Cinnamamide pharmacophore for anticonvulsant activity: evidence from crystallographic studies

Abstract

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), CHNO·0.33HO, (1), (2E)-N-(1-hydroxy-2-methylpropan-2-yl)-3-phenylprop-2-enamide, CHNO, (2), and (R,S)-(2E)-N-(1-hydroxy-3-methyl-butan-2-yl)-3-phenylprop-2-enamide, CHNO, (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 P2/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.

S(+)-(2E)-N-(2-Hydroxypropyl)-3-Phenylprop-2-Enamide (KM-568): A Novel Cinnamamide Derivative with Anticonvulsant Activity in Animal Models of Seizures and Epilepsy

“…3-Phenylprop-2-enamide moiety is almost planar with the values of interplanar angle between the plane of aromatic ring and the plane of amide group being 9.9(8), 16.5(7), 16.6(7), 16.3(6), 18.6(7), 11.1(8), 16.9(6) and 15.3(6) • , for molecules A, B, C, D, E, F, G and H, respectively. We have observed similar values earlier in the crystal structures of other cinnamamide derivatives [19,21,23,24]. It is worth notingthat this angle for determined crystal structure of racemic mixture of KM-568 has value 18.7(1) • [23].…”

Cinnamic Acid Derivatives as Cardioprotective Agents against Oxidative and Structural Damage Induced by Doxorubicin

“…The compounds used for the study were biologically active CA (cinnamic acid) derivatives previously synthesized by our group, with proven inhibitory potential for the CBR1 enzyme [22][23][24][25][26]. This paper presents the cardioprotective activity of the three most active derivatives: 5, 10, and 15.…”

“…Structures and purity of the compounds were confirmed using spectroscopic methods (NMR, LC/MS) as well as RP-HPLC, and additionally with crystallographic studies for compounds 5 and 15. The detailed synthesis procedures and physiochemical data of the compounds were previously published [23][24][25][26]. The chemical structures of the tested compounds are presented in Table 1.…”

Influence of protonation on the geometry of 2-{[(2,6-dimethylphenoxy)ethyl]amino}-1-phenylethan-1-ol: crystal structures of the free base and of its chloride and 3-hydroxybenzoate salt forms

“…In the last two decades, new groups of compounds have been intensively investigated as potential anticonvulsant drugs. Among them are cinnamamide derivatives (Guan et al, 2009;Gunia-Krzyz ˙ak et al, 2020;Z ˙esławska et al, 2018a), piperazine derivatives (Al-Ghorbani et al, 2015;Kumari et al, 2015;Pan ´czyk et al, 2018a;Sahu et al, 2020;Shaquiquzzaman et al, 2015), their chemical ISSN 2053ISSN -2296 hybrids (Prasanthi et al, 2018) and also various chemical substances containing aroxyalkyl or aminoalkanol moieties (Gunia-Krzyz ˙ak et al, 2016Pan ´czyk et al, 2018a,b).…”