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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

The UV spectra of compounds 1 (a), 13 (b) and 20 (c) in methanol and 1 (d), 13 (e) and 20 (f) in 2-methyl propan-2-ol.
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Figure 3: The UV spectra of compounds 1 (a), 13 (b) and 20 (c) in methanol and 1 (d), 13 (e) and 20 (f) in 2-methyl propan-2-ol.

Mentions: The UV absorption spectra were measured with a Shimadzu 1700 spectrophotometer. The UV spectra were taken in spectro quality solvents (Fluka) at a fixed concentration of 10-5 mol/L. All solvents were of the highest available grade and spectral purities and used without further purification The reported values of νmax are average from three measurements of the corresponding λmax. As expected, no significant differences between repeated measurements were observed and their uncertanity was considered to be negligible When broad bands appear (e.g., c, e and f in Figure 3), high order polynomial curves (n = 9) were fitted to the data by using Origin 8 and the absorption maxima were determined on the basis of the first derivative of the fitted curves.


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

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

The UV spectra of compounds 1 (a), 13 (b) and 20 (c) in methanol and 1 (d), 13 (e) and 20 (f) in 2-methyl propan-2-ol.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: The UV spectra of compounds 1 (a), 13 (b) and 20 (c) in methanol and 1 (d), 13 (e) and 20 (f) in 2-methyl propan-2-ol.
Mentions: The UV absorption spectra were measured with a Shimadzu 1700 spectrophotometer. The UV spectra were taken in spectro quality solvents (Fluka) at a fixed concentration of 10-5 mol/L. All solvents were of the highest available grade and spectral purities and used without further purification The reported values of νmax are average from three measurements of the corresponding λmax. As expected, no significant differences between repeated measurements were observed and their uncertanity was considered to be negligible When broad bands appear (e.g., c, e and f in Figure 3), high order polynomial curves (n = 9) were fitted to the data by using Origin 8 and the absorption maxima were determined on the basis of the first derivative of the fitted curves.

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