REPOSITORY DRUGS .4. 4',4'''-SULFONYLBISACETANILIDE(ACEDAPSONE,DADDS) AND RELATED SULFANILYLANILIDES WITH PROLONGED ANTIMALARIAL AND ANTILEPROTIC ACTION

Thirty-six sulfanilylanilides and related compounds were investigated as potential repository antimalarial and antileprotic agents. Seven compounds protected mice against challenge with Plasmodium berghei for 4 to >10 weeks following a single, subcutaneous 400-mg/kg dose. 4′,4‴-Sulfonylbisacetanilide (acedapsone, DADDS) (XIII) showed the longest duration of action and protected mice for 6-14 weeks against challenges with P. berghei and monkeys for 2-8 months against challenges with Plasmodium cynomolgi. Repository antimalarial effects were abolished or drastically reduced when DADDS was modified by: (1) replacement of the acetamide groups with a formamide function, (2) replacement of both acetamide groups with amide functions containing more than two carbon atoms, (3) N-alkylation of one acetamide function, (4) introduction of a chlorine atom at positions 2′ or 3′, or (5) replacement of the sulfone moiety by a thio, sulfinyl, oxalyl, or 2,2,2-trichloroethylidene linkage. Representative 4′,4‴-bis(N-acetylsulfanilyl)alkylenebisanilides (VIIIa-c), 4′-[N-(substituted vinyl)sulfanilyl]-acetanilides (IXa-d), 4′-[(2-acetamido-5-thiazolyl)sulfonyl]acetanilide (X), 3′,3‴-sulfonylbisacetanilide (XI), and 3,3′-[sulfonylbis(p-phenyleneiminomethylene)]di-2-thiazolidinethione (XII) also lacked appreciable repository action. A combination of cycloguanil pamoate and DADDS showed better activity than either component alone against drug-resistant plasmodia in experimental animals and in man. DADDS exhibited strong repository antileprotic action against Mycobacterium leprae in mice and in man. © 1969, American Chemical Society. All rights reserved.