Rat lung aldose reductase inhibition capacity of substituted indole hydrazide/hydrazone derivatives

Diabetes Mellitus is one of the most serious health problem facing both developed and developing countries. Long term complications lead to morbidity and mortality in patients with diabetes. Increased polyol pathway has been implicated in the pathogenesis of microvascular complications and cataract. Aldose reductase (AR) is the key enzyme of the polyol pathway, which converts glucose to sorbitol. Excessive accumulation of sorbitol is associated to the diabetic complications. Avoidance of sorbitol accumulation by inhibiting AR would be an efficient treatment. Due to the significance of AR as a potential drug target in the treatment of diabetic complications, there are increasing interests in the design and synthesis of AR inhibitors. In this study, 2-fluorophenylindol and 5-chloroindole hydrazide/hydrazone derivatives were tested for measuring the AR enzyme inhibitory activity. The enzyme activity was assayed by spectrophotometrically monitoring NADPH oxidation, which accompanies the reduction of D,L-glyceraldehyde used as substrate. Results showed in general 52-60 % inhibitory activity in halogen substituted indole derivatives. This study proposes a new approach for the in vitro AR inhibition activity properties and structure activity relationship of 2, 3-and 5-substituted indole ring. For the inhibitory activity, not only the indole ring is important, but also is the side chain containing the amide group and halogens.