Pyrido[1,2-a]pyrimidin-4-one Derivatives as a Novel Class of Selective Aldose Reductase Inhibitors Exhibiting Antioxidant Activity

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• 作者：Concettina La Motta ; Stefania Sartini ; Laura Mugnaini ; Francesca Simorini ; Sabrina Taliani ; Silvia Salerno ; Anna Maria Marini ; Federico Da Settimo ; Antonio Lavecchia ; Ettore Novellino ; Miriam Cantore
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：October 4, 2007
• 年：2007
• 卷：50
• 期：20
• 页码：4917 - 4927
• 全文大小：667K
• 年卷期：v.50,no.20(October 4, 2007)
• ISSN：1520-4804

文摘

2-Phenyl-pyrido[1,2-a]pyrimidin-4-one derivatives bearing a phenol or a catechol moiety in position 2 weretested as aldose reductase (ALR2) inhibitors and exhibited activity levels in the micromolar/submicromolarrange. Introduction of a hydroxy group in position 6 or 9 gave an enhancement of the inhibitory potency(compare 18, 19, 28, and 29 vs 13 and 14). Lengthening of the 2-side chain to benzyl determined a generalreduction in activity. The lack or the methylation of the phenol or catechol hydroxyls gave inactive (10-12, 21, 22, 25-27) or scarcely active (15, 17, 20) compounds, thus demonstrating that the phenol or catecholhydroxyls are involved in the enzyme pharmacophoric recognition. Moreover, all the pyridopyrimidinonesdisplayed significant antioxidant properties, with the best activity shown by the catechol derivatives. Thetheoretical binding mode of the most active compounds obtained by docking simulations into the ALR2crystal structure was fully consistent with the structure-activity relationships in the pyrido[1,2-a]pyrimidin-4-one series.