10.6084/m9.figshare.3203581.v1
Maria Paola Giovannoni
Maria Paola
Giovannoni
Igor A. Schepetkin
Igor A.
Schepetkin
Letizia Crocetti
Letizia
Crocetti
Giovanna Ciciani
Giovanna
Ciciani
Agostino Cilibrizzi
Agostino
Cilibrizzi
Gabriella Guerrini
Gabriella
Guerrini
Andrei I. Khlebnikov
Andrei I.
Khlebnikov
Mark T. Quinn
Mark T.
Quinn
Claudia Vergelli
Claudia
Vergelli
Cinnoline derivatives as human neutrophil elastase inhibitors
Taylor & Francis Group
2016
HNE binding site
HNE Ser 195 hydroxyl group
cinnoline derivatives
IC
neutrophil elastase inhibitors Compounds
HNE inhibitors
2016-04-27 13:37:26
Journal contribution
https://tandf.figshare.com/articles/journal_contribution/Cinnoline_derivatives_as_human_neutrophil_elastase_inhibitors/3203581
<p>Compounds that can effectively inhibit the proteolytic activity of human neutrophil elastase (HNE) represent promising therapeutics for treatment of inflammatory diseases. We present here the synthesis, structure–activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with a cinnoline scaffold. These compounds exhibited HNE inhibitory activity but had lower potency compared to <i>N</i>-benzoylindazoles previously reported by us. On the other hand, they exhibited increased stability in aqueous solution. The most potent compound, <b>18a</b>, had a good balance between HNE inhibitory activity (IC<sub>50</sub> value = 56 nM) and chemical stability (<i>t</i><sub>1/2</sub> = 114 min). Analysis of reaction kinetics revealed that these cinnoline derivatives were reversible competitive inhibitors of HNE. Furthermore, molecular docking studies of the active products into the HNE binding site revealed two types of HNE inhibitors: molecules with cinnolin-4(1<i>H</i>)-one scaffold, which were attacked by the HNE Ser195 hydroxyl group at the amido moiety, and cinnoline derivatives containing an ester function at C-4, which is the point of attack of Ser195.</p>