Patrick Donald A, Bakunov Stanislav A, Bakunova Svetlana M, Kumar E V K Suresh, Lombardy Richard J, Jones Susan Kilgore, Bridges Arlene S, Zhirnov Oksana, Hall James Edwin, Wenzler Tanja, Brun Reto, Tidwell Richard R
Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7525, USA.
J Med Chem. 2007 May 17;50(10):2468-85. doi: 10.1021/jm0612867. Epub 2007 Apr 18.
3,5-bis(4-amidinophenyl)isoxazole (3)-an analogue of 2,5-bis(4-amidinophenyl)furan (furamidine) in which the central furan ring is replaced by isoxazole-and 42 novel analogues were prepared by two general synthetic pathways. The 43 isoxazole derivatives were assayed against Trypanosoma brucei rhodesiense (T. brucei rhodesiense) 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 IC50 values less than 10 nM, five of which displayed cytotoxic indices (ratios of cytotoxic IC50 to antiprotozoal IC50 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 than 15 nM. Fourteen of these compounds had cytotoxic indices ranging between 10 and 120 times higher than that of furamidine, and five analogues exhibited high selectivity for P. falciparum over T. brucei rhodesiense.
3,5-双（4-脒基苯基）异恶唑（3）——2,5-双（4-脒基苯基）呋喃（喷他脒）的类似物，其中央呋喃环被异恶唑取代——以及42种新型类似物通过两种通用合成途径制备而成。对这43种异恶唑衍生物进行了体外抗罗德西亚布氏锥虫（罗德西亚布氏锥虫）STIB900、恶性疟原虫（恶性疟原虫）K1以及大鼠成肌细胞L6细胞（用于细胞毒性检测）的活性测定。11种化合物（3、13、16 - 18、22、26、29、31、37和41）表现出抗锥虫IC50值小于10 nM，其中5种化合物的细胞毒性指数（细胞毒性IC50与抗原生动物IC50值的比值）至少比喷他脒高10倍。18种化合物（4 - 8、12、14、18 - 22、25、26、28、29、32和43）对恶性疟原虫的活性比喷他脒更强，IC50值小于15 nM。这些化合物中有14种的细胞毒性指数比喷他脒高10至120倍，并且有5种类似物对恶性疟原虫的选择性高于罗德西亚布氏锥虫。
