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>