In silico identification of the active conformation of open-chain enaminoes with anticonvulsant activity

Abstract

A study about the relationship between molecular properties of open-chain enaminones and their anticonvulsant activity is presented in this paper. Geometry optimizations of the enaminones were performed at HF and DFT/B3LYP levels of theory using 6-31+G(d) basis set. The HOMO and LUMO energies were obtained at the same level of theory. The solvent effect was studied through IPCM. A Natural Bond Orbital (NBO) analysis was performed to analyze the possible association between the stability and the intramolecular hydrogen bond interaction energies. The stability order of the isomers in gas phase was the following: cis-1 > trans-4 > cis-2 > trans-3. The IPCM method showed that the trans-3 isomers are more stable that the cis-2 when the solvent effect was taken into account. Two important intramolecular hydrogen bonds were found by NBO analysis. According to our findings, these interactions could affect the activity of the two most stable isomers (cis-1 and trans-4). By contrast, trans-3 isomers did not present this type of interaction. Therefore, the latter isomers have a large flexibility and can adopt a conformation similar to the conformation of active ringed-enaminones. In addition, HOMO and LUMO energies suggested that the trans-3 isomers could be the most reactive species.