title: 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.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors.forename: Francesco
authors.initials: F
authors.lastname: Montalbano
authors.forename: Pedro M S D
authors.initials: PM
authors.lastname: Cal
authors.forename: Marta A B R
authors.initials: MA
authors.lastname: Carvalho
authors.forename: Lídia M
authors.initials: LM
authors.lastname: Gonçalves
authors.forename: Susana D
authors.initials: SD
authors.lastname: Lucas
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
authors.forename: Luís F
authors.initials: LF
authors.lastname: Veiros
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Pedro M P
authors.initials: PM
authors.lastname: Gois
mesh_terms: D001896:Boron Compounds / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D013237:Stereoisomerism
chemical_list: D001896:Boron Compounds; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D019272:Leukocyte Elastase