Synthesis, molecular structure, spectral analysis, and biological activity of new malonamide derivatives as α-glucosidase inhibitors

Two new malonamide derivatives were synthesized via the Michael addition of N-1,N-3-di(pyridin-2-y1) malonamide to alpha,beta-unsaturated ketones using a 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) catalyst at room temperature. All reactions efficiently furnished the desired malonamide derivatives, which differed only in their substitution on one phenyl group, with one derivative bearing a bromine substituent and the other bearing a methyl group. The structures of newly synthesized compounds were then elucidated by single -crystal X-ray diffraction, infrared spectroscopy, NMR spectroscopy, mass spectrometry, and elemental analysis. In addition, the synthesized compounds were evaluated for their in vitro cytotoxicity against cancer cell lines and for a-glucosidase inhibition. The target compounds exhibited enhanced aglucosidase inhibition activity (i.e., IC50 = 12.8 +/- 0.1 and 28.4 +/- 0.2 mu M) compared to the common drug acarbose (IC50 = 840 +/- 1.73 mu M). Both compounds were found to be non-cytotoxic against H460 (lung carcinoma) and T3T (normal fibroblast) cell lines. In addition, the bromo-substituted derivative exhibited weak cytotoxic against cervical cancer HeLa (IC50 = 13.8 +/- 0.4 mu M) and breast cancer MCF-7 (IC50 = 21.11 +/- 0.88 mu M) cell lines, while the methyl -substituted derivative showed weak cytotoxicity against the MCF-7 cell line (IC50 = 47.9 +/- 0.7 mu M). Density functional theory (DFT) B3LYP/6-311G(d,p) calculations were employed to examine the molecular structures and electronic properties of the prepared compounds. As expected, the bromo-derivative (2.2377 D) exhibited a higher polarity than the methyl-derivative (1.9160 D). Furthermore, the HOMO and LUMO diagrams were constructed and the electronic spectra of both compounds were assigned using time-dependent (TD)-DFT calculations. Finally, the calculated NMR chemical shifts correlated well with the experimental data. (C) 2016 Elsevier B.V. All rights reserved.