Synthesis, biological evaluation and X-ray crystallographic analysis of novel (E)-2-cyano-3-(het)arylacrylamides as potential anticancer agents

Abstract

• Eco-friendly synthesis of ( E )−2-cyano-3-(het)arylacrylamides in good yields. • NMR and FT-IR experimental analyses are reported and explained. • Crystallographic, Hirshfeld surface and energy frameworks analyses were performed. • The energy gap and chemical reactivity descriptors were computed using .cif files. • Anticancer activity was screened against 60 human cancer cell lines. We report the stereoselective synthesis of novel ( E )-2-cyano-3-(het)arylacrylamides 3 in high yields by a triethylamine-catalyzed Knoevenagel condensation of cyanoacetamide ( 1 ) with (het)arylaldehydes 2 in ethanol under mild reaction conditions. The products were full characterized by IR, 1D and 2D NMR spectroscopy, mass spectrometry, and elemental analysis. Additionally, structures 3 were studied and confirmed by single-crystal X-ray diffraction, observing that the cyanoacrylamide fragment affects considerably the crystal growth. The cooperative non-covalent interactions and Hirshfeld surface analysis are discussed. Moreover, quantum chemical descriptors such as frontier molecular orbitals and HOMO–LUMO energy gap, as well as global reactivity descriptors were computed by the B3LYP method with 6–31G(d,p) basis set implemented in CrystalExplorer using the crystallographic information files (.cif) obtained from the X-ray diffraction measurements. Ultimately, the ( E )-2-cyano-3-(het)arylacrylamides 3 exhibited moderate activity against T-47D breast, UACC-62 melanoma, NCI-H522 non-small cell lung, SR leukemia, and SNB-75 ovarian cancer cell lines with%GI values ranging from 7.98 to 14.83%.