Nemanja Trišović

Substituent and solvent effects on intramolecular charge transfer of 5-arylidene-2,4-thiazolidinediones.

The absorption spectra of twelve 5-arylidene-2,4-thiazolidinediones were recorded in twenty one solvents in the range from 300 to 600 nm. The effect of specific and non-specific solvent-solute interactions on the absorption maxima shifts were evaluated by using the Catalán solvent parameter set. Furthermore, the experimental findings were interpreted with the aid of ab initio MP2 and time-dependent density functional (TD-DFT) methods. It was found that different substituents significantly change the extent of conjugation in the molecules and further affect their intramolecular charge transfer character.

Azo-containing asymmetric bent-core liquid crystals with modulated smectic phases

A new series of azo-containing bent-core liquid crystals derived from 3-hydroxybenzoic acid has been synthesized. Their mesomorphic properties have been characterized by polarizing optical microscopy, differential scanning calorimetry, small-angle X-ray diffraction and electro-optic studies. Almost all the compounds form an enantiotropic modulated smectic (B7 type) phase over relatively broad temperature ranges. Structural modifications, such as the type and length of the terminal chains, the rigidity of wings, and the presence of a Cl-substituent in different positions of the bent core, affect the appearance and temperature range, but not the type of the mesophase of the investigated compounds. Light-induced changes in the texture and phase transition of the mesophase, attributed to the decrease of the order parameter due to trans–cis isomerization, have also been observed.

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

Prediction of clearing temperatures of bent-core liquid crystals using decision trees and multivariate adaptive regression splines

ABSTRACT Accurate prediction of transition temperature is very helpful for the design of new liquid crystals (LCs) because even small changes in structure can dramatically alter the transition temperature, and therefore the synthesis of LCs should not be governed only by chemical intuition. A quantitative structure–property relationship (QSPR) study was performed on 243 five-ring bent-core LCs in order to predict their clearing temperatures using molecular descriptors. Decision tree and multivariate adaptive regression splines (MARS), techniques well suited for high-dimensional data analysis, were applied to select important descriptors (dimension reduction) and to generate nonlinear models. These techniques were applied both on two-dimensional (2D) descriptors only and on the pool of 2D and 3D descriptors (2&3D). The obtained QSPR models were tested using 15% of available data, and their performance and ability to generalise were analysed using multiple statistical metrics. The best results for the external test set were obtained using the MARS model created with 2&3D descriptors, with a high correlation coefficient of r = 0.95 and a root mean squared error of 7.41 K. All metrics suggest that the proposed QSPR model, generated by MARS, is a robust and satisfactorily accurate approach for the prediction of clearing temperatures of bent-core LCs. GRAPHICAL ABSTRACT

Synthesis, structural and biological characterization of 5-phenylhydantoin derivatives as potential anticonvulsant agents

Considering the importance of hydantoin derivatives in treatment of status epilepticus, four 5-phenylhydantoins, whose lipophilicities were estimated to be similar to that of phenytoin, were synthesized. Evaluation of their anticonvulsant activities was performed on rats by subcutaneous pentylenetetrazol seizure test and intravenous pentylenetetrazol threshold test, and spontaneous locomotor activity test was used to assess possible sedative effects. X-ray analysis of three compounds suggested that certain analogies might be drawn between interactions in crystal packing and biological interactions responsible for their anticonvulsant activity. It was found that 5-ethyl-5-phenyl-3-propylhydantoin exhibits the most favorable pharmacological properties among the synthesized compounds, i.e., anticonvulsant activity comparable to phenytoin with lower liability for induction of sedation in rats.Graphical Abstract

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.

A QSPR study on the liquid crystallinity of five-ring bent-core molecules using decision trees, MARS and artificial neural networks

Accelerating progress in the discovery of new bent-core liquid crystal (LC) materials with enhanced features relies on the understanding of structure–property relationships that underline the formation of LC phases. The aim of this study was to develop a model for the prediction of LC behaviour of five-ring bent-core systems using a QSPR approach that combines dimension reduction techniques (e.g. genetic algorithms etc.) for the selection of molecular descriptors and decision trees, multivariate adaptive regression splines (MARS) and artificial neural networks (ANN) as classification methods. A total of 27 models based on separate pools of calculated molecular descriptors (2D; 2D and 3D) and published experimental outcomes were evaluated. Overall, the results suggest that the acquired ANN LC classifiers are usable for the prediction of LC behaviour. The best of these models showed high accuracy and precision (91% and 97%). Since the best classifier is able to successfully capture trends in a homologous series, it can be used not only to screen new bent-core structures for potential LCs, but also for the estimation of influence of structural modifications on LC phase formation, as well as for the evaluation of LC phase stability.

Solvatochromism of symmetrical 2,6-distyrylpyridines. An experimental and theoretical study

Seven symmetrical 2,6-distyrylpyridines, phenyl-substituted with hydrogen-bond donors, hydrogen-bond acceptors, halogens and hydrophobic moieties were synthesized and their spectroscopic characterization was done. Solvent effects on the absorption and fluorescence spectra were analyzed and quantified using the Kamlet-Taft and Catalán approach. The obtained results were rationalized by comparison of electrostatic potentials of the molecules in the ground and in excited state and by comparison of the frontier molecular orbitals (HOMO and LUMO), derived from quantum-mechanical calculations (HF, DFT, MP2). Analysis of the results revealed an important influence of non-specific (dispersive) interactions on the solvatochromic behavior of the compounds. 1D and 2D NMR data, in silico obtained conformational assembly of the compound, and the NMR analysis of molecular flexibility in solution (NAMFIS), were used to estimate population of conformers and to deconvolute the UV-Vis spectrum of representative derivative; inferring that the conformational assembly is more complex than was assumed in so far published literature data for this class of compounds. Along with this, the emission spectra of the representative compounds were decomposed by the Multivariate Curve Resolution analysis.

Structure-Retention Relationship Study of HPLC Data of Antiepileptic Hydantoin Analogues

In the study, 18 antiepileptic hydantoin analogues were investigated by means of reversed-phase HPLC on C-18 stationary phase and eluent acetonitrile-water. Quantitative structure-retention relationship (QSRR) study has been applied in order to understand factors that affect the retention which is closely correlated to the activity (ED₅₀ values). To overview the compounds for similarities and dissimilarities principal component analysis (PCA) has been applied. Six multiple linear regression models based on the most relevant descriptors were developed. Descriptors for MLR were selected according to variable importance calculated by partial least squares (PLS) analysis. Besides ALOGP the most important is aromatic ratio for mobile phases with more than 45% of acetonitrile, as well as electrotopological states when the % of acetonitrile is less than 40%. High agreement between experimental and predicted retention, obtained in the validation procedure, indicated the good quality of the derived QSRR models. For individual linear models, crossvalidation squared correlation coefficients (Q²) ranging from 0.697 to 0.837 were obtained. The residual values (difference between observed and calculated) agreed well within experimental error. Additionally, models were compared in terms of the smallest residual value by recently developed method of ranking based on the sum of ranking differences (SRD).

Towards understanding intermolecular interactions in hydantoin derivatives: the case of cycloalkane-5-spirohydantoins tethered with a halogenated benzyl moiety

A series of cycloalkane-5-spirohydantoins bearing a halogeno substituted benzyl group (X = Cl and Br) in position 3 has been synthesized and their structures (1–6) have been determined by a single crystal X-ray diffraction method. These compounds have multiple functional groups, which allow greater competition and/or cooperation among the different intermolecular interactions in the formation of their crystal structures. The molecules are linked together by paired N–H⋯O hydrogen bonds in R22(8) rings, while the C–H⋯O interactions lead to their further association into double chains. The contribution of the cycloalkyl ring depends on its conformational flexibility and the multiple C–H donor implications. In the case of compounds 1–4 bearing the cyclopentyl or the cyclohexyl ring, halogen bonding (X⋯O) interactions give rise to a supramolecular pseudo-hexagonal network. In addition, the C–H⋯X interactions with a higher degree of multifurcation at the halogen acceptor have an important role in the formation of the crystal structure. Regarding compounds 5 and 6 with the cycloheptane ring, the X⋯O interaction is absent, and along with the C–H⋯X interactions, these compounds realize an alternative crystal structure with an emphasis on the X⋯π interactions. The lattice energies of all these crystal structures, as well as the intermolecular pair energies, have been calculated using PIXEL and further partitioned into coulombic, dispersive, polarization and repulsive factors. The crystal structures have also been subjected to Hirshfeld surface analysis which reveals that approximately 75% of the close contacts correspond to relatively weak interactions. The application of both concepts has provided a new insight into the relationship between the molecular interactions and crystal structures of the hydantoin derivatives.