1-Benzopyran-4-one antioxidants as aldose reductase inhibitors.
Starting from the inhibitory activity of the flavonoid Quercetin, a series of 4H-1-benzopyran-4-one derivatives was synthesized and tested for inhibition of aldose reductase, an enzyme involved in the appearance of diabetic complications. Some of the compounds obtained display inhibitory activity similar to that of Sorbinil but are more selective than Quercetin and Sorbinil with respect to the closely related enzyme, aldehyde reductase, and also possess antioxidant activity. Remarkably, these compounds possess higher pKa values than carboxylic acids, a characteristic which could make the pharmacokinetics of these compounds very interesting. Molecular modeling investigations on the structures of inhibitors bound at the active site of aldose reductase were performed in order to suggest how these new inhibitors might bind to the enzyme and also to interpret structure-activity relationships.
Costantino
L
L
Dipartimento di Scienze Farmaceutiche, Dipartimento di Scienze Biomediche, and Dipartimento di Chimica, Università di Modena, Via Campi 183, 41100 Modena, Italy.
Rastelli
G
G
Gamberini
M C
MC
Vinson
J A
JA
Bose
P
P
Iannone
A
A
Staffieri
M
M
Antolini
L
L
Del Corso
A
A
Mura
U
U
Albasini
A
A
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry; D002417:Cattle; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007668:Kidney / Q000201:enzymology; D007908:Lens, Crystalline / Q000201:enzymology; D008077:Lipoproteins, LDL / Q000737:chemistry; D008079:Lipoproteins, VLDL / Q000737:chemistry; D008958:Models, Molecular; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship
D000975:Antioxidants; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D000449:Aldehyde Reductase