Study On The Design And Synthesis Of N - Benzylquinolinone Acetic Acid Compounds And The Inhibitory Activity Of Aldose Reductase

The structure of aldose reductase(ALR2), and its relationships with diabetic complications and nondiabetic diseases are reviewed briefly in this thesis. In recent years, ALR2 has received many attentions as a potent target for preventing or treating diabetic complications, cardiac disorders, inflammation, mood disorders, renal insufficiency, ovarian abnormalities and cancers, and its inhibitors have been investigated profoundly.Based on the structure features of carboxylic acids and chalcones with aldose reductase inhibitory activities and their action mechanisms on aldose reductase (ALR2), and the compl-eted works in our laboratory, a series of 2-(1-benzyl-6-methyl-4-oxo-1,4-dihyd-roquinolin-3-yl)acetic acids were designed and synthesized to find novel aldose reductase inhibitors(ARIs) with high activity and selectivity. Starting from aniline or substituted aniline,24 target comp-ounds were synthesized through a five-step procedure as aza-Michael addition, hydrolysis, Friedel-Crafts acylation, N-alkylation and Claisen-Schmidit condensation. The structures of these compounds were confirmed by 1H-NMR, MS and IR.Their target compounds were assayed on a crude enzymatic preparation from rat lenses, and Epalrestat was used as the reference standard. The results showed that the activities of tested compounds are weaker than the corresponding 2-[3-phenylmethylene-4-oxo-1(4H)-quinolinyl]acetic acids, but some compounds still kept some activities, with IC50 value ranging from 1.0μmol·L-1 to 22.0μmol·L-1. CompoundⅢ-3 exhibited the highest activity with IC50 of 1.096μmol·L-1. The molecular docking study showed that the exchange of benzyl and carboxy group would effect the interaction of target compounds with the hydrophobic pocket of ALR2 greatly, and decrease their inhibitory activities..