Jones M M, Singh P K, Lane J E, Rodrigues R R, Nesset A, Suarez C C, Bogitsh B J, Carter C E
Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA.
Arzneimittelforschung. 1996 Dec;46(12):1158-62.
The relative effectiveness of 20 iron chelating agents in suppressing the growth and multiplication of Trypanosoma cruzi epimastigotes has been examined in vitro. 1,2-Dimethyl-3-hydroxypyrid-4-one (L1) and several of its newly synthesised N-substituted analogs containing hydrophobic substituents were significantly more effective than deferoxamine, even though they possess only two donor sites for iron(III) while deferoxamine has six. Analogs with hydrophilic substituents were uniformly less active than L1 itself. Variations in effectiveness as the polarity of the compound is varied indicate that the ability to cross the cellular membrane is of critical importance in the determination of the in vitro trypanocidal activity of iron(III) chelating agents. A group of four tris(2-aminoethyl)amine based tris-imines were also screened, all of which had poor activity (0-28% inhibition). Among the other iron(III) chelating agents which showed a relatively high level of activity at 50 and 100 micrograms/ml were salicylhydroxamic acid (70 and 73% inhibition) and hydroxyurea (42 and 52% inhibition). N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid and acetohydroxamic acid exhibited only slight activity at 50 and 100 micrograms/ml. The best of these iron(III) chelating agents were as effective against the epimastigote form at both 50 and 100 micrograms/ml (74-82% inhibition) as benznidazole (81% inhibition), the drug currently used in the clinic.
已在体外研究了20种铁螯合剂对克氏锥虫前鞭毛体生长和增殖的抑制效果。1,2 - 二甲基 - 3 - 羟基吡啶 - 4 - 酮（L1）及其几种新合成的含有疏水取代基的N - 取代类似物比去铁胺更有效，尽管它们仅具有两个铁（III）供体位点而去铁胺有六个。具有亲水取代基的类似物活性均低于L1本身。随着化合物极性变化而产生的有效性差异表明，穿过细胞膜的能力对于确定铁（III）螯合剂的体外杀锥虫活性至关重要。还筛选了一组四种基于三（2 - 氨基乙基）胺的三 - 亚胺，它们的活性都很差（抑制率为0 - 28%）。在其他铁（III）螯合剂中，水杨羟肟酸（抑制率分别为70%和73%）和羟基脲（抑制率分别为42%和52%）在50和100微克/毫升时表现出相对较高的活性。N,N'-二（2 - 羟基苄基）乙二胺 - N,N'-二乙酸和乙酰羟肟酸在50和100微克/毫升时仅表现出轻微活性。这些铁（III）螯合剂中效果最好的在50和100微克/毫升时对前鞭毛体形式的抑制效果（74 - 82%）与临床目前使用的药物苯硝唑（抑制率81%）相当。
