enzymes releases the active free sulfanilamide. Succinyl-sulfathiazole was therefore
widely used for intestinal infections. The pyrimidine derivatives, such as sulfamerazine,
have a much longer duration of action and a broad antibacterial spectrum, including both
Gram-positive and Gram-negative organisms. Sulfisoxazole (9.91), although less active,
is better tolerated. Among the newer compounds, sulfamethoxine (9.92) has a spectacu-
lar half-life (about 150 hours) and requires administration only once a week. A sulfone,
acedapsone (9.93), has found successful use in the treatment and even the clinical cure
of the once dreaded leprosy (Hansen’s disease), caused by Mycobacterium leprae.
Some DHFR inhibitors are active against the bacterial enzyme even though originally
used against the malaria parasite. For instance, trimethoprim (9.94) is used in combi-
nation with sulfa drugs (co-trimoxazole (9.95)), attacking both the synthesis and the
proper functioning of DHFR. The therapeutic index, tolerance, delay in the develop-
ment of resistance, and antimicrobial spectrum of this synergistic combination of
two drugs are all spectacularly greater than the corresponding effects of the individual
drugs, to the extent that microorganisms unaffected by either drug alone are successfully
eliminated by the combination.
Structure–activity correlations for the sulfa-DHFR inhibitors, derived on the basis of
some 5000 compounds, have led to the deduction of the following regularities:
- The amino groups must be in the paraposition to the sulfonamide group, and this
amine must be unsubstituted or become unsubstituted in vivo. - The benzene ring can be substituted in positions 1 and 4 only.
- Sulfones, carboxamides, or ketones replacing the sulfonamide may retain activity,
but often at a lower level. - The sulfonamide nitrogen can be monosubstituted only, and heteroaromatic sub-
stituents increase the drug activity.
It is noteworthy that sulfanilamide structural modifications have led to other valuable
classes of drugs already discussed, including the hypoglycemic sulfonylureas and the
diuretic carbonic anhydrase inhibitors.
EXOGENOUS PATHOGENS AND TOXINS 579