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PLoS Negl Trop Dis. 2019 Feb 8;13(2):e0007129. doi: 10.1371/journal.pntd.0007129. [Epub ahead of print]

Evaluation of a class of isatinoids identified from a high-throughput screen of human kinase inhibitors as anti-Sleeping Sickness agents.

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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, Granada, Spain.
Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline, Tres Cantos, Spain.
Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States of America.


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.

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Conflict of interest statement

We have read the journal's policy and the authors of this manuscript have the following competing interests: Two of the co-authors (MSM-M, PM) are employed by GlaxoSmithKline. Data was provided, free of charge, by AstraZeneca.

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