Hu Laixing, Arafa Reem K, Ismail Mohamed A, Patel Alpa, Munde Manoj, Wilson W David, Wenzler Tanja, Brun Reto, Boykin David W
Department of Chemistry, Georgia State University, Atlanta, GA 30303-3083, USA.
Bioorg Med Chem. 2009 Sep 15;17(18):6651-8. doi: 10.1016/j.bmc.2009.07.080. Epub 2009 Aug 7.
A series of azaterphenyl diamidines has been synthesized and evaluated for in vitro antiprotozoal activity against both Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) and in vivo efficacy in the STIB900 acute mouse model for T. b. r. Six of the 13 compounds showed IC(50) values less than 7 nM against T. b. r. Twelve of those exhibited IC(50) values less than 6 nM against P. f. and six of those showed IC(50) values 0.6 nM, which are more than 25-fold as potent as furamidine. Moreover, two of them showed more than 40-fold selectivity for P. f. versus T. b. r. Three compounds 15b, 19d and 19e exhibited in vivo efficacy against T. b. r. much superior to furamidine, and equivalent to or better than azafuramidine. The antiparasitic activity of these diamidines depends on the ring nitrogen atom(s) location relative to the amidine groups and generally correlates with DNA binding affinity.
已合成了一系列氮杂三联苯二脒，并对其进行了体外抗寄生虫活性评估，以检测其对布氏罗得西亚锥虫（T. b. r.）和恶性疟原虫（P. f.）的活性，以及在STIB900急性小鼠模型中对T. b. r.的体内疗效。13种化合物中有6种对T. b. r.的IC(50)值小于7 nM。其中12种对P. f.的IC(50)值小于6 nM，6种的IC(50)值为0.6 nM，其效力是夫拉米定的25倍以上。此外，其中两种对P. f.相对于T. b. r.的选择性超过40倍。三种化合物15b、19d和19e对T. b. r.的体内疗效远优于夫拉米定，与氮杂夫拉米定相当或更好。这些二脒的抗寄生虫活性取决于环氮原子相对于脒基的位置，并且通常与DNA结合亲和力相关。
