Cinnamamide pharmacophore for anticonvulsant activity: evidence from crystallographic studies

A number of cinnamamide derivatives possess anticonvulsant activity due to the presence of a number of important pharmacophore elements in their structures. In order to study the correlations between anticonvulsant activity and molecular structure, the crystal structures of three new cinnamamide derivatives with proven anticonvulsant activity were determined by X-ray diffraction, namely (R,S)-(2E)-N-(2-hydroxybutyl)-3-phenylprop-2-enamide-water (3/1), C₁₃H₁₇NO₂·0.33H₂O, (1), (2E)-N-(1-hydroxy-2-methylpropan-2-yl)-3-phenylprop-2-enamide, C₁₃H₁₇NO₂, (2), and (R,S)-(2E)-N-(1-hydroxy-3-methyl-butan-2-yl)-3-phenylprop-2-enamide, C₁₄H₁₉NO₂, (3). Compound (1) crystallizes in the space group P-1 with three molecules in the asymmetric unit, whereas compounds (2) and (3) crystallize in the space group P2₁/c with one and two molecules, respectively, in their asymmetric units. The carbonyl group of (2) is engaged in an intramolecular hydrogen bond with the hydroxy group. This type of interaction is observed for the first time in these kinds of derivatives. A disorder of the substituent at the N atom occurs in the crystal structures of (2) and (3). The crystal packing of all three structures is dominated by a network of O-H...O and N-H...O hydrogen bonds, and leads to the formation of chains and/or rings. Furthermore, the crystal structures are stabilized by numerous C-H...O contacts. We analyzed the molecular structures and intermolecular interactions in order to propose a pharmacophore model for cinnamamide derivatives.