title: Antiprotozoal activity of dicationic 3,5-diphenylisoxazoles, their prodrugs and aza-analogues.
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.
authors.affiliation: University of North Carolina, Pathology & Laboratory Medicine, 805 Brinkhous-Bullitt Bldg, CB 7525, Chapel Hill, NC 27599-7525, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Patrick
authors.affiliation: University of North Carolina, Pathology & Laboratory Medicine, 805 Brinkhous-Bullitt Bldg, CB 7525, Chapel Hill, NC 27599-7525, USA.
authors.forename: Stanislav A
authors.initials: SA
authors.lastname: Bakunov
authors.affiliation: University of North Carolina, Pathology & Laboratory Medicine, 805 Brinkhous-Bullitt Bldg, CB 7525, Chapel Hill, NC 27599-7525, USA.
authors.forename: Svetlana M
authors.initials: SM
authors.lastname: Bakunova
authors.affiliation: Swiss Tropical and Public Health Institute, Medical Parasitology & Infection Biology, Socinstrasse 57, 4051 Basel, Switzerland; University of Basel, Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.affiliation: Swiss Tropical and Public Health Institute, Medical Parasitology & Infection Biology, Socinstrasse 57, 4051 Basel, Switzerland; University of Basel, Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.affiliation: 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.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D011355:Prodrugs / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D000981:Antiprotozoal Agents; D007555:Isoxazoles; D011355:Prodrugs
keywords: Antiprotozoal; Antitrypanosomal; Diamidine; Diarylisoxazole; Prodrug