Northeastern University Department of Chemistry & Chemical Biology, Boston, MA, United States of America.
Instituto de Parasitología y Biomedicina "López-Neyra" Consejo Superior de Investigaciones Cientificas (CSIC), Granada, Spain.
PLoS Negl Trop Dis. 2019 Feb 8;13(2):e0007129. doi: 10.1371/journal.pntd.0007129. eCollection 2019 Feb.
New treatments are needed for neglected tropical diseases (NTDs) such as Human African trypanosomiasis (HAT), Chagas disease, and schistosomiasis. Through a whole organism high-throughput screening campaign, we previously identified 797 human kinase inhibitors that grouped into 59 structural clusters and showed activity against T. brucei, the causative agent of HAT. We herein report the results of further investigation of one of these clusters consisting of substituted isatin derivatives, focusing on establishing structure-activity and -property relationship scope. We also describe their in vitro absorption, distribution, metabolism, and excretion (ADME) properties. For one isatin, NEU-4391, which offered the best activity-property profile, pharmacokinetic parameters were measured in mice.
需要新的治疗方法来治疗被忽视的热带病（NTDs），如非洲人类锥虫病（HAT）、恰加斯病和血吸虫病。通过全生物体高通量筛选活动，我们之前鉴定了 797 种人类激酶抑制剂，它们分为 59 个结构簇，并对引起 HAT 的病原体布氏锥虫具有活性。在此，我们报告了对由取代的靛红衍生物组成的这些簇之一的进一步研究结果，重点是建立结构-活性和性质关系范围。我们还描述了它们的体外吸收、分布、代谢和排泄（ADME）特性。对于一种具有最佳活性-性质特征的靛红衍生物 NEU-4391，在小鼠中测量了其药代动力学参数。
