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A matrix-focused structure-activity and binding site flexibility study of quinolinol inhibitors of botulinum neurotoxin serotype A.
Harrell, William A; Vieira, Rebecca C; Ensel, Susan M; Montgomery, Vicki; Guernieri, Rebecca; Eccard, Vanessa S; Campbell, Yvette; Roxas-Duncan, Virginia; Cardellina, John H; Webb, Robert P; Smith, Leonard A.
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  • Harrell WA; Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
  • Vieira RC; Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
  • Ensel SM; Department of Chemistry and Physics, Hood College, Frederick, MD 21701, United States.
  • Montgomery V; Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
  • Guernieri R; Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
  • Eccard VS; Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
  • Campbell Y; Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
  • Roxas-Duncan V; Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
  • Cardellina JH; Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
  • Webb RP; 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.
  • Smith LA; Medical Countermeasures Technology, Office of the Chief Scientist, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
Bioorg Med Chem Lett ; 27(3): 675-678, 2017 02 01.
Article en En | MEDLINE | ID: mdl-28043798
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Toxinas Botulínicas Tipo A / Hidroxiquinolinas Límite: Animals Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Toxinas Botulínicas Tipo A / Hidroxiquinolinas Límite: Animals Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido