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
Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
Department of Chemistry and Physics, Hood College, Frederick, MD 21701, United States.
Bioorg Med Chem Lett. 2017 Feb 1;27(3):675-678. doi: 10.1016/j.bmcl.2016.11.019. Epub 2016 Nov 9.
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 IC values ⩽1μM and 11 effective at ⩽2μM in an ex vivo assay.
我们最初发现了肉毒杆菌神经毒素A（BoNT/A）的8-羟基喹啉抑制剂，并对其中一种活性较高的先导化合物的对映体进行了分离/测试，结果表明其结合位点具有相当大的灵活性。我们设计了一项有限的研究来调查这种灵活性并探究构效关系；利用贝蒂反应，使用三种8-羟基喹啉、三种杂芳胺和四种取代苯甲醛开发了一种由36种喹啉醇BoNT/A轻链抑制剂组成的化合物矩阵。这项研究揭示了一些迄今为止最有效的基于喹啉醇的BoNT/A抑制剂，在一项体外试验中，有7种化合物的IC值≤1μM，11种在≤2μM时有效。
