α-Glucosidase inhibition is an important approach for controlling postprandial hyperglycemia in diabetes mellitus. In this study, a series of furan-linked 1,3,4-thiadiazole derivatives, including bis-Schiff bases 4a–c, bis-amide derivatives 5a–c, and macrocyclic cyclamide 8 were synthesized using a microwave/ultrasound-assisted protocol. The method provided a practical route to the target compounds with reduced reaction time; however, its environmental advantages are discussed cautiously because chlorinating and dehydrating reagents such as POCl3 and PCl5 were used. The structures of the synthesized compounds were characterized by FT-IR, 1H NMR, 1³C NMR, EI-MS, and elemental analysis. For compound 8, DFT/GIAO-NMR calculations were applied as supportive evidence to compare possible isomeric/tautomeric forms, and the revised correlation analysis suggested isomer C as the most probable structure. The synthesized compounds were evaluated for in vitro α-glucosidase inhibition, where compound 8 showed the highest activity in the tested series, with an IC50 value of 0.56 ± 0.031 µg/mL, comparable to acarbose (0.597 ± 0.022 µg/mL). Molecular docking suggested a favorable predicted binding mode for compound 8 within the selected α-glucosidase-related protein models, while 100 ns molecular dynamics simulations and MM/PBSA analysis supported the predicted stability of the compound 8–protein complex through stable RMSD, RMSF, Rg, SASA, hydrogen-bonding behavior, and binding free-energy trends. These computational results are presented as complementary support for the experimental findings and should not be considered independent confirmation of biological activity. Overall, compound 8 was identified as the most active α-glucosidase inhibitor among the synthesized derivatives, but further structural confirmation, expanded analogue synthesis, selectivity testing, cytotoxicity evaluation, and in vivo studies are required before drawing pharmacological or drug-development conclusions.
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