期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 36, 期 1, 页码 1810-1828出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2021.1956912
关键词
COX-2 inhibition; quinazolinone; anti-inflammatory; molecular modelling; Anticancer
资金
- National Institute of General Medical Sciences of the National Institutes of Health [P20 GM121334]
The novel compounds designed to increase COX-2 selectivity showed superior anti-inflammatory and antioxidant activity, as well as anticancer and improved analgesic effects. Both in vitro and in vivo studies support their potential role as anti-inflammatory agents.
Novel quinazolinones conjugated with indole acetamide (4a-c), ibuprofen (7a-e), or thioacetohydrazide (13a,b, and 14a-d) were designed to increase COX-2 selectivity. The three synthesised series exhibited superior COX-2 selectivity compared with the previously reported quinazolinones and their NSAID analogue and had equipotent COX-2 selectivity as celecoxib. Compared with celecoxib, 4 b, 7c, and 13 b showed similar anti-inflammatory activity in vivo, while 13 b and 14a showed superior inhibition of the inflammatory mediator nitric oxide, and 7 showed greater antioxidant potential in macrophages cells. Moreover, all selected compounds showed improved analgesic activity and 13 b completely abolished the pain response. Additionally, compound 4a showed anticancer activity in tested cell lines HCT116, HT29, and HCA7. Docking results were consistent with COX-1/2 enzyme assay results. In silico studies suggest their high oral bioavailability. The overall findings for compounds (4a,b, 7c, 13 b, and 14c) support their potential role as anti-inflammatory agents.
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