Synthesis and activity studies on some novel 1,4-disubstitutedpiperazine derivatives

ABSTRACTGürdal, E. E., Synthesis and Activity Studies On Some Novel 1,4-Disubstitutedpiperazines. Yeditepe University Institute of Health Sciences, Ph. D. Thesis of Pharmaceutical Chemistry Programme, Istanbul, 2012.In this study, fifty one compounds with structures of N-substituted-4-[((4-substituted)diphenyl)methyl]piperazine-1-thioamide/-carbothioamide and N-[substitutedbenzoyl/phenylsulfonyl]-4-[((4-substituted)diphenyl)methyl]piperazine were prepared. Seventy four compounds are original. In vitro cytotoxic activities were screened in comparison with the reference drugs camptothecin (positive control) and 5-fluorouracil (reference).Benzhydrylpiperazine, 4-chlorobenzhydrylpiperazine and 4,4?-difluoro-benzhydrylpiperazine were synthesized by reflux of piperazine and suitable benzhydryl chlorides in alkali medium. Compounds were synthesized with reactions of benzhydrylpiperazine derivatives with suitable isocyanates, isothiocyanates, benzoyl chlorides and sulfonyl chlorides in room temperature with triethylamine.Structures of compounds were clarified with IR, 1H-NMR, 13C-NMR, mass spectroscopies, X-Ray crystallography and elemental analyses, also their physical characteristics and Rf values on thin layer chromatography were determined. In vitro cytotoxic activity screening of compounds were performed with sulphorodamine B method against breast cancer (MCF-7), hepatocellular carcinoma (HUH-7) and colorectal carcinoma (HCT-116) cell lines.Against HUH-7 cell line, in general, 4-chlorobenzhydrylpiperazine derivatives were more potent than other derivatives. The most potent compound against this cell line was N-(4-cyanophenyl)-4-[(4-chlorophenyl)(phenyl)methyl]piperazine-1-carboxamide (compound 25; IC50 = 1.29 micromolar).The most potent compound against MCF-7 cell line was 1-(4-bromobenzoyl)-4-[bis(4-fluorophenyl)methyl]piperazine HCl (compound 36; IC50 = 2.21 micromolar).The most potent compounds against HCT-116 cell line were N-tert-butyl-4-(diphenylmethyl)piperazine-1-carboxamide (compound 2; IC50 = 1.01 micromolar) and N-(4-cyanophenyl)-4-[(4-chlorophenyl)(phenyl)methyl]piperazine-1-carboxamide (compound 25; IC50 = 1.81 micromolar).Keywords: Piperazine, 1-benzhydrylpiperazine derivatives, isocyanate, isothiocyanate, benzoyl chloride, sulfonyl chloride, cytotoxic activity