Synthesis and in Vitro Antiprotozoal Activities of Dicationic 3,5-Diphenylisoxazoles

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• 作者：Donald A. Patrick ; Stanislav A. Bakunov ; Svetlana M. Bakunova ; E. V. K. Suresh Kumar ; Richard J. Lombardy ; Susan Kilgore Jones ; Arlene S. Bridges ; Oksana Zhirnov ; James Edwin Hall ; Tanja Wenzler ; Reto
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：May 17, 2007
• 年：2007
• 卷：50
• 期：10
• 页码：2468 - 2485
• 全文大小：297K
• 年卷期：v.50,no.10(May 17, 2007)
• ISSN：1520-4804

文摘

3,5-Bis(4-amidinophenyl)isoxazole (3)-an analogue of 2,5-bis(4-amidinophenyl)furan (furamidine) in whichthe central furan ring is replaced by isoxazole-and 42 novel analogues were prepared by two general syntheticpathways. The 43 isoxazole derivatives were assayed against Trypanosoma brucei rhodesiense (T. bruceirhodesiense) STIB900, Plasmodium falciparum (P. falciparum) K1, and rat myoblast L6 cells (for cytotoxicity)in vitro. Eleven compounds (3, 13, 16-18, 22, 26, 29, 31, 37, and 41) exhibited antitrypanosomal IC₅₀values less than 10 nM, five of which displayed cytotoxic indices (ratios of cytotoxic IC₅₀ to antiprotozoalIC₅₀ values) at least 10 times higher than that of furamidine. Eighteen compounds (4-8, 12, 14, 18-22, 25,26, 28, 29, 32, and 43) were more active against P. falciparum than furamidine, with IC₅₀ values less than15 nM. Fourteen of these compounds had cytotoxic indices ranging between 10 and 120 times higher thanthat of furamidine, and five analogues exhibited high selectivity for P. falciparum over T. brucei rhodesiense.