Cinnoline derivatives as human neutrophil elastase inhibitors; Journal of Enzyme Inhibition and Medicinal Chemistry; Vol. 31, iss. 4

Cinnoline derivatives as human neutrophil elastase inhibitors; Journal of Enzyme Inhibition and Medicinal Chemistry; Vol. 31, iss. 4

Dettagli Bibliografici
Parent link:Journal of Enzyme Inhibition and Medicinal Chemistry
Vol. 31, iss. 4.— 2016.— [P. 628-639]
Ente Autore: Национальный исследовательский Томский политехнический университет Институт физики высоких технологий Кафедра биотехнологии и органической химии
Altri autori: Giovannoni M. P. Maria Paola, Schepetkin (Shchepyotkin) I. A. Igor Aleksandrovich, Crocetti L. Letizia, Ciciani G. Giovanna, Cilibrizzi A. Agostino, Guerrini G. Gabriella, Khlebnikov A. I. Andrey Ivanovich, Quinn M. T. Mark, Vergelli C. Claudia
Riassunto:Title screen
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 (IC50value = 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.
Режим доступа: по договору с организацией-держателем ресурса
Lingua:inglese
Pubblicazione: 2016
Soggetti:
электронный ресурс
труды учёных ТПУ
Accesso online:http://dx.doi.org/10.3109/14756366.2015.1057718
Natura: Elettronico Capitolo di libro
KOHA link:https://koha.lib.tpu.ru/cgi-bin/koha/opac-detail.pl?biblionumber=651577

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