Bakunova Svetlana M, Bakunov Stanislav A, Patrick Donald A, Kumar E V K Suresh, Ohemeng Kwasi A, Bridges Arlene S, Wenzler Tanja, Barszcz Todd, Jones Susan Kilgore, Werbovetz Karl A, Brun Reto, Tidwell Richard R
Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, North Carolina 27599, USA.
J Med Chem. 2009 Apr 9;52(7):2016-35. doi: 10.1021/jm801547t.
Diamidine 1 (pentamidine) and 65 analogues (2-66) have been tested for in vitro antiprotozoal activities against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, and for cytotoxicity against mammalian cells. Dications 32, 64, and 66 exhibited antitrypanosomal potencies equal or greater than melarsoprol (IC(50) = 4 nM). Nine congeners (2-4, 12, 27, 30, and 64-66) were more active against P. falciparum than artemisinin (IC(50) = 6 nM). Eight compounds (12, 32, 33, 44, 59, 62, 64, and 66) exhibited equal or better antileishmanial activities than 1 (IC(50) = 1.8 microM). Several congeners were more active than 1 in vivo, curing at least 2/4 infected animals in the acute mouse model of trypanosomiasis. The diimidazoline 66 was the most promising compound in the series, showing excellent in vitro activities and high selectivities against T. b. rhodesiense, P. falciparum, and L. donovani combined with high antitrypanosomal efficacy in vivo.
已对双脒1（喷他脒）和65种类似物（2 - 66）进行了体外抗寄生虫活性测试，以检测其对罗德西亚布氏锥虫、恶性疟原虫和杜氏利什曼原虫的活性，以及对哺乳动物细胞的细胞毒性。双阳离子化合物32、64和66表现出与美拉胂醇相当或更强的抗锥虫效力（IC(50)=4 nM）。九种同系物（2 - 4、12、27、30以及64 - 66）对恶性疟原虫的活性比青蒿素更强（IC(50)=6 nM）。八种化合物（12、32、33、44、59、62、64和66）表现出与1相当或更好的抗利什曼原虫活性（IC(50)=1.8 microM）。几种同系物在体内比1更具活性，在锥虫病急性小鼠模型中至少治愈了2/4的感染动物。双咪唑啉66是该系列中最有前景的化合物，在体外对罗德西亚布氏锥虫、恶性疟原虫和杜氏利什曼原虫表现出优异的活性和高选择性，同时在体内具有高抗锥虫效力。
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