7-Hydroxy-2-substituted-4-H-1-benzopyran-4-one derivatives as aldose reductase inhibitors: a SAR study.
On the basis of the results of molecular modelling studies performed on the aldose reductase (ALR2) inhibitor 7-hydroxy-2-(4'-hydroxybenzyl)-4H-1-benzopyran-4-one (compound A) bound at the active site of the enzyme, we synthesised and tested on bovine and human ALR2 several derivatives modified at position 2 of the benzopyran moiety, in order to confirm the hypothesised binding mode of this compound. The substitution of the methylene bridge with the isosteric sulphur substituent gives an active derivative, while substitution with a polar NH causes a decrease in inhibitory activity; this is in accordance to the previously reported structure in which the methylene linker was found to be adjacent to a hydrophobic aminoacid (Leu300). Among the substituents at 4' position examined, the most favourable for inhibitory activity are those able to act as hydrogen bond donors, supporting the hypothesis of the importance of the interaction with Thr113 for the inhibition of the enzyme.
Costantino
L
L
Dipartimento di Scienze Farmaceutiche, Modena e Reggio Emilia University, Via Campi 183, I-41100 Modena, Italy. constantino.luca@unimo.it
Del Corso
A
A
Rastelli
G
G
Petrash
J M
JM
Mura
U
U
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000494:pharmacology*; D002417:Cattle; D002855:Chromatography, Thin Layer; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship
D001578:Benzopyrans; D004791:Enzyme Inhibitors; D000449:Aldehyde Reductase