Studies On The Design, Synthesis Of Quinolinoneacetic Acids And Their Aldose Reductase Inhibitory Activities

Diabetes mellitus is a group of metabolic syndromes characterized by long-term hyperglycemia, which causes diabetic complications such as nephropathy, neuropathy, retinopathy and angiopathy. Although the precise etiologies for diabetic complications are not fully understood, it is widely accepted that they are closely related to the abnormality of polyol pathway, where aldose reductase is present. Thus, aldose reductase has received attention as a possible target to prevent or treat diabetic complications, and its inhibitors have been investigated profoundly.The investigational aldose reductase inhibitors（ARIs） mainly include cyclic imides and carboxylic acids, but most of them fail to be launched into the market because of a lack of efficacy or because of adverse side effects in clinical research, which are mainly attributed to pharmacokinetic problems and a lack of specificity for the target enzyme. To date, only two carboxylic acid ARIs, Epalrestat and Bendazac, were successfully marketed for treatment of diabetic neuropathy and retinopathy respectively. Therefore, making further insight into structure-activity relationships of carboxylic acid inhibitors appears to be significant for discovering novel ARIs with better pharmacodynamic and toxicological profiles. Based on the pharmacophore requirements of ARIs with high activity and selectivity, and the backbone structures of chalcone and carboxylic acid types of ARIs,（E）-2-[3-phenylmethylene-4-oxo-2, 3-dihydro-1（4H）-quinolinyl]acetic acids（Ⅰ） were designed, and 2-[3-phenylmethyl-4-oxo-1（4H）-quinolinyl]acetic acids（Ⅱ） were found during the course for the preparation of target compoundsâ… .According to the structures of target compounds, the corresponding ethyl（E）-2-[3-phenylmethylene-4-oxo-2, 3-dihydro-1（4H）-quinolinyl]acetic acids（5） were prepared from aniline or substituted aniline through a five-step procedure as addition, hydrolysis, cyclization, alkylation and condensation, and then target compoundsâ… -1～32 andâ…¡-14～57 were obtained by hydrolysing the relevant esters with an aqueous solution of sodium hydroxide under room temperature and reflux separately. The double bonds of（E）-2-[8-methyl-3-phenylmethyl-ene-4-oxo-2, 3-dihydro-1（4H）-quinolinyl]acetic acids were rearranged via the system HCOONH₄-Pd/C-H₂O to give Compoundâ…¡-1～13. A thorough literature survey revealed that all the 89 target compounds were synthesized for the first time, and their structures were characterized by ¹H-NMR, MS, IR and UV.The target compounds were assayed on a crude enzymatic preparation from rat lenses, and Epalrestat was used as the reference standard. The results showed that most of the test compounds displayed strong inhibitory activities in vitro, with IC₅₀ values in the low/submicromolar range 0.01～5μmol/L. Compoundsâ…¡-29(IC₅₀=0.0459μmol/L) andâ…¡-57(IC₅₀=0.0497μmol/L) exhibited higher activities than that of Epalrestat(IC₅₀=0.075μmol/L), and compoundsâ… -28(IC₅₀=0.088μmol/L) andâ…¡-54(IC₅₀=0.0913μmol/L) demonstrated comparable potency with that of Epalrestat.Based on the results from the evaluation of inhibitory activities of the target compounds, the structure-activity relationships of quinolinoneacetic acids were summarized, and then the molecular modeling study was carried out on selected compoundâ…¡-54 by docking into the active site of aldose reductase crystal structure to explore the possible binding mode of these compounds, which could form a base for the further structure-activity relationship research of quinolinoneacetic acids.