title: Pyrido[1,2-a]pyrimidin-4-one derivatives as a novel class of selective aldose reductase inhibitors exhibiting antioxidant activity.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. lamotta@farm.unipi.it
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.forename: Stefania
authors.initials: S
authors.lastname: Sartini
authors.forename: Laura
authors.initials: L
authors.lastname: Mugnaini
authors.forename: Francesca
authors.initials: F
authors.lastname: Simorini
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Silvia
authors.initials: S
authors.lastname: Salerno
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Marini
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Miriam
authors.initials: M
authors.lastname: Cantore
authors.forename: Paola
authors.initials: P
authors.lastname: Failli
authors.forename: Mario
authors.initials: M
authors.lastname: Ciuffi
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002396:Catechols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000201:enzymology; D007908:Lens, Crystalline / Q000201:enzymology; D008958:Models, Molecular; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014020:Tissue Extracts
chemical_list: D000975:Antioxidants; D002396:Catechols; D011725:Pyridines; D011743:Pyrimidines; D014020:Tissue Extracts; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase