Nowadays, diabetes mellitus (DM) has shown as a significant global health concern with a remarkable increase in its prevalence. In this study, we have focused our efforts to synthesize a new series of thiazolidin-4-ones bearing sulfonamide moiety (5a-h and 6a-h) via a multistep reaction strategy in high to excellent yields. Reaction of p-toluene sulfonyl chloride with ethyl glycinate or b-alanie afforded compounds 1a,b which then allowed to react with hydrazine to give the corresponding hydrazide deivatives 2a,b. The reaction of hydrazides 2a,b with different aromatic aldehydes resulted in the formation of hydrazone derivatives 3a-h and 4a-h. Finally compounds 3a-h and 4a-h were reacted with ethyl thioglycalate to give the expected thiazolidinone derivatives 5a-h and 6a-h respectively. The obtained products were characterized according to their elemental and spectral analyses. To find the antidiabetic potentials of the synthesized compounds (5a-h and 6a-h), in vitro a-amylase inhibitory activity compared to Glitazone as reference was performed. The results of the antidiabetic assay were very encouraging because compounds 5c, 5f, 5g and 5h showed excellent inhibitions activity against a-amylase enzyme.