New bis(2-aminoimidazoline) and bisguanidine DNA minor groove binders with potent in vivo antitrypanosomal and antiplasmodial activity
New bis(2-aminoimidazoline) and bisguanidine DNA minor groove binders with potent in vivo antitrypanosomal and antiplasmodial activity
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DOI：
10.1021/jm7013088
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发表时间：
2008-02-28
影响因子：
7.3
通讯作者：
Dardonville, Christophe
中科院分区：
文献类型：
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作者：
Rodriguez, Fernando;Rozas, Isabel;Dardonville, Christophe
体外测定了一系列75个胍和2-氨基咪唑啉类似物对布氏锥虫STIB900和恶性疟原虫K1的抑制作用。阳离子二苯类化合物对罗德氏疟原虫和恶性疟原虫的IC50值在纳摩尔范围内最高。5个化合物(7b、9a、9b、10b和14b)在难以治愈的罗德氏锥虫STIB900小鼠模型中，ip 20 mg/kg可使100%的小鼠治愈。总体而言，含有2-氨基咪唑啉阳离子的化合物比含胍的化合物具有更好的安全性。观察到三个系列化合物的AT位DNA结合亲和力与杀锥虫活性之间的相关性，支持部分由于DNA复合体的形成而产生抗锥虫作用的机制的观点。没有观察到抗疟原虫活性和体外抑制铁原卟啉IX生物矿化之间的相关性，这表明可能涉及其他作用机制。
A series of 75 guanidine and 2-aminoimidazoline analogue molecules were assayed in vitro against Trypanosoma brucei rhodesiense STIB900 and Plasmodium falciparum K1. The dicationic diphenyl compounds exhibited the best activities with IC50 values against T. b. rhodesiense and P. falciparum in the nanomolar range. Five compounds (7b, 9a, 9b, 10b, and 14b) cured 100% of treated mice upon ip administration at 20 mg/kg in the difficult to cure T. b. rhodesiense STIB900 mouse model. Overall, the compounds that bear the 2-aminoimidazoline cations benefit from better safety profiles than the guanidine counterparts. The observation of a correlation between DNA binding affinity at AT sites and trypanocidal activity for three series of compounds supported the view of a mechanism of antitrypanosomal action due in part to the formation of a DNA complex. No correlation between antiplasmodial activity and in vitro inhibition of ferriprotoporphyrin IX biomineralisation was observed, suggesting that additional mechanism of action is likely to be involved.