ANTIMALARIAL AND ANTISCHISTOSOMAL EFFECTS OF PROXIMAL HYDRAZINE AND HYDROXYLAMINE ANALOGS OF CHLOROQUINE AND QUINACRINE

Representative 4-(2,2-dialkylhydrazino)qiniolines (IV-VII), 6-chloro-9-(2,2-dialkylhydrazino)-2-methoxyacridines (VIII, IX), 12-(2,2-dialkylhydrazino)benz[b]acridines (X), 2,2′,-(benz[c]acridin-7-ylhydrazono)diethanol (XI), 7-chloro-4-{[2-(dialkylamino)ethoxy] amino}quinolines (XII), and 6-chloro-9-{[2-(dimethylamino)ethoxy]amino}-2-methoxyacridine (XIII) were synthesized to enable an assessment of the antiparasitic effects conferred by substituting a hydrazine or hydroxylamine moiety for the proximal amine function of chloroquine, quinacrine, and 7-{[3-(octylamino)propyl]amino} benz[c]acridine relatives. The compounds were isolated in 3-92% yield by the condensation of 4,7-dichloroquinoline, 4-chloro-6-methoxyquinoline, 4-chloro-6-methoxyquinaldine, 6,9-dichloro-2-methoxyacridine, 12-chlorobenz[6]acridine, or 7-chlorobenz[c]acridine with the appropriate 1,1-dialkylhydrazine or 2-(dialkylamino)ethoxyamine in phenol or EtOH. Among them, 6-methoxy-4-(morpholinoamino)quinaldine (IV) exhibited modest activity against Schistosoma mansoni in mice and effected a 28-51% reduction of live worms at drug-diet doses of 224-303 mg/kg daily for 14 days. Six compounds were active against a normal strain of Plasmodium berghei in mice at doses ranging from 2.7-219 mg/kg/day for 6 days. 7-Chloro-4-(4-methyl-1-piperazinylamino)quinoline (Vb) and 4,4′-(1,4-piperazinediyldiimino)bis(7-chloroquinoline) (VII) were approximately 28 and 27 times as potent as quinine, respectively, against P. berghei, but VII was highly cross-resistant with chloroquine. Structure-activity relationships are discussed. © 1969, American Chemical Society. All rights reserved.