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PLoS Negl Trop Dis. 2019 Feb 8;13(2):e0007129. doi: 10.1371/journal.pntd.0007129. eCollection 2019 Feb.

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

Author information

1
Northeastern University Department of Chemistry & Chemical Biology, Boston, MA, United States of America.
2
Instituto de Parasitología y Biomedicina "López-Neyra" Consejo Superior de Investigaciones Cientificas (CSIC), Granada, Spain.
3
Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline, Tres Cantos, Spain.
4
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.

Abstract

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.

PMID:
30735501
PMCID:
PMC6383948
DOI:
10.1371/journal.pntd.0007129
[Indexed for MEDLINE]
Free PMC Article

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