Development of phenolic Mannich bases as α-glucosidase and aldose reductase inhibitors: In vitro and in silico approaches for managing diabetes mellitus and its complications.

The rising incidence of type 2 diabetes mellitus (T2DM) and its related complications has created an urgent need for new therapeutic approaches. We herein describe the synthesis as well as biological investigation of a series of sixteen new phenolic Mannich base derivatives of thiazolidine-2,4-dione as α-glucosidase (α-Glu) and aldose reductase (ALR2) inhibitors, two crucial enzymes involved in T2DM and its complications. In vitro assays showed strong inhibitory activities, compound 12 (tetrahydroisoquinoline and α-methylcinnamyl substituted) exhibited the strongest inhibition of ALR2 (K: 0.024 µM); compound 10 (1-phenylpiperazine and α-methylcinnamyl substituted) displayed remarkable α-Glu inhibition (K: 0.370 µM). Computer-aided studies supported experimental observations and revealed key binding features like hydrogen bond, π-π stacking, and hydrophobic interactions, which were responsible for the exceptional binding capacity of the compound with the enzyme. Cytotoxicity assays performed on healthy cell lines (HUVEC and BEAS-B2) revealed that the tested compounds were non-toxic at inhibitory concentrations. ADME-T predictions indicated that compounds 10 and 12 satisfy key drug-likeness criteria, with favorable oral absorption and moderate solubility. These findings highlight the potential of compounds 10 and 12 as promising inhibitors for managing diabetes and its complications, providing a foundation for further optimization and therapeutic exploration.