Nebojša R. Banjac

Reversed-phase TLC and HPLC retention data in correlation studies with in silico molecular descriptors and druglikeness properties of newly synthesized anticonvulsant succinimide derivatives.

The properties relevant to pharmacokinetics of two series of newly synthesized succinimide derivatives have been studied. The properties under consideration have been either determined empirically, by reversed-phase liquid chromatography (TLC and HPLC technique), or calculated with the use of established theoretical medicinal chemistry/drug design software. Chromatographic techniques allowed determination of the retention constants R(M)⁰ and log k(w), which characterize lipophilicity of compounds. Considering potential pharmaceutical importance of succinimide derivatives, we (i) examined the retention behavior in the reversed-phase liquid chromatographic (RP LC) systems, in both planar and column LC, and (ii) determined the relationships between chromatographic data and selected structural features of analytes that are believed to markedly affect their processes of absorption, distribution, metabolism, excretion and toxicity (ADMETox). Significant relationships were found between the retention constants, R(M)⁰ and log k(w), and the in silico calculated bioactivity descriptors, in particular HIA (human intestinal absorption) and PPB (plasma protein binding) parameters. The R(M)⁰ and log k(w) values of the investigated compounds have been recommended for description of their lipophilicity and evaluating pharmacokinetic properties. In view of results of this study the newly synthesized succinimide agents meet pharmacokinetic criteria of preselection of drug candidates and hence qualify for pharmacodynamic phase of antiepileptic drug development. Best compromising human intestinal absorption and plasma protein binding features appear to be compounds A4, A5, A10 and A11.

Chromatographic retention parameters in correlation analysis with in silico biological descriptors of a novel series of N-phenyl-3-methyl succinimide derivatives.

Reversed-phase thin-layer chromatographic (RP TLC) retention coefficients for a newly designed series of N-phenyl-3-methyl succinimide derivatives, of a rationally expected anticonvusant activity, were determined as parameters of their lipophilicity. Basic pharmacokinetic descriptors of the agents were calculated in silico with the use of the established medicinal chemistry/drug design software. Highly significant, predictive relationships were found between the chromatographic retention constants and the bioactivity descriptors, which are assumed to account for drug absorption, distribution, elimination and toxicity (ADMETox) in humans. Among the agents investigated, the compounds with halogen substituent (Compounds nos. 9-13 in Fig. 1), were identified as the best drug candidates, because of their predicted proper pharmacokinetics, and have been selected for further research and development studies on new antiepileptic drugs. At the same time, among the congeners studied these can be indicated, which should not be rationally subjected to bioactivity tests.

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.

Buckwheat and quinoa seeds as supplements in wheat bread production

The aim of this work was to compare the nutritional characteristics of wheat bread with the bread produced of wheat flour supplemented with quinoa and buckwheat seeds. Bread making properties of these blends were analyzed in order to investigate their ability to make moulded bread. Quinoa (Chenopodium quinoa Will.) and buckwheat seeds were grown in the vicinity of Belgrade, Serbia. The addition of pseudocereal seeds (at levels of 30% and 40%) and a selected technological process, which included hydrothermal preparation of supplements, resulted with a valuable effect on nutritive value of breads. In comparison with the wheat bread that was used as control sample, the protein increase of 2% and the increase of crude fiber content at around 0.5% in 30% supplemented breads were registered. Furthermore, the incorporation of both seeds mixture at the level of 40%, increased the content of protein for 2.5% and fiber content for 0.4%. In regard to the starch, fat, and ash contents there were no major differences. The investigated breads were nutritionally superior to the wheat bread. Chemical composition of the selected seeds was also investigated. The results showed that the blends containing either 30% or 40% of selected seeds expressed high potential for the production of molded breads, as new baking products with enhanced nutritional composition. The applied technological procedure was modified in such way that for all blended combination of supplements it changed rheological properties of dough. Furthermore, it resulted in a good volume of breads with excellent sensory properties of aroma-odor and taste.

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

Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives

&NA; Design of a new drug entity is usually preceded by analysis of quantitative structure activity (properties) relationships, QSA(P)R. Six newly synthesized succinimide derivatives have been determined for (i) in silico physico‐chemical descriptors, pharmacokinetic and toxicity predictors, (ii) in vitro biological activity on four different carcinoma cell lines and on normal fetal lung cells and (iii) lipophilicity on liquid chromatography. All compounds observed were predicted for good permeability and solubility, good oral absorption rate and moderate volume of distribution as well as for modest blood brain permeation, followed by acceptable observed toxicity. In silico determined lipophilicity, permeability through jejunum and aqueous solubility were correlated with experimentally obtained lipophilic constants (by use of high pressure liquid chromatography) and linear correlations were obtained. Absorption rate and volume of distribution were predicted by chromatographic lipophilicity measurements while permeation through blood bran barrier was predicted dominantly by molecular size defined with molecular weight. Five compounds have demonstrated antiproliferative activity toward cervix carcinoma HeLa cell lines; three were cytotoxic against breast carcinoma MCF‐7 cells, while one inhibited proliferation of colon carcinoma HT‐29 cell lines. Only one compound was cytotoxic toward normal cell lines, while other compounds were proven as safe. Antiproliferative potential against HeLa cells was described as exponential function of lipophilicity. Based on obtained results, lead compounds were selected. Graphical abstract Figure. No caption available. HighlightsQSA(P)R analysis for six new succinimide derivatives was performed.Experimental lipophilicity and virtual pharmacokinetic properties were determined.Some compounds have demonstrated antiproliferative activity on carcinoma cell lines.