title: A matrix-focused structure-activity and binding site flexibility study of quinolinol inhibitors of botulinum neurotoxin serotype A.
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 IC50values ⩽1μM and 11 effective at ⩽2μM in an ex vivo assay.
authors.affiliation: Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
authors.forename: William A
authors.initials: WA
authors.lastname: Harrell
authors.affiliation: Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Vieira
authors.affiliation: Department of Chemistry and Physics, Hood College, Frederick, MD 21701, United States.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ensel
authors.affiliation: Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
authors.forename: Vicki
authors.initials: V
authors.lastname: Montgomery
authors.affiliation: Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Guernieri
authors.affiliation: Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
authors.forename: Vanessa S
authors.initials: VS
authors.lastname: Eccard
authors.affiliation: Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Campbell
authors.affiliation: Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
authors.forename: Virginia
authors.initials: V
authors.lastname: Roxas-Duncan
authors.affiliation: Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
authors.forename: John H
authors.initials: JH
authors.lastname: Cardellina
authors.affiliation: Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States. Electronic address: robert.p.webb6.civ@mail.mil.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Webb
authors.affiliation: Medical Countermeasures Technology, Office of the Chief Scientist, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
authors.forename: Leonard A
authors.initials: LA
authors.lastname: Smith
mesh_terms: D000818:Animals; D001665:Binding Sites; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006912:Hydroxyquinolines / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D020128:Inhibitory Concentration 50; D051379:Mice; D010791:Phrenic Nerve / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D065288:Serogroup; D013329:Structure-Activity Relationship
chemical_list: D006912:Hydroxyquinolines; D019274:Botulinum Toxins, Type A
keywords: Betti reaction products; Binding site flexibility; BoNT/A inhibitor; Botulinum neurotoxin serotype A; Structure-activity relationship