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

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.