3D-QSAR design of novel antiepileptic sulfamides

Gavernet, Luciana; Cabrera, M. Josefina Dominguez; Bruno-Blanch, Luis E.; Estiú, Guillermina

doi:10.1016/j.bmc.2006.06.010

Cited by 24 publications

(27 citation statements)

References 45 publications

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“…[2] Recently, the synthesis and biological evaluation in mice of novel antiepileptic ligand derivatives of valpromide (Vpd), such as N-ethylvalpromide (Etvpd), dimethylvalpromide (Dmvpd), Nisopropylvalpromide (Ipvpd), have been reported. [2,3] These new structures meet the essential structural and electronic features responsible for the protection against the Maximal Electroshock test (MES) [4,5] : a polar moiety comprising two closely located H-donor-acceptor groups and a steric contour formed by two hydrophobic regions (besides the nonpolar portion defined by the pharmacophore) in an orientation and size such that the interactions against them would be minimal.…”

Section: Introductionmentioning

confidence: 99%

Spectroscopy properties of the amide group in valpromide and some derivatives with antiepileptic activity

Massa

Castro

Jubert

2009

J Raman Spectroscopy

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Infrared spectra at 300 and 77 K and Raman spectra at 300 K of the valpromide (Vpd), N-substituted derivatives, Nethylvalpromide (Etvpd), N-isopropylvalpromide (Ipvpd) and the N,N-disubstituted derivative, N,N-dimethylvalpromide (Dmvpd) with antiepileptic activity, have been measured and analyzed with results derived from computational chemistry calculation. In agreement with theoretical predictions, experimental data indicate that while in Etvpd, Dmvpd and Ipvpd there are four different conformational co-existing components (Etvpd: TTCG + , TCCG − , TTTC, G + G + C G + ; Dmvpd: TTCC, G − TTA + , G + A − TC, G + A − C A + ; Ipvpd: TTCT, TCCT, TCCC, G − TTT) in the Vpd there are only three distinct stable conformations of C 1 symmetry group: TTC, TCT, G + G + T. Based on the accuracy of the B3LYP calculation, with the 6-31+G * * basis set estimated by comparison between the predicted values of the vibrational modes and the available experimental data, we performed a structural and vibrational study of the amide group in the Vpd and their derivatives. We found that small nonplanarity deviations of C( O)N backbone induce significant changes on the structural and spectroscopic properties. These are not compatible with the decreasing of the resonance effect as it is produced when the twisting around the C( O)-N increases.From the Natural Bond Orbital (NBO) analysis the existence of stabilizing electrostatic interactions of type C-H· · ·O/N and C-H· · ·H-N/C, which induce significant structural changes and a complex electronic redistribution of charge on the π -system in those structures becomes evident. We view this as a consequence of the filled electron density change Lewis-type NBOs type lp O1,2 , lp N1 , σ (C -H)N -acyl and empty non-Lewis NBOs type σ * (C -H)N -acyl , σ * N -H .

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Section: Introductionmentioning

confidence: 99%

Spectroscopy properties of the amide group in valpromide and some derivatives with antiepileptic activity

Massa

Castro

Jubert

2009

J Raman Spectroscopy

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“…Gavernet et al [186,187] synthesized a new set of sulfamide derivatives as novel ligands with anti-MES activity considering sulfamide functionality as the polar portion of the pharmacophore previously proposed by the same research group by means of bioisosteric replacement of the polar end groups (amide, carbamate, ester, urea, sulfonamide, sulfamate) which exist in older anticonvulsant compounds. They designed seventeen new sulfamide derivatives (64) based on the results of molecular modeling in order to understand the effect of hydrophilic and hydrophobic portions.…”

Section: Sulfamide Derivativesmentioning

confidence: 99%

“…Gavernet et al [185] designed and synthesized a set of new amino acid-derived sulfamide compounds as a continuation of their interest in sulfamide anticonvulsant compounds to improve the anticonvulsant activity of sulfamides by combining them with aminoacids [186,187]. Their anticonvulsant activities were tested according to ASP Fig.…”

Section: Amino Acid Derivativesmentioning

confidence: 99%

Recent Progress in Anticonvulsant Drug Research: Strategies for Anticonvulsant Drug Development and Applications of Antiepileptic Drugs for Non-Epileptic Central Nervous System Disorders

Dalkara

Karakurt²

2012

CTMC

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Major advances in antiepileptic drug therapy have taken place since 1950s. In the first period, several antiepileptic drugs (AEDs) such as phenobarbital, diphenylhydantoin, ethosuximide, carbamazepine, benzodiazepines and valproic acid were introduced to epilepsy treatment. After 1990 many new generation drugs (lamotrigine, topiramate, gabapentine, pregabaline, felbamate, lacosamide, levetiracetam etc.) have been developed. These novel AEDs have offered some advantages such as fewer side effects, fewer drug-drug interactions, and better pharmacokinetic properties. But pharmacoresistance and therapeutic failure in 20-25% of the patients remain the main reasons to continue efforts to find safer and more efficacious drugs and ultimate a treatment for this devastating disease. Several AEDs especially novel compounds have been found to be effective also in the treatment of several other neurologic and psychiatric disorders. Chemical diversity of the newer antiepileptic drugs as well as those currently in clinical development is another point that encourages medicinal chemists to study this subject. This review summarizes recent studies on the development of potential anticonvulsant compounds in different chemical structures, their structure-activity relationships and also therapeutic usages of AEDs other than epilepsy.

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“…The remaining 49 compounds were fitted to a previously defined pharmacophore (Figure 4) for anticonvulsant activity in the MES test [28,29]. Structures which at first sight did not accomplish the pharmacophore requisites were not fitted to the pharmacophore.…”

Section: Full Papersmentioning

confidence: 99%

A Combined Virtual Screening 2D and 3D QSAR Methodology for the Selection of New Anticonvulsant Candidates from a Natural Product Library

Gavernet¹,

Talevi²,

Castro³

et al. 2008

QSAR Comb. Sci.

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A virtual screening methodology combining a discriminant function (df) based on Dragon 2D-descriptors, general ADME filters, and a pharmacophore identified through superposition of rigid analogs was applied in order to identify new anticonvulsant agents among 10 903 natural products. Fifty-six compounds were selected from the application of this df, Lipinskis rule-of-five and other criteria for prediction of oral bioavailability, and the optimal value of log P for a compound to diffuse passively through the blood -brain barrier. Seven of these compounds were removed because they did not belong to descriptor space defined by the training set. The remaining 49 compounds were fitted to the pharmacophore structural constrains, selecting 7 structures with RMS distance value below 0.2. Systematic conformational analysis was performed to find the global minimum conformation, using the PM3 base included in Hyperchem 6.03. The global minimum conformations were further refined at a 6-31G** level with Gaussian 03. Restricted optimization was then performed to determine the energy difference between the energy minimum conformation and the active conformation defined by the pharmacophore, retaining those structures whose energy differences were below 7 kcal/mol. Four new potential anticonvulsants which fulfill the df and the pharmacophore requisites were selected. One of these structures, 2-(4,6-dimethyl-1-benzofuran-3-yl)acetic acid, was acquired and assayed in the MES and Rotorod tests, confirming anticonvulsant activity in mice at 30 and 100 mg/kg (0.5 and 4 h, i.p.) and absence of neurotoxicity at the tested doses.

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3D-QSAR design of novel antiepileptic sulfamides

Cited by 24 publications

References 45 publications

Spectroscopy properties of the amide group in valpromide and some derivatives with antiepileptic activity

Spectroscopy properties of the amide group in valpromide and some derivatives with antiepileptic activity

Recent Progress in Anticonvulsant Drug Research: Strategies for Anticonvulsant Drug Development and Applications of Antiepileptic Drugs for Non-Epileptic Central Nervous System Disorders

A Combined Virtual Screening 2D and 3D QSAR Methodology for the Selection of New Anticonvulsant Candidates from a Natural Product Library

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