Synthesis and Antiprotozoal Activity of Cationic 2-Phenylbenzofurans
| Autor: | Karl A. Werbovetz, Reto Brun, Todd Barszcz, Svetlana M. Bakunova, Stanislav A. Bakunov, Richard R. Tidwell, Tanja Wenzler |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Trypanosoma
medicine.drug_class Stereochemistry Antiprotozoal Agents Leishmania donovani Melarsoprol Trypanosoma brucei Mice Structure-Activity Relationship Trypanosomiasis Cations parasitic diseases Drug Discovery medicine Animals Artemisinin Benzofurans Leishmania Molecular Structure biology Chemistry Plasmodium falciparum Trypanosoma brucei rhodesiense biology.organism_classification Disease Models Animal Antiprotozoal Molecular Medicine medicine.drug Pentamidine |
| Zdroj: | Journal of Medicinal Chemistry. 51:6927-6944 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm800918v |
| Popis: | A series of cationically substituted 2-phenylbenzofurans 1- 49 have been synthesized, and their in vitro antiprotozoal properties against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, as well as cytotoxicity against mammalian cells, have been evaluated. Eight dications exhibited antitrypanosomal activities comparable to that of pentamidine and melarsoprol. Twenty-six compounds were more active than pentamidine, and seven dications demonstrated increased activities against P. falciparum than artemisinin. Five congeners were more active against L. donovani than pentamidine. Introduction of methoxy or hydroxy groups in the 7- and/or 2'-position afforded derivatives that were highly selective against T. b. rhodesiense, P. falciparum, and L. donovani. Fourteen 2-phenylbenzofurans displayed excellent in vivo efficacies in the acute mouse model of trypanosomiasis, curing 3/4 or 4/4 animals at 4 x 5 mg/kg. Diamidine 1 and di( N-isopropyl)amidine 45, administered at 4 x 1 mg/kg, exhibited potency comparable to that of melarsoprol, providing 3/4 and 2/4 cures, respectively. |
| Databáze: | OpenAIRE |
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