Antikinetoplastid antimitotic activity and metabolic stability of dinitroaniline sulfonamides and benzamides.
Antikinetoplastid antimitotic activity and metabolic stability of dinitroaniline sulfonamides and benzamides.
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DOI：
10.1016/j.bmc.2006.04.017
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发表时间：
2006-08
影响因子：
3.5
通讯作者：
Tesmol G. George;Jayaseharan Johnsamuel;Dawn A. Delfín;A. Yakovich;Mitali Mukherjee;M. Phelps;J. Dalton;D. Sackett;M. Kaiser;R. Brun;K. Werbovetz
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文献类型：
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作者：
Tesmol G. George;Jayaseharan Johnsamuel;Dawn A. Delfín;A. Yakovich;Mitali Mukherjee;M. Phelps;J. Dalton;D. Sackett;M. Kaiser;R. Brun;K. Werbovetz
N1-苯基-3，5-二硝基-N4，N4-二正丙基磺胺（1）和N1-苯基-3，5-二硝基-N4，N4-二正丁基磺胺（2）对动质体寄生虫显示出有效的体外抗有丝分裂活性，但显示出较差的体内活性。本文报道了17个新的二硝基苯胺磺酰胺和11个新的苯甲酰胺类似物。9种磺胺类药物对非洲锥虫的体外IC 50值低于500 nM，最具活性的抗动质体化合物也抑制纯化的利什曼原虫微管蛋白的体外组装，效力与2相似。虽然几种有效化合物在体外可被大鼠肝脏S9组分快速降解，但N1-（3-羟基）苯基-3，5-二硝基-N4，N4-二正丁基磺胺（21）在体外对非洲锥虫的IC 50值为260 nM，在体外代谢试验中稳定性大于2。
N1-Phenyl-3,5-dinitro-N4,N4-di-n-propylsulfanilamide (1) and N1-phenyl-3,5-dinitro-N4,N4-di-n-butylsulfanilamide (2) show potent in vitro antimitotic activity against kinetoplastid parasites but display poor in vivo activity. Seventeen new dinitroaniline sulfonamide and eleven new benzamide analogs of these leads are reported here. Nine of the sulfonamides display in vitro IC50values under 500nM against African trypanosomes, and the most active antikinetoplastid compounds also inhibit the in vitro assembly of purified leishmanial tubulin with potencies similar to that of 2. While several of the potent compounds are rapidly degraded by rat liver S9 fractions in vitro, N1-(3-hydroxy)phenyl-3,5-dinitro-N4,N4-di-n-butylsulfanilamide (21) displays an IC50value of 260nM against African trypanosomes in vitro and is more stable than 2 in the in vitro metabolism assay.