In this study, we synthesized 22 compounds in a series with various substitution on imidazo[2,1‐b][1,3,4]thiadiazole. The potential cytotoxic activity of these compounds investigated in leukemia cell lines by Differential Nuclear Staining (DNS). Our results identified two compounds, 2‐(4‐methoxybenzyl)‐6‐(2‐oxo‐2H‐chromen‐3‐yl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl thiocyanate and 6‐(4‐chlorophenyl)‐2‐(4‐methoxybenzyl)imidazo[2,1‐b][1,3,4]thiadiazole‐5‐carbaldehyde, exhibited the most cytotoxic effect against murine leukemia cells (L1210), human T‐lymphocyte cells (CEM) and human cervix carcinoma cells (HeLa) with IC50 values ranging between 0.79 and 1.6 μM. The results indicate that 2‐(4‐methoxybenzyl)‐6‐(2‐oxo‐2H‐chromen‐3‐yl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl thiocyanate is inducing phosphatidylserine externalization and caspase‐3 activation which are both a hallmark of apoptosis. Docking studies showed that 2‐(4‐methoxybenzyl)‐6‐(2‐oxo‐2H‐chromen‐3‐yl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl thiocyanate binds within the active sites of transforming growth factor beta (TGF‐β) type I receptor kinase domain by strong hydrogen binding and hydrophobic interactions.

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