Quinoline Carboxylic Acids, Synthesis And Aldose Reductase Inhibitory Activity Study

The pathogenic mechanisms of diabetic complications and the advances in the aldose reductase inhibitors(ARIs) were briefly reviewed in this thesis. It is well known that diabetic complications are coursed by the accumulation of sorbitol from the polyol pathway activated under hyperglycemic conditions. AIRs can correct the abnormal condition of polyol pathway, and become one of the therapeutic strategies that have been proposed to prevent or ameliorate long-term diabetic complications.Our aim is to find novel ARIs with high efficacy and selectivity, and explore the relationship between the distance from carboxy group to aromatic ring and the aldose reductase(AR) inhibitory activity. Based on the structure features of hydantoins, carboxylic acids and phenolic compounds with aldose reductase inhibitory activities and their action mechinism on AR, a series of 6-methyl-3 -substituted benzyl-4-oxoquinoline-1(4H)-formic acids and 3-[6-methyl-3-substituted phenzylmethyl-4-oxoquinoline-1(4H)-yl]propanoic acids were designed and synthesized, and their inhibitory activities were assayed on aldose reductase from rat lenses. Starting from p-toluidine, 25 target compounds were firstly prepared through a six-step procedure as aza-Michael addition, hydrolysis, Friedel-Crafts acylation, N-formylation or alkylation, Claisen-Schmidit condensition and hydrolysis. The structures of these compounds were confirmed by ~1H-NMR, MS and IR.The pharmacological results suggest that prolongating or shortening the distance between carboxylic group and aromatic ring result in a sharp decrease in the activity, and one methylene linker seems to be the best one.