二苯基阳离子型锥虫杀灭剂的构效关系研究：鏻盐相对于铵盐的卓越活性。
SAR Studies of Diphenyl Cationic Trypanocides: Superior Activity of Phosphonium over Ammonium Salts.
作者信息
Dardonville Christophe, Alkhaldi Abdulsalam A M, De Koning Harry P
机构信息
Instituto de Química Médica, IQM-CSIC , Juan de la Cierva 3, E-28006 Madrid, Spain.
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow, United Kingdom ; Department of Biology, College of Science, Aljouf University , Sakaka, Saudi Arabia.
出版信息
ACS Med Chem Lett. 2014 Dec 10;6(2):151-5. doi: 10.1021/ml500408d. eCollection 2015 Feb 12.
In previous studies, we have shown that phosphonium salt diphenyl derivatives are attractive antitrypanosomal hit compounds with EC50 values against Trypanosoma brucei in the nanomolar range. To evaluate the role of the cationic center on the trypanocidal activity and extend the structure-activity relationship (SAR) of this series, trialkylammonium, pyridinium, and quinolinium salt analogues were synthesized and evaluated in vitro against T. b. brucei. Similar SARs were observed with ammonium and phosphonium salts showing that charge dispersion and lipophilic groups around the cationic center are crucial to obtain submicromolar activities. The new compounds were equally effective against wild type (T. b. brucei s427) and resistant strains (TbAT1-KO and TbB48) of trypanosomes indicating that the P2 and high affinity pentamidine transporters (HAPT) are not essential to their trypanocidal action. Similarly to phosphonium salt derivatives, diffusion seems to be the main route of entry into trypanosomes.
在先前的研究中，我们已经表明，鏻盐二苯基衍生物是有吸引力的抗锥虫命中化合物，对布氏锥虫的EC50值在纳摩尔范围内。为了评估阳离子中心对杀锥虫活性的作用并扩展该系列的构效关系（SAR），合成了三烷基铵、吡啶鎓和喹啉鎓盐类似物，并在体外对布氏锥虫进行了评估。铵盐和鏻盐观察到类似的构效关系，表明阳离子中心周围的电荷分散和亲脂性基团对于获得亚微摩尔活性至关重要。新化合物对锥虫的野生型（布氏锥虫s427）和抗性菌株（TbAT1-KO和TbB48）同样有效，这表明P2和高亲和力喷他脒转运体（HAPT）对其杀锥虫作用不是必需的。与鏻盐衍生物类似，扩散似乎是进入锥虫的主要途径。
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