Abstract

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.

摘要

与吲哚乙酰胺(4a – c)、布洛芬 ( 7a – e)或硫代乙酰肼 ( 13a、b和14a-d )结合的新型喹唑啉酮旨在提高 COX-2 的选择性。与之前报道的喹唑啉酮类及其 NSAID 类似物相比，三个合成的系列表现出优异的 COX-2 选择性，并且与塞来昔布具有同等的 COX-2 选择性。与塞来昔布相比，4b、7c和13b在体内表现出相似的抗炎活性，而13b和14a对炎症介质一氧化氮的抑制作用更强，7在巨噬细胞中显示出更大的抗氧化潜力。此外，所有选定的化合物都显示出改善的镇痛活性，并且13b完全消除了疼痛反应。此外，化合物4a在测试的细胞系 HCT116、HT29 和 HCA7 中显示出抗癌活性。对接结果与COX-1/2酶测定结果一致。计算机研究表明它们具有高口服生物利用度。化合物（4a、b、7c、13b和14c）的总体发现支持它们作为抗炎剂的潜在作用。