Partition Coefficients of Three New Anticonvulsants

Hernández-Gallegos, Zurisaddai; Lehmann, Anne

doi:10.1002/jps.2600791118

Cited by 5 publications

(2 citation statements)

References 11 publications

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“…Our previous sodium channel SAR studies 3 suggested that log P was one of the parameters important for enhanced binding of hydantoins to the NVSC. We thus estimated the log P values for analogues 5-7 and 17-20 (Tables 1 and 2) by the approach we employed earlier, using reported experimentally measured log P values for the parent structures, 5-phenylhydantoin (log P ) 0.46) 30 and 2-hydroxy-2-phenylpropanamide (log P ) 1.2), 31 to which were added the appropriate π values for the substituents at C5 and N1 to provide the final log P. 32 The π values used were 0.50 for each CH 2 or CH 3 in the alkyl chain at C5 and 0.56 for an N-CH 3 substitute. For example, the log P for hydantoin 8 was calculated as (log P 5-phenylhydantoin + π 5-methyl + π N1-methylene + π methyl ) ) (0.46 + 0.50 + 0.56 + 0.50) ) 2.02.…”

Section: Resultsmentioning

confidence: 99%

Comparative Molecular Field Analysis of Hydantoin Binding to the Neuronal Voltage-Dependent Sodium Channel

et al. 1999

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Comparative molecular field analysis (CoMFA), a 3-D QSAR technique, is widely used to correlate biological activity with observed differences in steric and electrostatic fields. In this study, CoMFA was employed to generate a model, based upon 14 structurally diverse 5-phenylhydantoin analogues, to delineate structural and electrostatic features important for enhanced sodium channel binding. Correlation by partial least squares (PLS) analysis of in vitro sodium channel binding activity (expressed as log IC50) and the CoMFA descriptor column generated a final non-cross-validated model with R2 = 0.988 for the training set. The final CoMFA model explained the data better than a simpler correlation with log P (R2 = 0.801) for the same training set. The CoMFA steric and electrostatic maps described two general features that result in enhanced binding to the sodium channel. These include a preferred 5-phenyl ring orientation and a favorable steric effect resulting from the C5-alkyl chain. This model was then utilized to accurately predict literature sodium channel activities for hydantoins 14-20, which were not included in the training set. Finally the hydantoin CoMFA model was used to design the structurally novel alpha-hydroxy-alpha-phenylamide 21. Synthesis and subsequent sodium channel evaluation of compound 21 (predicted IC50 = 9 microM, actual IC50 = 9 microM), a good binder to the sodium channel, established that the intact hydantion ring is not necessary for efficient binding to this site. Thus alpha-hydroxy-alpha-phenylamides may represent a new class of ligands that bind with increased potency to the sodium channel.

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Section: Resultsmentioning

confidence: 99%

Comparative Molecular Field Analysis of Hydantoin Binding to the Neuronal Voltage-Dependent Sodium Channel

et al. 1999

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“…The data set was made up of derivatives of 1H-pyrazolo [3, 4-d]pyrimidine, 1H-pyrazole-5carboxylic and hydrazine carboxamide obtained from literatures (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) with their anticonvulsant activity against MES-induced seizure expressed as ED50 (mg/kg) (a measure of the dose quantity that is effective in 50% of the tested animals). The reported anti-MES activities of the selected compounds were recalculated to molar unit for easy comparison between molecules and subsequently, they were converted to logarithmic unit (i.e.…”

Section: Data Setmentioning

confidence: 99%

A novel QSAR model for designing, evaluating,and predicting the anti-MES activity of new 1H-pyrazole-5-carboxylic acid derivatives

Adedirin¹,

Uzairu²,

Shallangwa³

et al. 2017

Journal of the Turkish Chemical Society, Section A: Chemistry

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A quantitative structure-activity relationship (QSAR) study was performed to develop a model that relates the structures of 62 compounds, which have activity against maximal electroshock-induced seizure (MES), with their anti-MES activity. Molecular structures of the compounds were geometrically optimized and energetically minimized using a combination of modified Merck force field (MMFF) molecular mechanics, Austin model 1 (AM1) semi-empirical quantum mechanical and density functional theory (DFT) quantum mechanical method using the Becke's three parameter exchange functional (B3) hybrid with Lee, Yang and Parr correlation functional (LYP) and basis set of the double zeta split valence plus polarization quality 6-31G** i.e. B3LYP/6-31G**. Theoretically derived descriptors were obtained from the optimized structures, a genetic function approximation (GFA) algorithm was also applied to select the optimal descriptors and multiple linear regression (MLR) was used to establish a relationship between the anti-MES activity of the compounds and the optimal molecular descriptors. A six-parametric equation containing dipole moment (μ), energy of the lowest unoccupied molecular orbital (ϵLUMO), polar surface area (PSA), accessible surface area derived from wave function (WAA), sum of the square root of square of the charge on all atom of the molecule (QA) and sum of the square root of square of the charge on all fluorine atoms in the molecule was obtained as the QSAR model in the present study with good statistical qualities (R 2 =0.937, R 2 adj=0.928, F=104.11, R 2 pred=0.929 and Q 2 =0.913). The QSAR model was used to study estimate the anti-MES activities of 1H-pyrazole-5-carboxylic acid derivatives not yet synthesized. 10 out of the 101 screened compounds had improved anti-MES activity when compared to the template (i.e. ethyl 4-(4-chlorophenyl)-3-morpholino-1H-pyrrole-2-carboxylate, which is compound number 61 in the dataset) used to design the 101 derivatives. These 10 compounds were docked with voltage-gated sodium channel (PDB code: 2KaV) and their binding affinity were comparable to that of phenytoin (a standard drug known to possess anti-MES activity).

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Exploring the interplay of physicochemical properties, membrane permeability and giardicidal activity of some benzimidazole derivatives

Hernández-Covarrubias

Vilchis‐Reyes

Yépez‐Mulia

et al. 2012

European Journal of Medicinal Chemistry

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Partition Coefficients of Three New Anticonvulsants

Cited by 5 publications

References 11 publications

Comparative Molecular Field Analysis of Hydantoin Binding to the Neuronal Voltage-Dependent Sodium Channel

Comparative Molecular Field Analysis of Hydantoin Binding to the Neuronal Voltage-Dependent Sodium Channel

A novel QSAR model for designing, evaluating,and predicting the anti-MES activity of new 1H-pyrazole-5-carboxylic acid derivatives

Exploring the interplay of physicochemical properties, membrane permeability and giardicidal activity of some benzimidazole derivatives

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