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

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• 作者：William A. Harrell Jr.^a ; ^d ; Rebecca C. Vieira^a ; ^e ; Susan M. Ensel^b ; Vicki Montgomery^a ; Rebecca Guernieri^a ; Vanessa S. Eccard^a ; ^f ; Yvette Campbell^a ; Virginia Roxas-Duncan^a ; ^g ; John H. Cardellina II^a ; ^h ; Robert P. Webb^a ; ^{robert.p.webb6.civ@mail.mil} ; Leonard A. Smith^c
• 关键词：BoNTs ; botulinum neurotoxins ; BoNT/A ; botulinum neurotoxin serotype A ; HC ; heavy chain ; LC ; light chain ; SNARE ; soluble N-ethylmaleimide-sensitive factor attachment protein receptor ; SNAP-25 ; 25  ; kDa synaptosomal-associated protein ; BIG-IV ; Botulism Immune Globulin Intravenous (Human) ; SAR ; structure-activity relationship ; IC50 ; 50% inhibitory concentration ; MPNHDA ; mouse phrenic nerve hemidiaphragm assay
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：27
• 期：3
• 页码：675-678
• 全文大小：399 K
• 卷排序：27

文摘

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 ⩽1 μM and 11 effective at ⩽2 μM in an ex vivo assay.