Abstract Objectives Sulfonamide group is an important scaffold used for generating new building blocks with diverse biological activities. Considering priority of the sulfonamide structure, seven new sulfathiazole derivatives were synthesized and evaluated for their antiproliferative activity, in this study. Materials and methods Compounds 2a–g were synthesized using a two-step synthetic procedure starting from commercially available sulfathiazole. The antiproliferative activity of the compounds was investigated against A549 and NIH/3T3 cell lines by MTT assay, matrix metalloproteinase-9 (MMP-9) and cathepsin inhibition tests. Results Compound 2b bearing triazole ring exhibited highest inhibitory activity (IC 50 : 12.33 μg/mL) with selective profile which was better than cisplatin and it also inhibited MMP-9 with 53.67% percentage. Compounds 2c and 2e inhibited cathepsin L with percentages of 62.75 and 57.25%, whereas cathepsin D was poorly inhibited by the compounds. Conclusions Target compounds exhibited high to moderate antiproliferative activity and they displayed higher MMP-9 inhibition than cathepsin inhibition activity. 2b and 2e were identified as the most active compounds when evaluated, biologically.