Browsing by Subject "Botulinum Toxins, Type A--antagonists & inhibitors"
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Item A matrix-focused structure-activity and binding site flexibility study of quinolinol inhibitors of botulinum neurotoxin serotype A(Bioorganic & Medicinal Chemistry Letters, 2017-02-01) Harrell, William A. Jr.; Vieira, Rebecca C.; Ensel, Susan M.; Montgomery, Vicki; Guernieri, Rebecca; Eccard, Vanessa S.; Campbell, Yvette; Roxas-Duncan, Virginia; Cardellina, John H. II; Webb, Robert P.; Smith, Leonard A.; ChemistryOur 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.