Geometrical isomerism and conformational charges of selected open-ring enaminones in its neutral and protonated forms (original) (raw)
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Medicinal Chemistry Research, 2013
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. Keywords Open-chain enaminones Á Anticonvulsant activity Á Structure-activity relationship Á Active conformation Á Ab initio Á NBO analysis Electronic supplementary material The online version of this article (
Anticonvulsant Activity of Ringed Enaminones: A QSAR Study
QSAR & Combinatorial Science, 2009
The formalism of the QSAR Theory is employed to establish mathematical relationships that link the molecular structure of ringed enaminones to their observed antiepileptic activity. The design of predictive linear regression models, solely based on the available experimental information, involved the simultaneous analysis of 1312 theoretical descriptors calculated with Dragon software. This QSAR study that is based both on classic antiepileptics and second-generation anticonvulsant drugs, including compounds of the enaminone type, allowed the proposal of novel ringed enaminone derivatives as possible antiepileptic agents, posing a similar or even better predicted biological activity when compared to other commonly used drugs.
QSAR Study and Molecular Design of Open-Chain Enaminones as Anticonvulsant Agents
International Journal of Molecular Sciences, 2011
Present work employs the QSAR formalism to predict the ED 50 anticonvulsant activity of ringed-enaminones, in order to apply these relationships for the prediction of unknown open-chain compounds containing the same types of functional groups in their molecular structure. Two different modeling approaches are applied with the purpose of comparing the consistency of our results: (a) the search of molecular descriptors via multivariable linear regressions; and (b) the calculation of flexible descriptors with the CORAL (CORrelation And Logic) program. Among the results found, we propose some potent candidate open-chain enaminones having ED 50 values lower than 10 mg•kg −1 for corresponding pharmacological studies. These compounds are classified as Class 1 and Class 2 according to the Anticonvulsant Selection Project.
Bioorganic & Medicinal Chemistry, 1999
A new series of N-modified analogues of the VV-hemorphin-5 with aminophosphonate moiety have been synthesized, characterized and investigated for anticonvulsant activity. The novel peptide analogues were prepared by solid-phase peptide synthesis-Fmoc-strategy and were evaluated in the timed intravenous pentylenetetrazole infusion test (ivPTZ) and 6-Hz psychomotor seizure test in mice. The acute neurological toxicity was determined using the rotarod test. The redox potentials at glass carbonic electrode (GC) and the acid/base properties as pKa values of these peptide analogues were compared with the electrochemical behaviour of tyrosine-and tryptophan-containing peptides using different voltamperometric modes. Among the five tested peptide analogues, V3p was the most active against the ivPTZ test with effect comparable to that of the VV-hemorphin-5 (V1) used as a positive control. Dose-dependent elevation of the seizure threshold for myoclonic twitch and generalized clonic seizures was observed after i.c.v. administration of V2p, V4p and V5p as well as for forelimbs tonus in V4p peptides. The peptide analogues V2p-V5p were able to suppress dose-dependent psychomotor seizures in the 6-Hz test. In contrast, the V6p peptide showed either a pro-convulsant effect in the iv PTZ test or was inactive in the 6-Hz test. No changes in motor coordination were noted with the novel peptides. Docking study results suggest that kappa opioid receptor binding could be the mechanism of action of peptide derivatives with anticonvulsant activity. The results suggest that incorporation of aminophosphonate moiety at position 1 of the VV-hemorphin-5 scaffold deserve further evaluation in models of epilepsy and derivatization.
Synthesis and Structure of Two Isomeric Enaminones
Croatica Chemica Acta
The reaction of ethyl 2-hydroxy-4-(4-hydroxy-6-methyl-2H-pyran-2-on-3-yl)-4-oxo-2-butenoate (1) and 1-naphthylamine in ethanol affords two isomeric enaminones: ethyl 4-hydroxy-3-[3-(1-naphthylamino)-2-butenoyl]-2H-pyran-2-on-6-carboxylate (2) and ethyl 4-(4hydroxy-6-methyl-2H-pyran-2-on-3-yl)-2-(1-naphthylamino)-4-oxo-2-butenoate (3). The structures of both compounds were determined by the single crystal X-ray diffraction. Tautomerism may be involved in two parts of a molecule, in the cyclic part (pyrone ring) and in the side chain, to give a variety of possible tautomeric forms. Attention has been turned to the endo-enol enamine and exo-enol enamine tautomeric equilibrium, since both tautomers were found in the crystals of compounds with similar structures. The NMR spectroscopic data and X-ray structural analysis confirmed that both compounds exist in the endo-enol enamine form in the solution and in the crystalline state. The molecules are characterized by strong, intramolecular hydrogen bonds of N-H× × ×O and O-H× × ×O type reinforced by p-delocalization. The molecules as a whole are not planar, exhibiting planarity only in the central heteroconjugated moiety, while naphthyl rings are almost perpendicular to the central part.
2007
The resolution of 1-(4-aminophenyl)-7,8-methylenedioxy-1,2,3,5-tetrahydro-4H-benzodiazepin-4-one (6)-(R,S)-2 was accomplished by chiral HPLC. The absolute configuration of (þ)-2, determined by X-ray crystallographic analysis, was R. The in vivo anticonvulsant activity of the enantiomers (þ)-(R)-2 and (À)-(S)-2 is reported. It has been also demonstrated that compound -(R,S)-2 in vivo undergoes oxidative metabolism to derivative 1. Chirality 19:16-21, 2007. V V C 2006 Wiley-Liss, Inc.
Enaminones: Exploring Additional Therapeutic Activities
Journal of Pharmaceutical Sciences, 2007
Enaminones, enamines of b-dicarbonyl compounds, have been known for many years. Their early use has been relegated to serving as synthetic intermediates in organic synthesis and of late, in pharmaceutical development. Recently, the therapeutic potential of these entities has been realized. This review provides the background and current research in this area with emphasis of these agents as potential anticonvulsants, their proposed mechanisms of action, and as potential modulators of multidrug resistance (MDR).
6 Hz Active Anticonvulsant Fluorinated N-Benzamide Enaminones and Their Inhibitory Neuronal Activity
International Journal of Environmental Research and Public Health
A small library of novel fluorinated N-benzamide enaminones were synthesized and evaluated in a battery of acute preclinical seizure models. Three compounds (GSA 62, TTA 35, and WWB 67) were found to have good anticonvulsant activity in the 6-Hz ‘psychomotor’ 44-mA rodent model. The focus of this study was to elucidate the active analogs’ mode of action on seizure-related molecular targets. Electrophysiology studies were employed to evaluate the compounds’ ability to inhibit neuronal activity in central olfactory neurons, mitral cells, and sensory-like ND7/23 cells, which express an assortment of voltage and ligand-gated ion channels. We did not find any significant effects of the three compounds on action potential generation in mitral cells. The treatment of ND7/23 cells with 50 µM of GSA 62, TTA 35, and WWB 67 generated a significant reduction in the amplitude of whole-cell sodium currents. Similar treatment of ND7/23 cells with these compounds had no effect on T-type calcium cur...
An ab initio study of anticonvulsants
Journal of Molecular Structure-theochem, 1994
A systematic theoretical study of anticonvulsant compounds has been performed for the first time, utilizing ab initio molecular orbital techniques. The geometry and pharmacophore charge distribution, the effect of substituents and protonation of the imide nitrogen on the pharmacophore ring charge distribution and drug-receptor interactions have been studied in detail. The results indicate a rigid, typical and highly charged environment on the pharmacophore ring which is not altered by substituents or protonation of the imide nitrogen. The intermolecular interaction calculations indicate that the drug is capable of disrupting normal hydrogen-bonding patterns in lipoproteins or phospholipids. The results also indicate common cellular ions as strong competitors for the binding site.