Belkacem_2017_Med.Chem_13_744

BACKGROUND: 2,5-Diketopiperazine derivatives are considered to be an important classe of cyclic peptides due to their wide range of biological activities. OBJECTIVES: Synthesis of a new series of protected 2,5-diketopiperazine derivatives and evaluation of their in vitro biological activities. METHODS: A series of new mono-protected arylidene 2,5-diketopiperazine derivatives 3a-p have been prepared via Claisen-Schmidt condensation of the N,N-diacetyl-diketopiperazine 1 with a series of substituted arylaldehydes. All prepared compounds were characterized by 1D and 2D 1H/13C NMR and ESI-HRMS, and screened for their in vitro acetylcholenesterase, xanthine oxidase and alpha-amylase inhibition and cytotoxic (HCT-116, MCF-7 and OVCAR-3) activity. RESULTS: Among these compounds, the greatest activity against the alpha-amylase enzyme (percentage of inhibition (PI)=57.8+/-1.9%) was obtained for compound 3f bearing a phenoxy moiety. Moreover, the results demonstrated that some arylidene 2,5-diketopiperazines 3 exhibited significant cytotoxic activity against the three cell lines used. The compound 3g (4-PhCH2O.Ph) was found to be the most cytotoxic against the HCT-116, MCF-7 and OVCAR-3 cell lines (PI=83.2+/-2.4, 89.6+/-4.9 and 74.4+/-5.2%, respectively) followed by 3m (2-Br-5-F.Ph) then 3j (4-C2H5-3-NO2.Ph) which displayed a good cytotoxic potential against OVCAR-3 (PI=77.0+/-2.1 and 71.4+/-0.9%, respectively). CONCLUSION: A series of sixteen new arylidene diketopiperazines 3a-p were synthesized via Claisen-Schmidt condensation. Most of the piperazines 3a-p exhibited a good cytotoxic and antidiabetic effects.