Crystallographic studies of cinnamamide derivatives as a means of searching for anticonvulsant activity.

Abstract

A cinnamamide (3-phenylprop-2-enamide) core is present in many pharmacologically active compounds. We report three new crystal structures of N-substituted cinnamamide derivatives which were screened for anticonvulsant activity, namely (R,S)-(2E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide, C12H15NO2, (1), (R,S)-(2E)-N-(1-hydroxybutan-2-yl)-3-phenylprop-2-enamide, C13H17NO2, (2), and (2E)-1-(4-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one, C14H17NO2, (3). Compounds (1) and (2) crystallize in the Pbca space group with one molecule in the asymmetric unit, whereas compound (3) crystallizes in the P21/c space group with two molecules in the asymmetric unit. All the crystal structures are stabilized by intermolecular O-H...O hydrogen bonds and additionally by N-H...O hydrogen bonds in the structures of (1) and (2). The investigated compounds possess fragments that are considered as beneficial for anticonvulsant activity. The conformations of these compounds were analyzed in comparison with the characteristic features of the proposed pharmacophore model of anticonvulsants active in the maximal electroshock test, i.e. a phenyl ring or other hydrophobic unit, an electron-donor atom and a hydrogen-bond acceptor/donor domain. In the reported series, two calculated distances fitted the reference model, while the third did not. Structure-activity analysis suggests that anticonvulsant properties may be related to the N-atom substituent. It is beneficial to combine an electron-donor atom (e.g. an O atom) with an H atom in the substituent to ensure appropriate interactions with the molecular target. We analyzed the intermolecular interactions in order to find an appropriate spatial arrangement of the important features responsible for anticonvulsant activity.