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

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• 作者：Donald A. Patrick ; Stanislav A. Bakunov ; Svetlana M. Bakunova ; Tanja Wenzler ; Reto Brun ; Richard R. Tidwell
• 关键词：Diarylisoxazole ; Diamidine ; Prodrug ; Antiprotozoal ; Antitrypanosomal
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：1 January, 2014
• 年：2014
• 卷：22
• 期：1
• 页码：559-576
• 全文大小：900 K

文摘

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.