Chemotherapeutic Evaluation of Sulfanilamide Derivatives of Heterocyclic Amines

Abstract

The therapeutic success with which sulfanilamide has been used in a number of unrelated bacterial and several viral diseases has stimulated the search for more effective and less toxic drugs. The trend of these investigations has generally been to modify the sulfanilamide nucleus by substitution in the amine or amide group, replacement of the amide group or degradation of the sulfone group. These substitutions have generally been of the alkyl, aryl, or substituted-alkyl or substituted-aryl type. The few compounds formed by the substitution of heterocyclic radicals for amino or amide hydrogens were of no especial interest, prior to the advent of sulfapyridine, because of their relatively feeble therapeutic activity.

Of these, the heterocyclic azo compounds p-sulfonamidophenylazo-dihydrocupreine, 1 , 2 p-sulfonamidophenylazoapoquinine, 2 p-sulfonam-idophenylazoisoapoquinine, 2 and p-sulfonamidophenylazoisoquini-dine 2 and also tropinone bis-sulfonamideophenylhydrazone 2 possessed very litle therapeutic activity.

The amino substituted compounds p-furfurylideneaminophenyl-sulfonamide 3 and 2-pyrrolidone-5-carboxy-4'-aminophenylsulfona-mide 3 were claimed to be respectively less active and more active than sulfanilamide in streptococcic infections.

The two nitrogen-linked sulfones, 1-sulfanilylpiperidine 3 and 1-sul-fanilylpiperazine∗ were inactive, whereas 2-pyrrolidone-5-carboxy-4'-amino-phenylsulfinic acid 4 was reported to be as active as sulfanilamide.

The amide substituted compounds, p-aminophenylpiperidylsulfonamide 5 and 2-sulfanilamidopyridine (sulfapyridine) 6 were claimed to be respectively one-half as active and as good as or better than sulfanilamide against streptococcic infections. The latter compound, in adequate dosage, was claimed by Whitby 6 to save all mice infected intraperitoneally with 10,000 fatal doses of Types I, VII, and VIII pneumococci.

Subsequent investigations have shown sulfapyridine to be fractionally superior to sulfanilamide against mouse infections of approximately 10 to 1000 fatal doses of pneumococci 7-11 and of almost equal efficacy against experimental pneumococcus pneumonia 11 and menin-gitis 7 , 11 of rats.