Antiprotozoal activity of dicationic 3,5-diphenylisoxazoles,their prodrugs and aza-analogues

Fifty novel prodrugs and aza-analogues of 3,5-bis(4-amidinophenyl)isoxazole and its derivatives were prepared. Eighteen of the 24 aza-analogues exhibited IC₅₀ values below 25 nM against Trypanosoma brucei rhodesiense or Plasmodium falciparum. Six compounds had antitrypanosomal IC₅₀ values below 10 nM. Twelve analogues showed similar antiplasmodial activities, including three with sub-nanomolar potencies. Forty-four diamidines (including 16 aza-analogues) and the 26 prodrugs were evaluated for efficacy in mice infected with T. b. rhodesiense STIB900. Six diamidines cured 4/4 mice at daily 5 mg/kg intraperitoneal doses for 4 days, giving results far superior to pentamidine and furamidine. One prodrug attained 3/4 cures at daily 25 mg/kg oral doses for 4 days.     

Trypanosoma rhodesiense: evaluation of the antitrypanosomal action of 2,5-bis(4-guanylphenyl)furan dihydrochloride

The antitrypanosomal activity of 2,5-bis(4-guanylphenyl)furan dihydrochloride was evaluated with Trypanosoma rhodesiense in a primate model and its toxicological profile determined. The new antitrypanosomal agent failed to show chemotherapeutic advantages over pentamidine and investigation of the compound was halted.