Postprandial hyperglycemia can be controlled by delaying the absorption of glucose resulting from carbohydrate digestion. α-Amylase is the initiator of the hydrolysis of polysaccharides, and therefore developing α-amylase inhibitors can lead to development of new treatments for metabolic disorders like diabetes mellitus. In the present work, we set out to rationally develop α-amylase inhibitors based on the thiazolidine-4-one scaffold. The structures of all these newly synthesized hybrids were confirmed by spectroscopic analysis (IR, <sup>1</sup>H-NMR, MS). The appearance of two sets of signals for some protons in <sup>1</sup>H NMR revealed the existence of a mixture of 2<i>E</i>,5<i>Z</i> (37.1-42.0%) and 2<i>Z</i>,5<i>Z</i> isomers (58.4-62.8%), which was further supported by DFT studies. All the newly synthesized compounds have potential inhibitory properties as revealed through <i>in vitro</i> α-amylase inhibition activity. Compound <b>5a</b> at 100 μg mL<sup>-1</sup> concentration showed a remarkable inhibition of 90.04%. <i>In vitro</i> α-amylase inhibition was further supported by docking studies of compound <b>5a</b> against the active site of human pancreatic α-amylase (PDB ID: ; 2QV4). The docking studies revealed that the bonding interactions found between <b>5a</b> and human pancreatic α-amylase are similar to those responsible for α-amylase inhibition by acarbose.