Design, Synthesis and Biological Evaluation of Novel Piperazinone Derivatives as Cytotoxic Agents

Purpose: In this study, a series of piperazin-2-one derivatives were prepared through bioisostericsubstitution of the imidazole ring of L-778,123 (imidazole-containing FTase inhibitor) andrearrangement of groups based on the tipifarnib structure. Final compounds were evaluated fortheir cytotoxic activities on cancer and normal cell lines by MTT assay.Methods: Methyl α-bromophenylacetic acid and 1-(3-chlorophenyl) piperazin-2-onewere synthesized using previously described methods. Methyl 2-(4-chlorophenyl)-2-(4-(3-chlorophenyl)-3-oxopiperazin-1-yl) acetate was prepared by reaction between these twocompounds in presence of potassium carbonate. Finally, methoxy group of ester was substitutedby various amines such as guanidine, thiourea, urea and hydrazide. The synthesized compoundswere tested for their cytotoxicity against colon cancer (HT-29) and lung cancer (A549) celllines as well as MRC-5 (normal fetal lung fibroblasts) cells as a healthy cell line using MTTcolorimetric assay method.Results: Replacement of imidazole moiety with guanidine, thiourea, and hydrazide couldincrease cytotoxicity toward all three cell lines. Some substituents, such as amine, urea, andhydroxylamine exhibited significant cytotoxicity (<500 μM) but lower than L-778,123 asstandard compound. Hydroxyl and methoxy substituents did not show significant cytotoxicity.Imidazole substituent group revealed cytotoxicity similar to L-778,123 All compounds showedlower cytotoxic activity against normal cell lines compared with cancer cell lines.Conclusion: It seems the electron density of substituted groups and rearrangement of groupsmay significantly increase cytotoxic activity.