Cinnoline derivatives as human neutrophil elastase inhibitors

Cinnoline derivatives as human neutrophil elastase inhibitors

Podrobná bibliografie
Parent link:Journal of Enzyme Inhibition and Medicinal Chemistry
Vol. 31, iss. 4.— 2016.— [P. 628-639]
Korporativní autor: Национальный исследовательский Томский политехнический университет Институт физики высоких технологий Кафедра биотехнологии и органической химии
Další autoři: 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
Shrnutí: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
Vydáno: 2016
Témata:
электронный ресурс
труды учёных ТПУ
On-line přístup:http://dx.doi.org/10.3109/14756366.2015.1057718
Médium: Elektronický zdroj Kapitola
KOHA link:https://koha.lib.tpu.ru/cgi-bin/koha/opac-detail.pl?biblionumber=651577

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