Direct Synthesis and Anticancer Properties of Novel Piperazine-Linked Homobivalent Tetrazole-5-thione Derivatives

A novel series of homobivalent 1,4-disubstituted tetrazole-5-thiones with piperazine moiety as a linker group were synthesized and evaluated for their antiproliferative activity. Simple access to these com­pounds has been designed via copper-catalyzed [3+2]-cycloaddition reaction between bis-azides generated in situ from 1,1′-(piperazine-1,4-diyl)bis(2-chloroethan-1-one) and 1,4-bis(2-bromoethyl)piperazine and a set of organic isothiocyanates. This one-pot two-step procedure resulted in introduction of various functional groups to the tetrazole scaffold. The in vitro antiproliferative activity of the newly synthesized compounds was evaluated, and their potential cytotoxic effect against human colorectal HCT 116, breast MCF-7 and liver HepG2 cancer cell lines was revealed. 4,4′-[Piperazine-1,4-diylbis(ethane-2,1-diyl)]bis[1-(3,4,5-trimethoxy­phenyl)-1,4-dihydro-5H-tetrazole-5-thione] showed the highest activity against HCT 116, MCF-7 and HepG2 cell lines compared to the commercially available 5-flurouracil as reference drug.