2. Academic Validation
  3. Antiprotozoal activity of dicationic 3,5-diphenylisoxazoles, their prodrugs and aza-analogues

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

  • Bioorg Med Chem. 2014 Jan 1;22(1):559-76. doi: 10.1016/j.bmc.2013.10.050.
Donald A Patrick 1,  Stanislav A Bakunov 1,  Svetlana M Bakunova 1,  Tanja Wenzler 2,  Reto Brun 2,  Richard R Tidwell 3
Affiliations

Affiliations

  • 1 University of North Carolina, Pathology & Laboratory Medicine, 805 Brinkhous-Bullitt Bldg, CB 7525, Chapel Hill, NC 27599-7525, USA.
  • 2 Swiss Tropical and Public Health Institute, Medical Parasitology & Infection Biology, Socinstrasse 57, 4051 Basel, Switzerland; University of Basel, Petersplatz 1, 4003 Basel, Switzerland.
  • 3 University of North Carolina, Pathology & Laboratory Medicine, 805 Brinkhous-Bullitt Bldg, CB 7525, Chapel Hill, NC 27599-7525, USA. Electronic address: Tidwell@med.unc.edu.
PMID: 24268543 DOI: 10.1016/j.bmc.2013.10.050
Abstract

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.

Keywords

Antiprotozoal; Antitrypanosomal; Diamidine; Diarylisoxazole; Prodrug.

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