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

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 cluster...

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Bibliographic Details
Published in:PLoS neglected tropical diseases 2019-02, Vol.13 (2), p.e0007129-e0007129
Main Authors: Klug, Dana M, Diaz-Gonzalez, Rosario, Pérez-Moreno, Guiomar, Ceballos-Pérez, Gloria, García-Hernández, Raquel, Gomez-Pérez, Veronica, Ruiz-Pérez, Luis Miguel, Rojas-Barros, Domingo I, Gamarro, Francisco, González-Pacanowska, Dolores, Martínez-Martínez, María S, Manzano, Pilar, Ferrins, Lori, Caffrey, Conor R, Navarro, Miguel, Pollastri, Michael P
Format: Article
Language:English
Subjects:
African trypanosomiasis
Antibiotics
Biology
Biology and Life Sciences
Chagas disease
Chemistry
Clinical trials
Clusters
Dosage and administration
Drug therapy
Drugs
Excretion
High-throughput screening
Identification
Inhibitors
Kinase inhibitors
Kinases
Medical treatment
Medicine and Health Sciences
Metabolism
Nervous system
Parasites
Parasitic diseases
Pharmacokinetics
Pharmacology
Schistosomiasis
Tropical climate
Tropical diseases
Trypanosomiasis
Vector-borne diseases
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Description
Summary: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.
ISSN:1935-2735
1935-2727
1935-2735
DOI:10.1371/journal.pntd.0007129