Synthesis and activity studies on some novel benzothiazole-piperazine derivatives

In this study, ten compounds with structures of N-(4-methyl-1,3-benzothiazole-2-yl)-2-(N-substitutedpiperazine-1-yl)acetamide were prepared, of those, nine compounds are original. In vitro cytotoxic activities of these compounds were determined by sulphorodamine B assay. Starting material 2-amino-4-methylbenzothiazole was dissolved in benzene:triethylamine mixture and acetylated with chloroacetyl chloride to give 2-chloro-N-(4-methyl-1,3-benzothiazole-2-yl)acetamide. N-(4-methyl-1,3-benzothiazole-2-yl)-2-(N-substitutedpiperazine-1-yl)acetamide was synthesized with reaction of N-substituted piperazine and 2-chloro-N-(4-methyl-1,3-benzothiazole-2-yl)acetamide in acetone and with anhydrous K2CO3. Structure of compounds were elucidated with UV, IR, 1H-NMR, 13C-NMR, mass spectrometry and elemental analysis; also their physical characteristics and Rf values on thin layer chromatography were determined. In vitro cytotoxic activity screening of the compounds were performed with sulphorodamine B assay against breast (MCF7), hepatocellular (HUH7) and colorectal (HCT-116) cancer cell lines. Against HCT-116 cell line, in general, aroyl substituted derivatives were found to be more potent than others. The most active compounds against this cell line are compound 1 (GI50= 3.5 µM), compound 8 (GI50= 0.9 µM) ve compound 10 (GI50= 1.3 µM). Against MCF7 cell line, N-(4-methyl-1,3-benzothiazol-2-yl)-2-[4-(2-furoyl)piperazin-1-yl]acetamide (compound 10; GI50= 4.3 µM) is the most potent derivative. Other highly active derivatives are compound 6 (GI50= 9.7 µM) and compound 8 (GI50= 9.2 µM). Compounds 5 and 9 do not show cytotoxicity against this cell line. Against HUH7 cell line, aroyl substituted derivatives were more potent than others. The most potent compound against this cell line is N-(4-methyl-1,3-benzothiazol-2-yl)-2-(4-benzoylpiperazin-1-yl)acetamide (compound 8; GI50= 0.7 µM). In addition, alkyl derivatives have less cytotoxicity than aryl derivatives. Aroyl substituted compounds 8 and 10 were found to be the most active derivatives. In addition, further investigation of compounds 8 and 10 by Hoechst staining and FACS revealed that these compounds cause apoptosis by cell cycle arrest at subG1 phase.