Pyrido[1,2-a]pyrimidin-4-one derivatives as a novel class of selective aldose reductase inhibitors exhibiting antioxidant activity
| Autor: | C. LA MOTTA, S. SARTINI, L. MUGNAINI, F. SIMORINI, S. TALIANI, S. SALERNO, A. M. MARINI, G. PRIMOFIORE, F. DA SETTIMO, LAVECCHIA, ANTONIO, NOVELLINO, ETTORE, M. CANTORE, P. FAILLI, M. CIUFFI |
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| Přispěvatelé: | C., LA MOTTA, S., Sartini, L., Mugnaini, F., Simorini, S., Taliani, S., Salerno, A. M., Marini, G., Primofiore, F., DA SETTIMO, Lavecchia, Antonio, Novellino, Ettore, M., Cantore, P., Failli, M., Ciuffi |
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Aldose reductase (ALR2) inhibitor Pyridines Stereochemistry Catechols 2-phenylpyrido[1 2-a]pyrimidin-4-one aldose reductase aldehyde reductase aldose reductase inhibitor reactive oxygen species protein kinase C mitogenactivated protein kinase poly(ADP-ribose)polymerase aldo-keto reductase thiobarbituric acid reactive substances molecular dynamics structure-activity relationship malondialdehyde Kidney Antioxidants Structure-Activity Relationship chemistry.chemical_compound Aldehyde Reductase Lens Crystalline Drug Discovery Animals Humans Structure–activity relationship Moiety antidiabetic drug Catechol Aldose reductase Binding Sites Bicyclic molecule biology Tissue Extracts molecular docking Aldose reductase inhibitors Rats Pyrimidines chemistry Docking (molecular) Enzyme inhibitor biology.protein Molecular Medicine |
| Popis: | 2-Phenyl-pyrido[1,2-a]pyrimidin-4-one derivatives bearing a phenol or a catechol moiety in position 2 were tested as aldose reductase (ALR2) inhibitors and exhibited activity levels in the micromolar/submicromolar range. 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 general reduction 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 catechol hydroxyls are involved in the enzyme pharmacophoric recognition. Moreover, all the pyridopyrimidinones displayed significant antioxidant properties, with the best activity shown by the catechol derivatives. The theoretical binding mode of the most active compounds obtained by docking simulations into the ALR2 crystal structure was fully consistent with the structure-activity relationships in the pyrido[1,2-a]pyrimidin-4-one series. |
| Databáze: | OpenAIRE |
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