ABSTRACT
A series of nitroheterocyclic compounds were designed with linkages to melamine or benzamidine groups that are known substrates of the P2 aminopurine and other transporters in African trypanosomes of the brucei group. Several compounds showed in vitro trypanotoxicity with 50% inhibitory concentrations in the submicromolar range. Although most compounds interacted with the P2 transporter, as judged by their ability to inhibit adenosine transport via this carrier, uptake through this route was not necessary for activity since
TbAT1
-null mutant parasites, deficient in this transporter, retained sensitivity to these drugs. One compound, a melamine-linked nitrofuran, also showed pronounced activity against parasites in mice. Studies into the mode of action of this compound indicated that neither reductive, nor oxidative, stress were related to its trypanocidal activity ruling out a genotoxic effect in
T. brucei
, distinguishing it from some other, mammalian cell toxic, trypanocidal nitroheterocycles.
摘要
研究人员设计了一系列与三聚氰胺或联苯胺基团连接的硝基杂环化合物,这些基团是非洲布氏锥虫中 P2 氨基嘌呤和其他转运体的已知底物。一些化合物显示出体外锥虫毒性,50% 的抑制浓度在亚微摩范围内。虽然大多数化合物都能与 P2 转运体相互作用,因为它们能抑制腺苷通过这一载体的转运,但通过这一途径摄取腺苷并不是活性的必要条件,因为 TbAT1 和 TbAT2 转运体都能抑制腺苷的转运。
TbAT1
-缺失这种转运体的突变寄生虫对这些药物仍然敏感。一种与三聚氰胺相连的硝基呋喃化合物对小鼠体内的寄生虫也显示出明显的活性。对这种化合物作用模式的研究表明,还原压力和氧化压力都与这种化合物的杀锥虫活性无关,这就排除了它对布鲁氏原虫的基因毒性作用。
布氏锥虫
因此,它有别于其他一些对哺乳动物细胞有毒的杀锥虫硝基杂环化合物。