a NEUROFARBA, Pharmaceutical and Nutraceutical Section , University of Florence , Sesto Fiorentino , Italy.
b Department of Microbiology and Immunology , Montana State University , Bozeman , MT , USA.
J Enzyme Inhib Med Chem. 2018 Dec;33(1):1108-1124. doi: 10.1080/14756366.2018.1480615.
We report the synthesis and biological evaluation of a new series of 3- or 4-(substituted)phenylisoxazolones as HNE inhibitors. Due to tautomerism of the isoxazolone nucleus, two isomers were obtained as final compounds (2-NCO and 5-OCO) and the 2-NCO derivatives were the most potent with IC values in the nanomolar range (20-70 nM). Kinetic experiments indicated that 2-NCO 7d and 5-OCO 8d are both competitive HNE inhibitors. Molecular modelling on 7d and 8d suggests for the latter a more crowded region about the site of the nucleophilic attack, which could explain its lowered activity. In addition molecular dynamics (MD) simulations showed that the isomer 8d appears more prone to form H-bond interactions which, however, keep the reactive sites quite distant for the attack by Ser195. By contrast the amide 7d appears more mobile within the active pocket, since it makes single H-bond interactions affording a favourable orientation for the nucleophilic attack.
我们报告了一系列新的 3-或 4-（取代）苯基异恶唑酮作为 HNE 抑制剂的合成和生物学评价。由于异恶唑酮核的互变异构现象，最终得到了两种异构体（2-NCO 和 5-OCO），其中 2-NCO 衍生物的活性最强，IC 值在纳摩尔范围内（20-70 nM）。动力学实验表明，2-NCO 7d 和 5-OCO 8d 均为竞争性 HNE 抑制剂。对 7d 和 8d 的分子建模表明，后者在亲核攻击部位周围的区域更为拥挤，这可能解释了其活性降低的原因。此外，分子动力学（MD）模拟表明，异构体 8d 更容易形成氢键相互作用，但这些相互作用使反应位点与 Ser195 的攻击保持相当远的距离。相比之下，酰胺 7d 在活性口袋内似乎更具流动性，因为它只形成氢键相互作用，从而为亲核攻击提供有利的取向。
