sulphonamides are more active clinically when compared to sulphonamides e.g.
1. SULFANILAMIDE (SNM):
Very less soluble in water.
Should be given with NaHCO3
More effective against skin infections.
2. SULFADIAZINE (SDZ):
10 times more potent than SNM.
More soluble in water than SNM but can
crystallize in kidney due to high acidic
level so should be given with NAHCO3.
3. SULFAMERAZINE (SMZ):
5 times more active than SNM.
50% less active than SDZ due to addition
of –CH3 group in pyrimidine (pyr) ring.
Water solubility is more than
SULFADIAZINE (SDZ).
4. SULFADIMIDINE:
Activity is comparable to
SULFANILAMIDE (SNM).
Very much soluble in water.
5. SULFAPYRIDINE:
Water solubility is 1:3500.
It is comparable to Sulfadiazine (SDZ)
in efficacy but is more toxic than
Sulfadiazine (SDZ) in terms of crystalluria.
6. SULFAMETHIAZOLE:
Oral absorption is adequate.
More potent than sulfanilamide (SNM).
7. SULFISOXAZOLE:
Also effective against
Gram-negative bacteria.
Very much soluble in water.
8. SULFAMETHOXAZOLE:
Oral absorption is less than Sulfisoxazole.
Efficacy is similar to Sulfisoxazole
with larger half-life.
9. SULFACETAMIDE:
Very much soluble in water.
Used for ophthalmic infections.
10. SULFAGUANIDINE:
Not well absorbed orally.
Used for GIT infections.
11. SULFATHIAZOLE:
Show moderate solubility in water.
Show relatively low toxicity.
Much more effective as compared
to sulfanilamide (SNM).
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