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Solvent effects on the structure-property relationship of anticonvulsant hydantoin derivatives: A solvatochromic analysis.

Trišović N, Valentić N, Ušćumlić G - Chem Cent J (2011)

Bottom Line: Considering the pharmaceutical importance of hydantoins, a set of 25 derivatives of phenytoin, nirvanol and 5-methyl-5-phenylhydantoin, the lipophilicities of which were gradually increased by the introduction of different alkyl, cycloalkyl and alkenyl groups in position N3, was synthesized.The UV absorption spectra of the investigated compounds were recorded in the region from 200 to 400 nm, in selected solvents of different polarities.In view of the results of this study, the investigated hydantoin derivatives met the pharmacokinetic criteria for pre-selection as drug candidates and qualified them for the pharmacodynamic phase of antiepileptic drug development.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Organic Chemistry, Faculty of Technology and Metallurgy, University of Belgrade, Karnegijeva 4, 11000 Belgrade, Serbia. naca@tmf.bg.ac.rs.

ABSTRACT
Considering the pharmaceutical importance of hydantoins, a set of 25 derivatives of phenytoin, nirvanol and 5-methyl-5-phenylhydantoin, the lipophilicities of which were gradually increased by the introduction of different alkyl, cycloalkyl and alkenyl groups in position N3, was synthesized. Their properties under consideration were either estimated empirically, by UV/Vis spectroscopy, or calculated using established medicinal chemistry software. The UV absorption spectra of the investigated compounds were recorded in the region from 200 to 400 nm, in selected solvents of different polarities. The effects of solvent dipolarity/polarizability and solvent-solute hydrogen bonding interactions were analyzed by means of the linear solvation energy relationship (LSER) concept proposed by Kamlet and Taft. Furthermore, the relationships between solvent-solute interactions and selected structural features of the solutes, which are believed to markedly affect the processes of absorption, distribution, metabolism, excretion and toxicity (ADMETox), were discussed. Satisfactory correlations were found between hydrogen bonding properties and solute size and the in silico calculated bioactivity descriptors, in particular %Abs. (human intestinal absorption), log BB (blood-brain barrier permeation) and log kA (protein binding affinities) parameters. In view of the results of this study, the investigated hydantoin derivatives met the pharmacokinetic criteria for pre-selection as drug candidates and qualified them for the pharmacodynamic phase of antiepileptic drug development.

No MeSH data available.


Related in: MedlinePlus

A comparison between the experimental (νexp) and the calculated absorption frequencies (νcalc). The open points present data for the following alcohols: butan-1-ol, butan-2-ol and 2-methyl propan-2-ol.
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Figure 4: A comparison between the experimental (νexp) and the calculated absorption frequencies (νcalc). The open points present data for the following alcohols: butan-1-ol, butan-2-ol and 2-methyl propan-2-ol.

Mentions: Solvent dipolarity/polarizability and hydrogen bonding are the principal factors in controlling pathways of energy dissipation following the electronic excitation. Their individual contributions are quantified by means of the LSER concept using Eq. (2). The solvent parameters are shown in the Table 3[16,23]. The correlation of the spectroscopic data was carried out in terms of multiple linear regressions. On the basis of high values of the multiple correlation coefficients and the Fisher criterion, the correlation results of the absorption frequencies of studied molecules in the selected solvent set with the π*, β and α parameters can be considered as satisfactory. The regression values νo, s, b and a fit at the 95% confidence level are presented together with the corresponding standard errors in Table 4. The general effectiveness of the quantification and interpretation of solvent effects on the shifts of the absorption maxima of the investigated molecules is presented in Figure 4 by means of a plot of νexp versus νcalc (R = 0.989). It can be seen that the Kamlet-Taft equation describes better the experimental data for HBA solvents than for HBD solvents. The largest, but still acceptable discrepancies were obtained for aliphatic alcohols with bulky alkyl groups (butan-1-ol, butan-2-ol, 2-methyl propan-2-ol). This might be ascribed to steric interactions which the Kamlet-Taft equation does not take into account. The similar situations were reported in the literature [24,25]. However, this was afterwards overcome by inclusion of the Taft steric parameter in the analysis of structural effects on ADMETox properties of the molecules investigated in this work.


Solvent effects on the structure-property relationship of anticonvulsant hydantoin derivatives: A solvatochromic analysis.

Trišović N, Valentić N, Ušćumlić G - Chem Cent J (2011)

A comparison between the experimental (νexp) and the calculated absorption frequencies (νcalc). The open points present data for the following alcohols: butan-1-ol, butan-2-ol and 2-methyl propan-2-ol.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3750111&req=5

Figure 4: A comparison between the experimental (νexp) and the calculated absorption frequencies (νcalc). The open points present data for the following alcohols: butan-1-ol, butan-2-ol and 2-methyl propan-2-ol.
Mentions: Solvent dipolarity/polarizability and hydrogen bonding are the principal factors in controlling pathways of energy dissipation following the electronic excitation. Their individual contributions are quantified by means of the LSER concept using Eq. (2). The solvent parameters are shown in the Table 3[16,23]. The correlation of the spectroscopic data was carried out in terms of multiple linear regressions. On the basis of high values of the multiple correlation coefficients and the Fisher criterion, the correlation results of the absorption frequencies of studied molecules in the selected solvent set with the π*, β and α parameters can be considered as satisfactory. The regression values νo, s, b and a fit at the 95% confidence level are presented together with the corresponding standard errors in Table 4. The general effectiveness of the quantification and interpretation of solvent effects on the shifts of the absorption maxima of the investigated molecules is presented in Figure 4 by means of a plot of νexp versus νcalc (R = 0.989). It can be seen that the Kamlet-Taft equation describes better the experimental data for HBA solvents than for HBD solvents. The largest, but still acceptable discrepancies were obtained for aliphatic alcohols with bulky alkyl groups (butan-1-ol, butan-2-ol, 2-methyl propan-2-ol). This might be ascribed to steric interactions which the Kamlet-Taft equation does not take into account. The similar situations were reported in the literature [24,25]. However, this was afterwards overcome by inclusion of the Taft steric parameter in the analysis of structural effects on ADMETox properties of the molecules investigated in this work.

Bottom Line: Considering the pharmaceutical importance of hydantoins, a set of 25 derivatives of phenytoin, nirvanol and 5-methyl-5-phenylhydantoin, the lipophilicities of which were gradually increased by the introduction of different alkyl, cycloalkyl and alkenyl groups in position N3, was synthesized.The UV absorption spectra of the investigated compounds were recorded in the region from 200 to 400 nm, in selected solvents of different polarities.In view of the results of this study, the investigated hydantoin derivatives met the pharmacokinetic criteria for pre-selection as drug candidates and qualified them for the pharmacodynamic phase of antiepileptic drug development.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Organic Chemistry, Faculty of Technology and Metallurgy, University of Belgrade, Karnegijeva 4, 11000 Belgrade, Serbia. naca@tmf.bg.ac.rs.

ABSTRACT
Considering the pharmaceutical importance of hydantoins, a set of 25 derivatives of phenytoin, nirvanol and 5-methyl-5-phenylhydantoin, the lipophilicities of which were gradually increased by the introduction of different alkyl, cycloalkyl and alkenyl groups in position N3, was synthesized. Their properties under consideration were either estimated empirically, by UV/Vis spectroscopy, or calculated using established medicinal chemistry software. The UV absorption spectra of the investigated compounds were recorded in the region from 200 to 400 nm, in selected solvents of different polarities. The effects of solvent dipolarity/polarizability and solvent-solute hydrogen bonding interactions were analyzed by means of the linear solvation energy relationship (LSER) concept proposed by Kamlet and Taft. Furthermore, the relationships between solvent-solute interactions and selected structural features of the solutes, which are believed to markedly affect the processes of absorption, distribution, metabolism, excretion and toxicity (ADMETox), were discussed. Satisfactory correlations were found between hydrogen bonding properties and solute size and the in silico calculated bioactivity descriptors, in particular %Abs. (human intestinal absorption), log BB (blood-brain barrier permeation) and log kA (protein binding affinities) parameters. In view of the results of this study, the investigated hydantoin derivatives met the pharmacokinetic criteria for pre-selection as drug candidates and qualified them for the pharmacodynamic phase of antiepileptic drug development.

No MeSH data available.


Related in: MedlinePlus