Limits...
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

Structures of the investigated 3,5-disubstituted-5-phenylhydantoins.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3750111&req=5

Figure 1: Structures of the investigated 3,5-disubstituted-5-phenylhydantoins.

Mentions: In a recent paper [15], reversed-phase TLC and HPLC retention data were used in correlation studies with molecular descriptors of the pharmacokinetic properties of anticonvulsant succinimide derivatives. The aim of the present study was to apply the solvatochromic comparison method to quantify and correlate multiple solvent effects on the transport properties and interactions of various hydantoins having potential for pharmacological application. A set of twenty five derivatives of phenytoin, nirvanol and 5-methyl-5-phenylhydantoin, the lipophilicities of which were gradually increased by the introduction of alkyl, cycloalkyl and alkenyl substituents at the N3 position (Figure 1), was synthesized. Their UV absorption spectra were recorded in the region 200-400 nm in fifteen solvents of different polarities. To obtain an insight into the various modes of solvation determining the absorption energies, the effects of solvent dipolarity/polarizability (nonspecific solvent-solute interactions) and hydrogen bonding (specific solvent-solute interactions) on the absorption spectra were interpreted by means of a linear solvation energy relationship (LSER) using the Kamlet-Taft Equation of the form:


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

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

Structures of the investigated 3,5-disubstituted-5-phenylhydantoins.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Structures of the investigated 3,5-disubstituted-5-phenylhydantoins.
Mentions: In a recent paper [15], reversed-phase TLC and HPLC retention data were used in correlation studies with molecular descriptors of the pharmacokinetic properties of anticonvulsant succinimide derivatives. The aim of the present study was to apply the solvatochromic comparison method to quantify and correlate multiple solvent effects on the transport properties and interactions of various hydantoins having potential for pharmacological application. A set of twenty five derivatives of phenytoin, nirvanol and 5-methyl-5-phenylhydantoin, the lipophilicities of which were gradually increased by the introduction of alkyl, cycloalkyl and alkenyl substituents at the N3 position (Figure 1), was synthesized. Their UV absorption spectra were recorded in the region 200-400 nm in fifteen solvents of different polarities. To obtain an insight into the various modes of solvation determining the absorption energies, the effects of solvent dipolarity/polarizability (nonspecific solvent-solute interactions) and hydrogen bonding (specific solvent-solute interactions) on the absorption spectra were interpreted by means of a linear solvation energy relationship (LSER) using the Kamlet-Taft Equation of the form:

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