Synthesis of pyrido[1,2a]pyrimidin-4-one derivatives as COX inhibitors

Synthesis of Pyrido[1,2-a]pyrimidin-4-one derivatives as COX inhibitors During recent years it became clear that atherosclerosis is a complex condition and that different factors contribute to trigger and sustain vessel wall damage. Actually recent studies showed that not only blood lipid concentration plays an important role but also inflammatory processes contribute to the development and rupture of the vulnerable plaque1. On the basis of these considerations we decided to develop a novel class of molecules showing antioxidant and anti-inflammatory properties. A natural class of compounds able to act with pleiotropic effects is represented by flavonoids (the most abundant polyphenols present in human diet), that showed anti-inflammatory, antiviral, antiplatelet, antihemorragic and antiallergic properties, as well as antioxidant effects being able to scavenge hydroxyl radicals, superoxide anions and lipid peroxyl radicals. Flavonoids are based on the structure of 2-phenylchroman, differing one from each other in the orientation of hydroxyl or methyl groups, the position of the phenyl substituent, the degree of unsaturation and the types of sugar attached. Structure-activity studies indicate that the presence of 3-hydroxyl group on the heterocyclic ring and the catechol moiety in position 2 favors antioxidant activity, in particular the hydroxyl group on the ring in position 2 appears to be crucial for antioxidant activity. The anti-inflammatory activity of flavonoids, showed in vitro or in cellular models, involves the inhibition of different pro-inflammatory mediators synthesis, such as eicosanoids, cytokines, adhesion molecules and C-reactive protein2,3. However the flavonoids possess an inadequate therapeutic index. On the basis of this previously considerations the research group where I did my thesis decided to focus attention on a class of derivatives, with 2-phenyl-pyrido[1,2-a]pyrimidin-4-one scaffold, with antioxidant properties4. So we considered that a good starting point to develop a class of molecules able to act also as anti-inflammatory compounds. For these reasons I brought suitable modifications on the heterocyclic core in order to obtain structural similarity to well-known therapeutic selective COX-2 inhibitors. References 1. Michos, E. D.; Blumenthal, R. S. Prevalence of Low Low-Density Lipoprotein Cholesterol With Elevated High Sensitivity CReactive Protein in the U.S.: Implications of the JUPITER (Justification for the Use of Statins in Primary Prevention: AnIntervention Trial Evaluating Rosuvastatin) Study. J. Am. Coll.Cardiol. 2009, 53, 931-935. 2. Serafini M.; Peluso I.; Raguzzini A. Flavonoids as antiinflammatory agents. Proc Nutr Soc. 2010, 69, 273-278. 3. Xue Qin C.; Chen X,; Hughes R.A.; et al. Understanding the cardioprotective effects of flavonols: discovery of relaxant flavonols without antioxidant activity. J. Med. Chem. 2008, 51, 1874-1884. 4. La Motta C.; Sartini S.; Mugnaini L.; Simorini F.; et al. Pyrido[1,2-a]pyrimidin-4-one Derivatives as a Novel Class of Selective Aldose Reductase Inhibitors Exhibiting Antioxidant Activity. J. Med. Chem. 2007, 50, 4917-4927