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

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


getmorefigures.php?uid=PMC3750111&req=5

Figure 2: Preparation of the investigated 3,5-disubstituted-5-phenylhydantoins.

Mentions: 5,5-Diphenylhydantoin was commercially obtained (Fluka), while 5-ethyl-5-phenylhydantoin and 5-methyl-5-phenylhydantoin were synthesized by a modification of the method of Bucherer and Lieb [19]. The appropriate ketone was heated with (NH4)2CO3 and KCN in 50% ethanol (Figure 2a). The obtained compounds were alkylated at the N3 position using the corresponding alkyl halide in K2CO3/N,N-dimethylformamide to obtain compounds 1-7 and 11-25 (Figure 2b) [20]. When the reaction with alkyl halogenide did not occur due to a change in the reaction pathway or gave a low yield, the derivatives (8-10) were obtained by the Biltz reaction from benzil, respectively urea, and KOH in ethanol (Figure 2c) [21]. The chemical structures and the purities of the synthesized 3,5-disubstituted-5-phenylhydantoins were confirmed by their melting points, and FT-IR, 1H and 13C NMR spectra [Additional file 1].


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

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

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

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

Figure 2: Preparation of the investigated 3,5-disubstituted-5-phenylhydantoins.
Mentions: 5,5-Diphenylhydantoin was commercially obtained (Fluka), while 5-ethyl-5-phenylhydantoin and 5-methyl-5-phenylhydantoin were synthesized by a modification of the method of Bucherer and Lieb [19]. The appropriate ketone was heated with (NH4)2CO3 and KCN in 50% ethanol (Figure 2a). The obtained compounds were alkylated at the N3 position using the corresponding alkyl halide in K2CO3/N,N-dimethylformamide to obtain compounds 1-7 and 11-25 (Figure 2b) [20]. When the reaction with alkyl halogenide did not occur due to a change in the reaction pathway or gave a low yield, the derivatives (8-10) were obtained by the Biltz reaction from benzil, respectively urea, and KOH in ethanol (Figure 2c) [21]. The chemical structures and the purities of the synthesized 3,5-disubstituted-5-phenylhydantoins were confirmed by their melting points, and FT-IR, 1H and 13C NMR spectra [Additional file 1].

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