St. Jude Children's Hospital, Department of Chemical Biology and Therapeutics, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA.
Bioorg Med Chem Lett. 2013 Jul 15;23(14):4127-31. doi: 10.1016/j.bmcl.2013.05.049. Epub 2013 May 23.
We previously reported the phenylchloronitrobenzamides (PCNBs), a novel class of compounds active against the species of trypanosomes that cause Human African Trypanosomiasis (HAT). Herein, we explored the potential to adjust the reactivity of the electrophilic chloronitrobenzamide core. These studies identified compound 7d that potently inhibited the growth of trypanosomes (EC50=120nM for Trypanosoma b. brucei, 18nM for Trypanosoma b. rhodesiense, and 38nM for Trypanosoma b. gambiense) without significant cytotoxicity against mammalian cell lines (EC50>25μM for HepG2, HEK293, Raji, and BJ cell lines) and also had good stability in microsomal models (t1/2>4h in both human and mouse). Overall these properties indicate the compound 7d and its analogs are worth further exploration as potential leads for HAT.
我们之前曾报道过苯氯硝酰胺（PCNBs），这是一类对引起人类非洲锥虫病（HAT）的锥虫种具有活性的新型化合物。在此，我们探索了调整亲电氯硝酰胺核心反应性的潜力。这些研究确定了化合物 7d，它能有效抑制锥虫的生长（对布氏锥虫的 EC50=120nM，对罗得西亚锥虫的 EC50=18nM，对冈比亚锥虫的 EC50=38nM），而对哺乳动物细胞系（对 HepG2、HEK293、Raji 和 BJ 细胞系的 EC50>25μM）没有明显的细胞毒性，并且在微粒体模型中也具有良好的稳定性（在人和小鼠中 t1/2>4h）。总的来说，这些特性表明化合物 7d 及其类似物值得进一步探索，作为 HAT 的潜在先导化合物。
