Discovery of new heterocycles with activity against human neutrophile elastase based on a boron promoted one-pot assembly reaction

Org Biomol Chem. 2013 Jul 21;11(27):4465-72. doi: 10.1039/c3ob40614h.

Abstract

Herein we demonstrate for the first time that a boron promoted one-pot assembly reaction may be used to discover novel enzyme inhibitors. Inhibitors for HNE were simply assembled in excellent yields, high diastereoselectivities and IC50 up to 1.10 μM, based on components like salicylaldehyde, aryl boronic acids and amino acids. The combination of synthetic, biochemical, analytical and theoretical studies allowed the identification of the 4-methoxy or the 4-diethyl amino substituent of the salicylaldehyde as the most important recognition moiety and the imine alkylation, lactone ring opening as key events in the mechanism of inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Boron Compounds / chemistry*
  • Boron Compounds / pharmacology*
  • Drug Design
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Leukocyte Elastase / antagonists & inhibitors*
  • Leukocyte Elastase / metabolism
  • Models, Molecular
  • Stereoisomerism

Substances

  • Boron Compounds
  • Enzyme Inhibitors
  • Heterocyclic Compounds
  • Leukocyte Elastase