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 N-benzoylindazoles previously reported by us. On the other hand, they exhibited increased stability in aqueous solution. The most potent compound, 18a, had a good balance between HNE inhibitory activity (IC50 value = 56 nM) and chemical stability (t1/2 = 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(1H)-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.

Cinnoline derivatives as human neutrophil elastase inhibitors / Giovannoni, Maria Paola; Crocetti, Letizia; Ciciani, Giovanna; Cilibrizzi, Agostino; Guerrini, Gabriella; Vergelli, Claudia. - In: JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY. - ISSN 1475-6366. - ELETTRONICO. - 31:(2016), pp. 628-639. [10.3109/147563662015.1057718]

Cinnoline derivatives as human neutrophil elastase inhibitors

GIOVANNONI, MARIA PAOLA;CROCETTI, LETIZIA;CICIANI, GIOVANNA;GUERRINI, GABRIELLA;VERGELLI, CLAUDIA
2016

Abstract

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 N-benzoylindazoles previously reported by us. On the other hand, they exhibited increased stability in aqueous solution. The most potent compound, 18a, had a good balance between HNE inhibitory activity (IC50 value = 56 nM) and chemical stability (t1/2 = 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(1H)-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.
2016
31
628
639
Goal 3: Good health and well-being for people
Giovannoni, Maria Paola; Crocetti, Letizia; Ciciani, Giovanna; Cilibrizzi, Agostino; Guerrini, Gabriella; Vergelli, Claudia
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1007329
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