Isoxazol-5(2H)-one: a new scaffold for potent human neutrophil elastase (HNE) inhibitors

Abstract

Human neutrophil elastase (HNE) is an important target for the development of novel and selective inhibitors to treat inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis, structure–activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with an isoxazol-5(2H)-one scaffold. The most potent compound (2o) had a good balance between HNE inhibitory activity (IC₅₀ value =20 nM) and chemical stability in aqueous buffer (t_1/2=8.9 h). Analysis of reaction kinetics revealed that the most potent isoxazolone derivatives were reversible competitive inhibitors of HNE. Furthermore, since compounds 2o and 2s contain two carbonyl groups (2-N-CO and 5-CO) as possible points of attack for Ser195, the amino acid of the active site responsible for the nucleophilic attack, docking studies allowed us to clarify the different roles played by these groups.

Graphical Abstract

Keywords:

• Isoxazol-5(2H)-one
• human neutrophil elastase
• HNE inhibitor
• chemical stability
• molecular docking

Disclosure statement

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); University of Montana System Research Initiative: 51040-MUSRI2015-03; and the Montana State University Agricultural Experiment Station.

Additional information

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); University of Montana System Research Initiative: 51040-MUSRI2015-03; and the Montana State University Agricultural Experiment Station.