Nataša V. Valentić

Quantum mechanical and spectroscopic (FT-IR, 13C, 1H NMR and UV) investigations of potent antiepileptic drug 1-(4-chloro-phenyl)-3-phenyl-succinimide.

This study represents an integrated approach towards understanding the vibrational, electronic, NMR, and structural aspects, and reactivity of 1-(4-chloro-phenyl)-3-phenyl-succinimide (CPPS). A detailed interpretation of the FT-IR, UV and NMR spectra were reported. The equilibrium geometry, bonding features, and harmonic vibrational frequencies have been investigated with the help of density functional theory (DFT) B3LYP method using 6-31G(d,p) and 6-311++G(d,p) basis set. The scaled theoretical wavenumber showed very good agreement with the experimental values. The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by the Gauge-Invariant Atomic Orbital (GIAO) method. Stability of the molecule, arising from hyperconjugative interactions and charge delocalization, has been analyzed using Natural Bond Orbital (NBO) analysis. The results show that ED in the σ(*) and π(*) antibonding orbitals and second order delocalization energies E(2) confirm the occurrence of intramolecular charge transfer (ICT) within the molecule. UV-Vis spectrum of the compound was recorded and the electronic properties, such as HOMO and LUMO energies, were calculated by Time-Dependent DFT (TD-DFT) approach. To estimate chemical reactivity of the molecule, the molecular electrostatic potential (MEP) surface map is calculated for the optimized geometry of the molecule.

Synthesis, structure and solvatochromic properties of some novel 5-arylazo-6-hydroxy-4-phenyl-3-cyano-2-pyridone dyes

BackgroundA series of some novel arylazo pyridone dyes was synthesized from the corresponding diazonium salt and 6-hydroxy-4-phenyl-3-cyano-2-pyridone using a classical reaction for the synthesis of the azo compounds.ResultsThe structure of the dyes was confirmed by UV-vis, FT-IR, 1H NMR and 13C NMR spectroscopic techniques and elemental analysis. The solvatochromic behavior of the dyes was evaluated with respect to their visible absorption properties in various solvents.ConclusionsThe azo-hydrazone tautomeric equilibration was found to depend on the substituents as well as on the solvent. The geometry data of the investigated dyes were obtained using DFT quantum-chemical calculations. The obtained calculational results are in very good agreement with the experimental data.

The retention behavior of some uracil derivatives in normal and reversed-phase chromatography. Lipophilicity of the compounds

The chromatographic behavior of newly synthesized uracil derivatives has been studied by normal and reversed-phase thin-layer chromatography. Benzene—methanol, benzene—acetonitrile, and benzene—isopropanol were used as mobile phases in normal-phase chromatography and water—methanol and water—acetonitrile in reversed-phase chromatography. The mechanism of retention on different TLC supports was investigated. The retention constants determined for the uracils are discussed in terms of the physico-chemical properties of both the solutes and stationary and mobile phases. RM0 values derived by extrapolation from reversed-phase chromatography were correlated with the hydrophobicity log P calculated by use of the commercial program ACD/logP. In normalphase chromatography values for C0 (= RM0/n) were correlated with the hydrophobicity log P. Good correlation was obtained for both types of chromatography. Retention constants RM0 and C0 can be used to express the lipophilicity of the compounds investigated.

New derivatives of hydantoin as potential antiproliferative agents: biological and structural characterization in combination with quantum chemical calculations

Two new series of hydantoin derivatives, 3-(4-substituted benzyl)-5,5-diphenyl- and 3-(4-substituted benzyl)-5-ethyl-5-phenylhydantoins, were synthesized and their antiproliferative activity was tested against human colon cancer HCT-116 and breast cancer MDA-MB-231 cell lines. The presence of different substituents on both hydantoin and benzyl moieties changed the antiproliferative activity of the investigated hydantoins, whereby most of the compounds showed superior antiproliferative activity against MDA-MB-231 than against the HCT-116 cell line. The structure of three compounds was studied by single-crystal X-ray diffraction. The general structural characteristic is the presence of N–H···O hydrogen bonds in crystal packings. The molecular geometry and bonding features of the investigated hydantoins in the ground states were calculated using the density functional method. The relationship between structure and antiproliferative activity was discussed. The data presented in this investigation afford guidelines for the preparation of new hydantoin derivatives with greater antiproliferative activity.Graphical Abstract

Synthesis of azo pyridone dyes

Over 50% of all colorants which are used nowdays are azo dyes and pigments, and among them arylazo pyridone dyes (and pigments) have became of interest in last several decades due to the high molar extinction coefficient, and the medium to high light and wet fastness properties. They find application generally as disperse dyes. The importance of disperse dyes increased in the 1970s and 1980s due to the use of polyester and nylon as the main synthetic fibers. Also, disperse dyes were used rapidly since 1970 in inks for the heat-transfer printing of polyester. The main synthetic route for the preparation of azo dyes is coupling reaction between an aromatic diazo compound and a coupling component. Of all dyes manufactured, about 60% are produced by this reaction. Arylazo pyridone dyes can be prepared from pyridone moiety as a coupling component, where substituent can be on nitrogen, and diazonim salts which can be derived from different substituted anilines or other heterocyclic derivatives. In addition, arylazo dyes containing pyridone ring can be prepared from arylazo diketones or arylazo ketoesters (obtained by coupling β-diketones or β-ketoesters with diazonim salts) by condensation with cyanoacetamide. Disazo dyes can be prepared by tetrazotizing a dianiline and coupling it with a pyridone or by diazotizing aniline and coupling it with a dipyridone. Trisazo dyes can be also prepared by diazotizing of aniline and coupling it with a tripyridone or by hexazotizing a trianiline and coupling it with a pyridone. The main goal of this paper is to give a brief review on the synthesis of arylazo pyridone dyes due to the lack of such reviews. In addition, some properties of arylazo pyridone dyes as light fastness and azo-hydrazon tautomerism are disccused.

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

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.

Solvatochromic and quantum chemical investigations of newly synthesized succinimides: substituent effect on intramolecular charge transfer

Two series of 1-aryl-3-phenyl- and 1-aryl-3,3-diphenylpyrrolidine-2,5-diones were synthesized and their solvatochromic properties were studied in a set of 15 solvents of different polarity. The effect of specific and non-specific solvent–solute interactions on the position of their absorption bands was evaluated by using the solvent parameter sets of Kamlet and Taft. The interpretation of the effect of different substituent patterns on the solvatochromic properties of the investigated compounds was based on quantum chemical calculations performed by the density functional theory (DFT)/CAM-B3LYP method using the 6-311G(d,p) basis set. The theoretical absorption frequencies show very good agreement with the experimental values. The energy gaps between the HOMO and LUMO orbitals were also analyzed. It is demonstrated that different substituents change the conjugation effect and further determine the pathways of intramolecular charge transfer.Graphical abstract

Synthesis, structure and biological properties of active spirohydantoin derivatives

Spirohidantoins represent an pharmacologically important class of heterocycles since many derivatives have been recognized that display interesting activities against a wide range of biological targets. First synthesis of cycloalkanespiro-5-hydantoins was performed by Bucherer and Lieb 1934 by the reaction of cycloalkanone, potassium cyanide and ammonium-carbonate at reflux in a mixture of ethanol and water. QSAR (Quantitative Structure-Activity Relationship) studies showed that a wide range of biological activities of spirohydantoin derivatives strongly depend upon their structure. This paper describes different methods of synthesis of spirohydantoin derivatives, their physico-chemical properties and biological activity. It emphasizes the importance of cycloalkanespiro-5-hydantoins with anticonvulsant, antiproliferative, antipsychotic, antimicrobial and antiinflammatory properties as well as their importance in the treatment of diabetes. Numerous spirohydantoin compounds exhibit physiological activity such as serotonin and fibrinogen antagonist, inhibitors of the glycine binding site of the NMDA receptor also, antagonist of leukocyte cell adhesion, acting as allosteric inhibitors of the protein-protein interactions. Some spirohydantoin derivatives have been identified as antitumor agents. Their activity depends on the substituent presented at position N-3 of the hydantoin ring and increases in order alkene > ester > ether. Besides that, compounds that contain two electron withdrawing groups (e.g. fluorine or chlorine) on the third and fourth position of the phenyl ring are better antitumor agents than compounds with a single electron withdrawing group. [Projekat Ministarstva nauke Republike Srbije, br. 172013]