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 Ki 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.