George Tesmol G, Johnsamuel Jayaseharan, Delfín Dawn A, Yakovich Adam, Mukherjee Mitali, Phelps Mitch A, Dalton James T, Sackett Dan L, Kaiser Marcel, Brun Reto, Werbovetz Karl A
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, 43210, USA.
Bioorg Med Chem. 2006 Aug 15;14(16):5699-710. doi: 10.1016/j.bmc.2006.04.017. Epub 2006 May 3.
N(1)-Phenyl-3,5-dinitro-N(4),N(4)-di-n-propylsulfanilamide (1) and N(1)-phenyl-3,5-dinitro-N(4),N(4)-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 IC(50) values under 500 nM 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, N(1)-(3-hydroxy)phenyl-3,5-dinitro-N(4),N(4)-di-n-butylsulfanilamide (21) displays an IC(50) value of 260 nM against African trypanosomes in vitro and is more stable than 2 in the in vitro metabolism assay.
N(1)-苯基-3,5-二硝基-N(4),N(4)-二正丙基磺胺（1）和N(1)-苯基-3,5-二硝基-N(4),N(4)-二正丁基磺胺（2）对动基体寄生虫显示出强大的体外抗有丝分裂活性，但体内活性较差。本文报道了17种新的二硝基苯胺磺胺和11种这些先导化合物的新苯甲酰胺类似物。其中9种磺胺对非洲锥虫的体外IC(50)值低于500 nM，最具活性的抗动基体化合物还能抑制纯化的利什曼原虫微管蛋白的体外组装，其效力与化合物2相似。虽然几种强效化合物在体外会被大鼠肝脏S9组分迅速降解，但N(1)-(3-羟基)苯基-3,5-二硝基-N(4),N(4)-二正丁基磺胺（21）在体外对非洲锥虫的IC(50)值为260 nM，并且在体外代谢试验中比化合物2更稳定。
