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

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

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.