title: Cinnoline derivatives as human neutrophil elastase inhibitors.
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.
authors.affiliation: a NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze , Sesto Fiorentino , Italy .
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Giovannoni
authors.affiliation: b Department of Immunology and Infectious Diseases , Montana State University , Bozeman , MT , USA .
authors.forename: Igor A
authors.initials: IA
authors.lastname: Schepetkin
authors.affiliation: a NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze , Sesto Fiorentino , Italy .
authors.forename: Letizia
authors.initials: L
authors.lastname: Crocetti
authors.affiliation: a NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze , Sesto Fiorentino , Italy .
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ciciani
authors.affiliation: c Department of Chemistry , Imperial College London , South Kensington , London , UK .
authors.forename: Agostino
authors.initials: A
authors.lastname: Cilibrizzi
authors.affiliation: a NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze , Sesto Fiorentino , Italy .
authors.forename: Gabriella
authors.initials: G
authors.lastname: Guerrini
authors.affiliation: d Department of Biotechnology and Organic Chemistry , Tomsk Polytechnic University , Tomsk , Russia , and.|e Department of Chemistry , Altai State Technical University , Barnaul , Russia.
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Khlebnikov
authors.affiliation: b Department of Immunology and Infectious Diseases , Montana State University , Bozeman , MT , USA .
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
authors.affiliation: a NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze , Sesto Fiorentino , Italy .
authors.forename: Claudia
authors.initials: C
authors.lastname: Vergelli
mesh_terms: D004305:Dose-Response Relationship, Drug; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D053491:Proteinase Inhibitory Proteins, Secretory / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D006574:Heterocyclic Compounds, 2-Ring; D053491:Proteinase Inhibitory Proteins, Secretory; D019272:Leukocyte Elastase; C476282:cinnoline
keywords: Cinnoline; human neutrophil elastase; inhibitory activity