Abstract

Mice infected with Plasmodium berghei were given graded doses of 4,4'-diaminodiphenylsulfone (DDS) and acyl derivatives of DDS on two schedules: a single dose and daily for six days. The minimum curative doses were defined as the schedules permitting survival 5 times as long as controls. In these tests, 4,4'-diformamidodiphenylsulfone (DFD) was more effective than DDS. The minimum curative dose of each compound was tested against varied doses of para-aminobenzoic acid to find the ratio of para-aminobenzoic acid/drug which reversed the effect of the drug. All derivatives of DDS were similarly reversed. When given i.v., in dimethylsulfoxide, DFD and DDS had an equal and weak effect against P. berghei; when given every eight hours i.p., DFD was less effective than DDS. DFD, but not 4,4'-diacetamidodiphenylsulfone (DAD), was deacylated in mouse plasma in vitro. DAD was deacylated in vivo less rapidly than DFD. The action of acyl derivatives of DDS in mice appears to be through conversion to DDS. The blood level of DDS after i.p. doses of DFD and DAD is proportional to the solubility of the drugs and rates of in vivo deacylation. Data support a similar mechanism of action for DDS and sulfadiazine in the folate pathway.