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

Eur J Med Chem. 2014 Sep 12:84:687-97. doi: 10.1016/j.ejmech.2014.07.054.

Sujeet Kumar ¹, Mahesh Hegde ², Vidya Gopalakrishnan ², Vinaya Kumar Renuka ¹, Sureshbabu A Ramareddy ¹, Erik De Clercq ³, Dominique Schols ³, Anil Kumar Gudibabande Narasimhamurthy ⁴, Sathees C Raghavan ², Subhas S Karki ⁵

Affiliations

1 Department of Pharmaceutical Chemistry, KLE University's College of Pharmacy, Bangalore 560010, India.
2 Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India.
3 Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium.
4 Dept. of Physics, M. S. Ramaiah Institute of Technology, Bangalore 560054, India.
5 Department of Pharmaceutical Chemistry, KLE University's College of Pharmacy, Bangalore 560010, India. Electronic address: subhasskarki@gmail.com.

PMID: 25064346 DOI: 10.1016/j.ejmech.2014.07.054

Abstract

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.

Keywords

Anti-cancer drugs; Apoptosis; Cancer therapeutics; Cell death; Cytotoxicity.

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