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

Bioorg Med Chem Lett. 2017 Feb 1;27(3):675-678. doi: 10.1016/j.bmcl.2016.11.019. Epub 2016 Nov 9.

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.

Keywords: Betti reaction products; Binding site flexibility; BoNT/A inhibitor; Botulinum neurotoxin serotype A; Structure-activity relationship.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Botulinum Toxins, Type A / antagonists & inhibitors*
  • Botulinum Toxins, Type A / metabolism
  • Hydroxyquinolines / chemistry*
  • Hydroxyquinolines / metabolism
  • Hydroxyquinolines / toxicity
  • Inhibitory Concentration 50
  • Mice
  • Phrenic Nerve / drug effects
  • Phrenic Nerve / metabolism
  • Protein Binding
  • Serogroup
  • Structure-Activity Relationship

Substances

  • Hydroxyquinolines
  • Botulinum Toxins, Type A