Synthesis, biological evaluation, and molecular modelling studies of potent human neutrophil elastase (HNE) inhibitors

J Enzyme Inhib Med Chem. 2018 Dec;33(1):1108-1124. doi: 10.1080/14756366.2018.1480615.

Abstract

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 IC50 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.

Keywords: HNE; Isoxazol-5(2H)-one; molecular modelling; stability.

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Leukocyte Elastase / antagonists & inhibitors*
  • Leukocyte Elastase / metabolism
  • Models, Molecular*
  • Molecular Structure
  • Proteinase Inhibitory Proteins, Secretory / chemical synthesis
  • Proteinase Inhibitory Proteins, Secretory / chemistry
  • Proteinase Inhibitory Proteins, Secretory / pharmacology*
  • Structure-Activity Relationship

Substances

  • Isoxazoles
  • Proteinase Inhibitory Proteins, Secretory
  • Leukocyte Elastase

Grants and funding

This research was supported in part by National Institutes of Health IDeA Program COBRE Grant GM110732; USDA National Institute of Food and Agriculture Hatch project 1009546; the Ministry of Education and Science of the Russian Federation (project No. 4.8192.2017), Montana University System Research Initiative: 51040-MUSRI2015–03; Montana State University Agricultural Experiment Station.