Synthesis, biological evaluation, and molecular modeling of 3,5-substituted-N1-phenyl-N4,N4-di-n-butylsulfanilamides as antikinetoplastid antimicrotubule agents.
Synthesis, biological evaluation, and molecular modeling of 3,5-substituted-N1-phenyl-N4,N4-di-n-butylsulfanilamides as antikinetoplastid antimicrotubule agents.
复制标题
作为抗动质体抗微管剂的 3,5-取代-N1-苯基-N4,N4-二正丁基磺酰胺的合成、生物学评价和分子建模。
DOI：
10.1016/j.bmc.2007.06.042
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发表时间：
2007
影响因子：
3.5
通讯作者：
Werbovetz,KarlA
中科院分区：
文献类型：
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作者：
George,TesmolG;Endeshaw,MollaM;Morgan,RachelE;Mahasenan,KiranV;Delfín,DawnA;Mukherjee,MitaliS;Yakovich,AdamJ;Fotie,Jean;Li,Chenglong;Werbovetz,KarlA
二硝基苯胺因其对这些生物体的微管蛋白的选择性活性而作为抗原生动物先导化合物而受到关注，但由于其潜在的致突变硝基而引起了人们的担忧。N1-苯基-3，5-二硝基-N4，N4-二正丁基磺胺（GB-II-150，化合物2b）的类似物是一种抗非洲锥虫和利什曼原虫的选择性抗有丝分裂剂，其硝基被氨基、氯、氰基、羧酸酯、甲酯、酰胺和甲基酮部分取代。二氰基化合物5显示出与2b相当的IC 50值，其针对纯化的利什曼原虫微管蛋白组装体（6.6对7.4μM）、布氏锥虫体外生长（0.26对0.18μM）、杜氏利什曼原虫无鞭毛体体外生长（4.4对2.3μM）以及针对Vero细胞的体外毒性（16对9.7μM）。计算研究提供了一个合理的抗寄生虫的活性顺序，这些类似物和进一步深入了解的作用，在3和5位的磺胺环的取代基。
Dinitroanilines are of interest as antiprotozoal lead compounds because of their selective activity against the tubulin of these organisms, but concern has been raised due to the potentially mutagenic nitro groups. Analogues of N1-phenyl-3,5-dinitro-N4,N4-di-n-butylsulfanilamide (GB-II-150, compound 2b), a selective antimitotic agent against African trypanosomes and Leishmania, have been prepared where the nitro groups are replaced with amino, chloro, cyano, carboxylate, methyl ester, amide, and methyl ketone moieties. Dicyano compound 5 displays IC50values that are comparable to 2b against purified leishmanial tubulin assembly (6.6 vs 7.4μM), Trypanosoma brucei brucei growth in vitro (0.26 vs 0.18μM), Leishmania donovani axenic amastigote growth in vitro (4.4 vs 2.3μM), and in vitro toxicity against Vero cells (16 vs 9.7μM). Computational studies provide a rationale for the antiparasitic order of activity of these analogues and further insight into the role of the substituents at the 3 and 5 positions of the sulfanilamide ring.