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ID: ALA4000225

Journal: Bioorg Med Chem Lett

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

Authors: Harrell WA, Vieira RC, Ensel SM, Montgomery V, Guernieri R, Eccard VS, Campbell Y, Roxas-Duncan V, Cardellina JH, Webb RP, Smith LA.

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.

CiteXplore: 28043798

DOI: 10.1016/j.bmcl.2016.11.019