A matrix-focused structure-activity and binding site flexibility study of quinolinol inhibitors of botulinum neurotoxin serotype A

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10.1016/j.bmcl.2016.11.019
 http://hdl.handle.net/11603/17360

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Stevenson University Faculty and Staff Works
Stevenson University Beverly K. Fine School of the Sciences Faculty and Staff Works

Author/Creator

Author/Creator ORCID

Date

2017-02-01

Type of Work

Journal Article
Text

Department

Chemistry

Program

Citation of Original Publication

Harrell, W. A., Jr, Vieira, R. C., Ensel, S. M., Montgomery, V., Guernieri, R., Eccard, V. S., Campbell, Y., Roxas-Duncan, V., Cardellina, J. H., 2nd, Webb, R. P., & Smith, L. A. (2017). A matrix-focused structure-activity and binding site flexibility study of quinolinol inhibitors of botulinum neurotoxin serotype A. Bioorganic & Medicinal Chemistry Letters, 27(3), 675–678. https://doi.org/10.1016/j.bmcl.2016.11.019

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Subjects

Botulinum Toxins, Type A--antagonists & inhibitors
Hydroxyquinolines--chemistry
Animals
Binding Sites
Botulinum Toxins, Type A--metabolism
Hydroxyquinolines--metabolism
Hydroxyquinolines--toxicity
Inhibitory Concentration 50
Mice
Phrenic Nerve/metabolism
Phrenic Nerve--drug effects
Phrenic Nerve--metabolism
Protein Binding
Serogroup
Structure-Activity Relationship

Abstract

Our initial discovery of 8-hydroxyquinoline inhibitors of BoNT/A and separation/testing of enantiomers of one of the more active leads indicated considerable flexibility in the binding site. We designed a limited study to investigate this flexibility and probe structure-activity relationships; utilizing the Betti reaction, a 36 compound matrix of quinolinol BoNT/A LC inhibitors was developed using three 8-hydroxyquinolines, three heteroaromatic amines, and four substituted benzaldehydes. This study has revealed some of the most effective quinolinol-based BoNT/A inhibitors to date, with 7 compounds displaying IC50 values ⩽1μM and 11 effective at ⩽2μM in an ex vivo assay.