Design, synthesis, and aldose reductase inhibitory effect of some novel carboxylic acid derivatives bearing 2-substituted-6-aryloxo- pyridazinone moiety

Abstract

The polyol pathway is a two-step metabolic pathway in which glucose is reduced to sorbitol and then converted to fructose. The first and rate limiting enzyme of this pathway, aldose reductase (ALR2), is a drug target for treating diabetic complications and inflammation. Given the common features of the known inhibitors, we designed a series of pyridazinone bearing benzoic acid derivatives and then we carried the carboylic acid group onto pyridazinone and synthesized them. We evaluated the com- pounds against ALR2. Our results showed that all the compounds showed submicromolar or low micro- molar inhibitory activity against ALR2. Compound 1 and 3 were found more active than the reference compound (epalrestat) with IC50 values of 0.278 μM (Ki =0.042±0.006 μM, competitive) and 0.188 μM (Ki =0.024±0.001 μM, competitive) respectively. Moreover, non carboxylic acid derivative 16c and the es- ter counterparts of 1, 3, and 12 (1c, 3c, and 12c) showed submicromolar activity against ALR2. According the results, we are able to establish some SARs in order to use in our further studies.