2-(4-Chlorobenzyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazoles: Synthesis, cytotoxic activity and mechanism of action

• Two derivatives 4i and 5i emerged as the most potent against all the cell lines.
• These derivatives act by inducing apoptosis without arresting cell cycle.
• SAR studies indicated that, CHO & SCN substituents are required for good activity.
• Coumarin group preferred over aryl group at 6th position for good activity.

The cytotoxic activity of a new series of 2-(4′-chlorobenzyl)-5,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazoles against different human and murine cancer cell lines is reported. Among the tested compounds, two derivatives namely 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde 4i and 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate 5i emerged as the most potent against all the cell lines. To investigate the mechanism of action, we selected compounds 4i for cell cycle study, analysis of mitochondrial membrane potential and Annexin V-FITC flow cytometric analysis and DNA fragmentation assay. Results showed that 4i induced cytotoxicity by inducing apoptosis without arresting the cell cycle.

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