Evaluation of substituted ebselen derivatives as potential trypanocidal agents

[Display omitted] Human African trypanosomiasis is a disease of sub-Saharan Africa, where millions are at risk for the illness. The disease, commonly referred to as African sleeping sickness, is caused by an infection by the eukaryotic pathogen, Trypanosoma brucei. Previously, a target-based high th...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2017-02, Vol.27 (3), p.537-541
Main Authors: Gordhan, Heeren M., Patrick, Stephen L., Swasy, Maria I., Hackler, Amber L., Anayee, Mark, Golden, Jennifer E., Morris, James C., Whitehead, Daniel C.
Format: Article
Language:English
Subjects:
Antiprotozoal Agents - chemical synthesis
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - pharmacology
Azoles - chemical synthesis
Azoles - chemistry
Azoles - pharmacology
Dose-Response Relationship, Drug
Ebselen
Hexokinases
Molecular Structure
Organoselenium Compounds - chemical synthesis
Organoselenium Compounds - chemistry
Organoselenium Compounds - pharmacology
Parasitic Sensitivity Tests
Structure-Activity Relationship
Trypanocidal Agents - chemical synthesis
Trypanocidal Agents - chemistry
Trypanocidal Agents - pharmacology
Trypanosoma brucei brucei - drug effects
Trypanosomes
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Summary:[Display omitted] Human African trypanosomiasis is a disease of sub-Saharan Africa, where millions are at risk for the illness. The disease, commonly referred to as African sleeping sickness, is caused by an infection by the eukaryotic pathogen, Trypanosoma brucei. Previously, a target-based high throughput screen revealed ebselen (EbSe), and its sulfur analog, EbS, to be potent in vitro inhibitors of the T. brucei hexokinase 1 (TbHK1). These molecules also exhibited potent trypanocidal activity in vivo. In this manuscript, we synthesized a series of sixteen EbSe and EbS derivatives bearing electron-withdrawing carboxylic acid and methyl ester functional groups, and evaluated the influence of these substituents on the biological efficacy of the parent scaffold. With the exception of one methyl ester derivative, these modifications ablated or blunted the potent TbHK1 inhibition of the parent scaffold. Nonetheless, a few of the methyl ester derivatives still exhibited trypanocidal effects with single-digit micromolar or high nanomolar EC50 values.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2016.12.021