Stereoselective synthesis of Z-acrylonitrile derivatives: catalytic and acetylcholinesterase inhibition studies

Abstract

In the present study, a focused library of (Z)-acrylonitrile analogues (library A & B) were synthesized, which were typically accessed via a facile Knoevenagel condensation between p-nitrophenylacetonitrile and appropriately substituted aromatic aldehydes (1a–i) and 3-formyl chromones (3a–c). This new synthetic eco-friendly approach resulted in a remarkable improvement in the synthetic efficiency (83–92% yield), high purity, minimizing the production of chemical wastes without using highly toxic reagents for the synthesis and, more notably, it improved the selectivity for (Z)-acrylonitrile derivatives. By performing DFT calculations, it was found that the (Z)-isomer of compound 2b is stabilized by 2.61 kcal mol⁻¹ more than the (E)-isomer. All of the compounds were tested for acetylcholinesterase (AChE) inhibition. Compounds 2a and 4c, displayed the strongest inhibition, with IC₅₀ values of 0.20 μM and 0.22 μM respectively. The methoxy group at the para-position of phenyl ring A was found to be essential for AChE inhibition.