Novel pyridazinone-based N-phenylacetamides as α-glucosidase-selective and dual α-glucosidase/aldose reductase inhibitors: Synthesis, SAR analysis, and cytotoxicity evaluation

Diabetes mellitus is characterized by chronic hyperglycaemia and severe metabolic and vascular complications. Dual modulation of α-glucosidase, which regulates intestinal carbohydrate digestion, and Aldose Reductase (ALR2), a key polyol pathway enzyme, represents a valuable strategy for controlling postprandial glucose elevation and diabetes-associated complications. Here, nineteen novel pyridazinone-based N-phenylacetamide derivatives were designed, synthesized, and evaluated against α-glucosidase and ALR2. Although the structures of the fluorinated analogues were supported by HRMS and characteristic ¹³C¹⁹F coupling patterns, further direct analytical confirmation by ¹⁹F NMR or elemental analysis will be addressed in future studies. The design strategy replaced the carboxylate group of previously reported pyridazinone-carboxylate inhibitors with an amide moiety to improve drug-like properties while maintaining inhibitory activity. Most derivatives showed strong α-glucosidase inhibition, with K_i values of 11.68-743.30 nM. Compound 10 displayed the most favourable balanced profile, with Ki values of 11.68 ± 1.45 nM for α-glucosidase and 72.64 ± 2.95 nM for ALR2, outperforming acarbose and epalrestat. Structure-activity relationship analysis suggested that electron-withdrawing substituents, particularly trifluoromethyl and halogen groups, contributed substantially to inhibitory potency. Docking studies supported the experimental findings by revealing favourable catalytic-pocket interactions, whereas L929 cytotoxicity assays indicated generally low toxicity. Overall, these findings demonstrate that pyridazinone-based N-phenylacetamides constitute a promising scaffold for developing compounds with preferential α-glucosidase inhibition, while compound 10 represents a particularly promising dual α-glucosidase/ALR2-active candidate. However, since the present study did not include profiling against other aldo-keto reductase isoforms, including AKR1B10, compound 10 should not yet be considered an AKR-selective ALR2 inhibitor. Broader AKR isoform selectivity profiling is therefore required before its further development as a therapeutically relevant lead compound.