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

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%. (c) 2021 Elsevier B.V. All rights reserved.

Automated summary

This study reported the stereoselective synthesis of novel (E)-2-cyano-3-(het)arylacrylamides 3 through a Knoevenagel condensation reaction, with high yields and moderate anti-cancer activity against various cancer cell lines.