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

•Design, synthesis and aldose reductase (ALR2) inhibitory effect of novel pyridazinone derivatives are presented.•21 new compounds were synthesized and evaluated against ALR2.•All the compounds showed micromolar or submicromolar activity against ALR2 with IC50 values lower than 1.9 µM.•Compound 3 was docked to 4LB4 with a docking score of -7.962. The inhibitor-active site interactions were observed through Trp 20, Lys 21, and Trp 111.•2-substituted-6-aryloxo-pyridazinone moiety was found as a suitable scaffold for ALR2 inhibition. 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 compounds against ALR2. Our results showed that all the compounds showed submicromolar or low micromolar 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 ester 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. [Display omitted]