Antiprotozoal activity of dicationic 3,5-diphenylisoxazoles,their prodrugs and aza-analogues |
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| Institution: | 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;3. University of Basel, Petersplatz 1, 4003 Basel, Switzerland;1. Institute of Medical Mission, Department of Tropical Medicine, 97074 Würzburg, Germany;2. Laboratory of Molecular Physiology, Institute of Experimental Medicine, School of Medicine Luis Razetti, Faculty of Medicine, Universidad Central de Venezuela, Caracas, Venezuela;3. Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany;1. Centro de Investigação em Química, Department of Chemistry and Biochemistry, Faculty of Science, University of Porto, Rua do Campo Alegre, 687, P-4169-007, Portugal;2. Department of Chemistry, University of North Texas, Denton, TX 76203, USA;1. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy;2. Department of Chemical Sciences, University of Padova, Via F. Marzolo 1, 35131 Padova, Italy;3. Department of Biomedical Sciences, University of Padova, Via G. Colombo 3, 35121 Padova, Italy;4. Department of Chemistry and Industrial Chemistry, University of Pisa, Via Risorgimento 35, 56126 Pisa, Italy;1. ZMBH, Universitat Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany;2. School of Chemistry & Environmental Sciences, The Manchester Metropolitan University, Faculty of Science and Engineering, John Dalton Building, Chester Street, Manchester M1 5GD, UK;1. N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation;2. Chemical Block Ltd, 3 Kyriacou Matsi, 3723 Limassol, Cyprus;3. R.E. Kavetsky Institute of Experimental Oncology, Pathology and Radiobiology, National Academy of Sciences of Ukraine, 45 Vasyl’kivska Street, 03022 Kyiv, Ukraine;4. Department of Biological and Medicinal Chemistry, Moscow Institute of Physics and Technology, Institutsky Per. 9, Dolgoprudny, Moscow Region, 141700, Russia;5. ChemDiv, 6605 Nancy Ridge Drive, San Diego, CA 92121, USA;6. N.K. Kol’tsov Institute of Developmental Biology RAS, 26 Vavilov Street, 119334 Moscow, Russian Federation |
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| 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. |
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| Keywords: | Diarylisoxazole Diamidine Prodrug Antiprotozoal Antitrypanosomal |
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