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To create new anticonvulsant drugs, two series of spirohydantoins derived from β-tetralone bearing a 4-substituted benzyl group (1a−1g) or a 2-(4-substituted phenyl)-2-oxoethyl group (2a−2f) in position 3 of the hydantoin ring were synthesized. The chemical structure of these compounds was confirmed by determination of the melting point, elemental analysis and FT-IR, 1H NMR, 13C NMR and UV-Vis spectroscopic methods. Effects of the substituents in the benzyl moiety on the shift of the absorption maxima of compounds 1a−1g and 2a−2f were analyzed using the Hammett's equation. Namely, a split in the Hammett plot at the parent compounds 1a and 2a revealed different electronic transitions within the molecules with the electron-donating substituents from those bearing the electron-accepting substituents, thus the electron-accepting effect on the shift of the absorption maxima being considerably stronger. The influence of the chemical structure on the pharmacokinetically relevant properties of the investigated hydantoin derivatives was evaluated using the Lipinski’s rule of five, Veber, Egan and Ghose's empirical criteria, as well as different in silico methods. When compared to phenytoin (5,5-diphenylhydantoin) as the referent drug, compounds with a halogen or electron-donating substituent are expected to possess better intestinal absorption and passage through the blood-brain barrier. Depending on the nature of the substituent present in the benzyl moiety, compounds 1a−1g and 2a−2f can be potent activators/inhibitors of some cytochrome P450 izoenzymes including CYP1A2, CYP2C19 and CYP2C9. Regarding biological activity profile, compounds with the electron-accepting substituents are likely to reveal the pharmacological potential similar to that of phenytoin, while those bearing electron-donating substituents are predicted to have the antimigrenic activity. All compounds were found to bear a low risk of being mutagenic or tumorigenic. The calculated molecular descriptors indicate that the investigated compounds fulfill necessary empirical criteria which qualify them as interesting drug candidates. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 172013]

Novel succinimide derivatives were synthesized from 3-methyl-3-phenylsuccinic acid and substituted anilines under solvent-free conditions by using microwave irradiation. All obtained compounds were characterized by ultraviolet (UV), Fourier-transform infrared (FT-IR), 1H and 13С nuclear magnetic resonance (NMR) spectroscopy as well as by elemental analysis. The influence of the substituent electronic effects on spectroscopic data was analyzed by applying the Hammett equation. Moreover, a detailed interpretation and comparison of experimentally obtained and theoretically calculated FT-IR, UV and NMR spectra was performed. Density functional theory (DFT) calculated data of the investigated succinimides were obtained and analyzed in order to determine their structural, spectroscopic and electronic properties. Furthermore, ADMET factor profiling and in-silico prediction of potential biological activities of novel succinimide derivatives have been performed. Novi derivati sukcinimida sintetisani su polazeći od 3-metil-3-fenilćilibarne kiseline i supstituisanih analina u mikrotalasnom reaktoru u odsustvu rastvarača. Sva jedinjenja su okarakterisana primenom UV-vidljive spektroskopije, infracrvene spektroskopije sa Furijeovom transformacijom (FT-IR), protonske nuklearne magnetne rezonancije (1H NMR), nuklearne magnetne rezonancije ugljenika-13, (13С NMR), kao i elementalnom analizom. Uticaj elektronskih efekata supstituenata na spektroskopske podatke analiziran je upotrebom Hametove jednačine. Takođe, izvršena je detaljna interpretacija, kao i poređenje eksperimentalno dobijenih i teorijski izračunatih FT-IR, UV i NMR spektara. Pored toga, urađeno je ADMET (engl. absorption, distribution, metabolism, excretion and toxicity) profilisanje i in-silico predviđanje potencijalne biološke aktivnosti novosintetisanih derivata sukcinimida.

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]

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.

A series of six novel 2-(5-arylidene-2,4-dioxotetrahydrothiazole-3-yl)propanoic acids and six corresponding methyl esters were synthesized. All compounds were characterized by melting points, elemental analysis, FT-IR, 1H and 13C NMR spectroscopy. Crystal structure of methyl-2-(5-(4-methoxybenzylidene)-2,4--dioxotetrahydrothiazole-3-yl)propionate was confirmed by X-ray analysis. The antiproliferative activity of all synthesized compounds against human colon cancer, breast cancer and myelogenous leukemia cell lines, i.e. HCT-116, MDA-231 and K562, respectively, was evaluated. The results indicate that antiproliferative activity of the synthesized esters is better than the activity of the corresponding acids. All synthesized compounds showed significant antiproliferative effects against HCT116 cells in all tested concentrations (0.01–100 μM). Moreover, in vitro antimicrobial activity against a wide range of tested microorganisms was examined.

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 CH. 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. p 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. This is the peer-reviewed version of the following article: Crystengcomm, 2017, 19, 3, 469-483 [https://dx.doi.org/10.1039/C6CE02210C] [http://cer.ihtm.bg.ac.rs/handle/123456789/2204]

In the last three or four decades disperse dyes derived from pyridones (in particular azo pyridone dyes) have gained in importance, and are widely used in various fields. These compounds have excellent coloration properties, and are suitable for the dyeing of polyester fabrics. Basic features of these dyes are simplicity of their synthesis by diazotation and azo coupling. They generally have high molar extinction coefficient with medium to high light and wet fastness. The absorption maxima of these dyes show their visible absorption wavelength ranging from yellow to orange, which can be attributed to poorly delocalized electrons in the pyridone ring. However, there are several dyes with deep colors such as red or violet. Pyridone dyes with alkyl and aryl groups in ortho position to azo group show 2-pyridone/2-hydroxypyridine tautomerism, while those containing OH and NHR groups conjugated with the azo group show azo-hydrazone tautomerism. Determining azo-hydrazone tautomerism could be therefore interesting, since the tautomers have different physico-chemical properties and most importantly different coloration. The literature on azo-hydrazone tautomerism, determination of equilibrium position, and investigation of substituent and solvent influence on tautomerism has been summarized in the presented review. The general conclusion is that the equilibrium between two tautomers is influenced by the structure of the compounds and by the solvents used. The tautomeric behavior patterns of the arylazo pyridone dyes in the reviewed literature has been studied using various instrumental techniques, including FT-IR, UV-vis, and NMR spectroscopy. The quantum chemical calculations related to the azo-hydrazon tautomerism have also been included. A large number of pyridone dyes exist in hydrazone form in solid state, while in solvents there is a mixture of tautomers. In addition, the X-ray single-crystal diffraction data analysis of some commercial pyridone dyes has been discussed concluding that they all crystallize in the hydrazone form. Arilazo piridonske boje su obojene supstance koje zbog svojih specifičnih svojstava kao i primene u različitim industrijskim oblastima predstavljaju značajan predmet istraživanja u poslednjih nekoliko decenija. Osnovna svojstva ovih boja su visoki ekstinkcioni koeficijenti kao i dobra postojanost na mokre obrade. Arilazo piridonske boje su pogodne za bojenje sintetskih vlakana i daju nijanse izmeću žute i narandžaste. Zbog uticaja strukture na obojenost, azo-hidrazon tautomerija je tema velikog broja radova. U ovom radu sumirana su dosadašnja istraživanja koja se odnose na azo-hidrazon tautomeriju arilazo pridonskih boja, kao i na mogućnost odrećivanja odnosa tautomera korišćenjem različitih spektroskopskih metoda. Osim toga, razmatrana su i istraživanja koja se bave ispitivanjem kristalne strukture tautomera koji se koriste kao komercijalne boje.

A new procedure for the synthesis of known azo pyridone dyes is presented. A series of 5-(substituted arylazo)-6-hydroxy-4-methyl-3- cyano-2-pyridones were prepared from ethyl 3-oxo-2-(substituted phenyldiazenyl)butanoates and cyanoacetamide in acetone using potassium hydroxide as a catalyst by simple refluxing the reaction mixture. The structure of these dyes was confirmed by FT-IR, NMR and UV-Vis spectroscopy.

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 2-diketones or 2-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. Preko 50% svih obojenih supstanci koje se danas koriste su azo boje i pigmenti. U ova jedinjenja spadaju i arilazo piridonske boje (i pigmenti), koje se koriste kao disperzne boje, a takođe nalaze primenu i kao komponente u inkdžet grafičkim bojama i LCD ekranima. Kada se koriste kao disperzne boje uglavnom daju žute nijanse i poseduju dobru do odličnu postojanost na mokre obrade i svetlost. U ovom radu je dat kratak prikaz sinteze arilazo piridonskih boja pri čemu je na izabranim primerima ilustrovana sinteza monoazo, disazo i trisazo boja na bazi piridona. Osnovni način dobijanja azo boja pa i arilazo piridonskih boja je reakcija diazokuplovanja, koja se kombinuje sa drugim reakcijama da bi se dobile boje željene strukture. U rada su takođe razmatrana svojstva arilazo pirodonskih boja, kao što su postojanost na svetlost i azo-hidrazon tautomerija.

Oxaprozin (3-(4,5-diphenyloxazol-2-yl)propanoic acid) is a nonsteroidal anti-inflammatory drug (NSAID) used in the treatment of numerous inflammatory musculoskeletal diseases, including rheumatoid arthritis, osteoarthritis, tendonitis, ankylosing spondylitis and bursitis. It is the first representative member of the diaryl- substituted heterocyclic compounds, which have found clinical use as selective cyclooxygenase-2 (COX-2) inhibitors. The U.S. Food and Drug Administration (FDA) approved its official use in 1992. Both the anti-inflammatory and analgesic properties of oxaprozin are mainly due to the potent inhibition of COX. However, oxaprozin-induced benefits might be also regulated by other COX-independent pathways. It has been shown that oxaprozin induced direct proapoptotic effects in CD40L-treated human monocytes independently of COX inhibition. It also has several advantages in the treatment of inflammatory diseases in comparison to other NSAIDs such as aspirin, naproxen, indomethacin and phenylbutazone, which enabled oxaprozin to become one of the most used NSAIDs in America. Oxaprozin, as other members of the group of NSAIDs, can cause gastrointestinal complications, but significantly lower due to relatively high pKa value. In this paper, the importance of oxaprozin in the treatment of arthritis and its pharmacokinetic properties were described, therewith its activity and side effects were compared with other commercially available anti-inflammatory drugs. Oksaprozin (3-(4,5-difeniloksazol-2-il)propanska kiselina) jeste nesteroidni anti-inflamatorni agens koji se koristi za simptomatsko lečenje inflamacije, bola i reumatoidnih oboljenja. U ovom radu prikazani su različiti postupci dobijanja oksaprozina, njegovih derivata i detaljan opis mehanizma reakcija sinteze, kao i njegova fizička i hemijska svojstva. Pored osnovnih molekulskih osobina koje su značajne za aktivnost oksaprozina kao nesteroidnog anti-inflamatornog leka, navedeni su najznačajniji podaci SAR (eng. Structure-Activity Relationship) studije sintetisanih njegovih analoga. Istaknut je značaj oksaprozina u lečenju artritisa, njegova farmakokinetička svojstva i poređena je njegava aktivnost i sporedni efekti sa ostalim komercijalno dostupnim anti-inflamatornim lekovima.

A series of some new pyridone arylazo dyes was synthesized from the corresponding diazonium salts and 4,6-diphenyl-3-cyano-2-pyridone using the classical reaction for the synthesis of the azo compounds. The structures of these dyes were confirmed by UV-vis, FTIR and 1H-NMR spectroscopic techniques. The solvatochromism of the dyes was evaluated with respect to visible absorption properties in various solvents. The effects of solvent dipolarity/polarizability and solvent/solute hydrogen bonding interactions were analyzed by means of the linear solvation energy relationship concept proposed by Kamlet and Taft. The 2-pyridone/2-hydroxypiridine tautomeric equilibration was found to depend on the substituents as well as on the solvents.

Solvent effects on the reactivity of cycloalkenecarboxylic, cycloalkeneacetic, 2-substituted cyclohex-1-enecarboxylic, 2-substituted benzoic, 2-substituted cyclohex-1-eneacetic, 2-substituted phenylacetic, 2-phenylcyclohex-1-enecarboxylic, 2-phenylbenzoic and 2-phenylacrylic acids with diazodiphenylmethane (DDM) were investigated. In order to explain the kinetic results through solvent effects, the second-order rate constants for the reaction of the examined acids with DDM were correlated using the Kamlet-Taft solvatochromic equation. The correlations of the kinetic data were realized by means of multiple linear regression analysis and the solvent effects on the reaction rates were analyzed in terms of the contributions of the initial and the transition state. The signs of the equation coefficients support the proposed mechanism. Solvation models for all the investigated acids are suggested. The quantitative relationship between the molecular structure and the chemical reactivity is also discussed.

The aim of this investigation is the development of the optimal laboratory procedure for the synthesis of calcium and sodium citrate and the application of obtained results in a project for a semi-industrial installation for its production. These salts are used as an additive in numerous food and pharmaceutical products. Basically, they have to satisfy quality requirements, which is the reason why the procedure for their synthesis needs to be optimized in aspects of selection of reactants, their molar ratio, necessary laboratory equipment, reactant addition order, working temperature, isolation of final product from the reaction mixture, yield and product quality. A semi-industrial installation for the production of calcium and sodium citrate will be projected on the basis of the results of this investigation. The importance of this investigation is the fact that these salts are not produced in our country and the entire quantity (about 20 t per year) is imported. Kalcijum- i natrijum-citrat se koriste u prehrambenoj i farmaceutskoj industriji kao regulatori kiselosti, emulgatori, stabilizatori itd. Ove soli se ne proizvode u našoj zemlji i sva potrebna količina (oko 20 tona godišnje) se uvozi. Cilj ovog rada je da se izvrši optimizacija postupka sinteze kalcijum- i natrijum-citrata na laboratorijskom nivou i da se dobijeni rezultati primene za projektovanje poluindustrijskog postrojenja za njihovu proizvodnju. Optimizacija postupka za sintezu ovih soli obuhvata: izbor reaktanata i njihovog molskog odnosa, laboratorijsku opremu, redosled dodavanja reaktanata, izbor radne temperature, izdvajanje gotovog proizvoda iz reakcione smeše, prinos i kvalitet proizvoda. Kvalitet proizvoda mora da zadovolji standarde neophodne za prehrambenu i farmaceutsku industriju. Na osnovu rezultata istraživanja ostvarenih u laboratorijskim uslovima predložena je sinteza u poluindustrijskom postrojenju za proizvodnju citrata.

Organic solvents may appear in wastewaters and other industrial waste streams containing dyes, therefore, their photodegradation catalyzed by TiO2 should be investigated. Solvent effect on photodegradation of CI Reactive Orange 16 has been studied using simulated solar light and P-25 TiO2. Methyl, ethyl and isopropyl alcohol as well as acetone were used as solvents. Photodegradation reaction was faster in methyl than in ethyl alcohol while in water was the slowest. RO16 photodegradation efficiency and reaction rate decreased in the presence of small concentration of ethanol. Higher photodegradation efficiency was observed for higher ethanol concentration. For acetone, photodegradation decreased as concentration of acetone increased. It seems that protic solvents at higher concentrations promote reaction, while at low concentrations slow down reaction. Aprotic solvents slow down reaction. U radu je ispitivan uticaj organskih rastvarača na fotodegradaciju sintetske boje (C.I. Reactive Orange 16) u vodi u prisustvu TiO2 kao katalizatora upotrebom simulirane sunčeve svetlosti. Kao rastvarači korišćeni su metil-alkohol, etil-alkohol, izopropil-alkohol i aceton. Reakcije su izvođene kako u čistim rastvaračima tako i pri različitim odnosima rastvarač/voda. Fotodegradacija boje je praćena UV/Vis spektrofotometrijom.

A novel strategy for the prediction of the transition temperature of bent-core liquid crystals (LCs) based on the combination of multi filter feature selection and group method of data handling (GMDH) type neural networks is reported. An entire set of 243 compounds was randomly divided into a training set of 207 compounds and a test set of 36 compounds. Descriptors were selected from a pool of 2D, and two pools of 2D and 3D ones, optimized by molecular mechanics (MM) and semi-empirical (SE) method. The reduction of the pool of descriptors was performed using multi filters based on chi square and v-WSH algorithm, while the final subset selection was performed by GMDH algorithm during the learning process. The obtained 2D, MM and SE GMDH models have 11, 13 and 16 descriptors, respectively, and demonstrate good generalization and predictive ability (R-2 = 0.92). The final models were subjected to a randomization test for validation purpose. Those models appear to be not only suitable for prediction, but they also allow the identification of key structural features that alter the transition temperature of bent-core LCs.

Cancer is the major health problem affecting the mankind of today. Most of the drugs used in traditional chemotherapy are very limited and the discovery of novel, more active, more selective and less toxic ones is still very intensive. A chemometric approach was applied in the study of antiproliferative activity against human colon cancer and breast cancer as well as in the study of lipophilicity of 3-(4-substituted benzyl)-5-ethyl-5-phenyl- and 3-(4-substituted benzyl)- 5,5-diphenylhydantoins. Hierarchical clustering analysis (HCA) shows that the investigated hydantoins have higher antiproliferative activity against human breast cancer cells than against human colon cancer cells. However, some hydantoins at the highest applied concentration reverse antiproliferative effect, higher against the human colon cancer cells and lower against human breast cancer cells. Principal component analysis (PCA) gives better insight into the activity of hydantoins related to their structural changes. It distinguishes more active compounds from the less active ones according to various criteria. Generally, more lipophilic 5,5-diphenylhydantoins exhibit a higher antiproliferative activity comparing to less lipophilic 5-ethyl-5-phenylhydantoins. Also, a substituent attached to benzyl moieties affects the activity additionally. The activity is particularly pronounced for compounds with cyano, methyl, chloro and bromo group. Halogen substituent were superior in antiproliferative capacity particularly in the series of 5,5-diphenylhydantoins.

A series of 5-(3- and 4-substituted phenylazo)-4,6-dimethyl-3-cyano-2-pyridones were synthesized, starting from acetylacetone and arenediazonium salt, followed by condensation with cyanoacetamide using a modified literature procedure. The experimental investigation included modification of the synthetic procedure in terms of solvent, temperature, isolation techniques as well as purification and identification of the products. The azo dyes were characterized by melting point, IR, UV/Vis, 1H NMR and MS data. HPLC analyses were also performed. The 2-hydroxypyridine/ 2-pyridone tautomeric equilibration was found to depend on the polarity of the applied solvents. A color assessment of the solid dyes and dyed polyester fabrics was also performed and the correlation between the colour and the structure of the dyes is discussed. U okviru rada sintetisani su 5-(3- i 4-supstituisani fenilazo)-4,6-dimetil-3-cijano- 2-piridoni, kondenzacijom proizvoda reakcije acetilacetona i odgovarajuće diazonijumove soli sa cijanoacetamidom. Dobijene azo boje su okarakterisane temperaturama topljenja, IR, UV/Vis, 1 HNMRi MS podacima. Čistoća dobijenih boja ispitivana je HPLC metodom. Utvrđeno je da ravnoteža 2-hidroksipiridin/2-piridon zavisi od polarnosti rastvarača. Određeni su parametri obojenja poliestarskih tkanina bojenih sintetisanim azo bojama. Takođe je ispitivana i obojenost azo boja u čvrstom obliku.

A series of 1,3,5-trisubstituted isocyanurates (substituents: CH2CH2OH CH2CH=CH2 and CH2CH2COOH) was synthesized according to a modified literature procedure. Experimental investigations included modification of the synthetic procedure in terms of the starting materials, solvents, temperature isolation techniques, as well as purification and identification of the products. All the synthesized isocyanurates were identified by their melting point and FTIR, 1H NMR and UV spectroscopic data. Fourier transform infrared spectrophotometry was also used to study the interaction between ammonium perchlorate, hydroxyl terminated poly(butadiene), carboxyl terminated poly(butadiene), poly(butadiene-co-acrylonitrile), poly(propylene ether) cyclotrimethylenetrinitramine and the compounds synthesized in this work which can serve as bonding agents. The results show that tris(2-hydroxyethyl)isocyanurate is a universal bonding agent for the ammonium perchlorate/carboxyl terminated poly(butadiene)/cyclotrimethylenetrinitramine composite propellant system. 1,3,5-Trisupstituisani izocijanurati (supstituenti: CH2CH2OH, CH2CH=CH2 i CH2CH2COOH) su sintetizovani koristeći modifikovane literaturne postupke. Pri tome su menjani reaktanti, rastvarači, temperatura, način izolovanja kao i način prečišćavanja proizvoda. Svi dobijeni izocijanurati su okarakterisani temperaturama topljenja, FTIR, 1H NMR i UV podacima. FTIR je takođe korišćen za proučavanje interakcija između amonijumperhlorata, poli(butadiena) sa hidroksi i karboksi krajnjim grupama, poli(butadien-ko-akrilonitrila) poli(propilenetra), ciklotrimetilennitramina i jedinjenja sintetizovanih u ovom radu koji mogu poslužiti kao vezivni agensi.

The rate constants for the reaction of diazodiphenylmethane with 2-(2-substituted cyclohex-1-enyl)acetic acids and 2-(2-substituted phenyl)acetic acids, previously determined in seven hydroxylic solvents, were correlated using the total solvatochromic equation, of the form logk = logk0 + s?*+ a? + b?, the two-parameter model, logk=logk0 + s?*+ a? and a single parameter model logk = logk0 + b?, where ?*is a measure of the solvent polarity, ? represents the scale of solvent hydrogen bond acceptor basicities and ? represents the scale of solvent hydrogen bond donor acidities. The correlations of the kinetic data were carried out by means of multiple linear regression analysis and the solvent effects on the reaction rates were analyzed in terms of initial state and transition state contributions.

Absorption spectra of some 3-N-(4-substituted phenyl)-5-carboxy uracils, previously determined in twelve solvents, are correlated with substituent sp + values or by dual substituent parameter correlations involving sI and sR + values. The substituents at the phenyl nucleus are as follows: H, Cl, Br, I, Me, Et, OMe, COOH and NO2. Considering the structure of the investigated system, it is very probable that the effect of the substituent at the phenyl nucleus on the electronic spectra of the substituted uracils is influenced by resonance interactions between the electron pairs of both the nitrogen atoms, the carbonyl groups and the substituent itself. The polarity of the reaction medium also affects the complex resonance interactions in the molecules of the investigated compounds. The obtained results support a suggestion made by Brownlee and Topsom that UV/visible spectral shifts can conform to reasonable precise linear free energy relationships if the substituent is not a part of the chromophoric system.

Electrocatalytic decolorization of the arylazo pyridone dyes has been investigated in the presence of sodium chloride using DSA Ti/PtOx electrode in the diluted sodium hydroxide. Decolorization can be attributed to the indirect oxidation of the investigated dyes by the electrogenerated hypochlorite formed from the chloride oxidation. Electrochemical decolorization has been investigated for the different sodium hydroxide concentration in the range from 40 mg dm-3 to 4 g dm-3, sodium chloride concentration in the range from 15 to 40 g dm-3, agitation speed in the range from 150 to 500 rpm, currents in the range of 100 to 250 mA, and dye concentration from 5 to 20 mg dm-3. The optimum electrolysis conditions have been suggested. Effect of substituents on the reaction rate has also been studied. [Projekat Ministarstva nauke Republike Srbije, br. OI172013, OI172046]

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 center dot center dot center dot 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.

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.

A series of novel Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) complexes with oxaprozin (Hoxa), a nonsteroidal anti-inflammatory drug, has been synthesized. The drug and complexes have been characterized by elemental and thermogravimetric (TG) analysis, Fourier transform (FT)-IR, H-1-NMR, C-13-NMR, UV-Vis spectroscopy and magnetic susceptibility measurements. The (pseudo)octahedral geometry has been proposed for all complexes based on electronic spectra and magnetic moments. With exception of the Cu(II) complex, where bridging bidentate mode of COO groups has been found, FT-IR spectra confirmed chelately coordinated COO groups in the other complexes. The general formula of the complexes is [M(H2O)(2)(oxa)(2)]center dot xH(2)O, with x=2 for M=Mn, Co and Ni and x=1.5 for Zn. The binuclear Cu(II) complex, [Cu-2(H2O)(2)(OH)(oxa)(3)]center dot 2H(2)O, has strong Cu-Cu interactions of antiferromagnetic type. The complexes and Hoxa did not exhibit the cytotoxic effect to peritoneal macrophages. For the first time these complexes have been tested for their in vitro antiproliferative activity against human colon and breast cancer cell lines, HCT-116 and MDA-231, respectively. For all investigated compounds significant antiproliferative effects have been observed. Ni(II) complex has been shown to be a promising antiproliferative agent exerting excellent activity against HCT-116 even in nanomolar concentrations.

Succinimide is a cycle imide of succinic acid that is present in numerous biologically active compounds including anticonvulsants, antitremor, anti-Parkinson's agents. This paper describes different ways of synthesis of succinimide derivatives, their physical properties and reactivity. Also, the most widely used succinimide anticonvulsants and the analysis of structure-activity relationships of anticonvulsant drugs in terms of lipophilicity and hydrogen bonding are presented here. Sukcinimidi su ciklični imidi ćilibarne (sukcinske) kiseline, koji se primenjuju u medicini kao antikonvulzivi. Mogu se, takođe, koristiti u tretiranju drugih cerebralnih oboljenja, kao na primer tremora, Parkinsonove bolesti, itd. U ovom radu su prikazani postupci dobijanja sukcinimida, koji se upotrebljavaju u medicini, kao i njihova struktura i fizičke i hemijske osobine. Razmatran je uticaj strukture na antikonvulzivnu aktivnost različitih derivata sukcinimida sa aspekta lipofilnosti i mogućnosti uspostavljanja vodoničnih veza.

A series of twelve 3-substituted-5,5-diphenylhydantoins was synthesized, including some whose anticonvulsant activities have already been reported in the literature. Their antiproliferative activities against HCT-116 human colon carcinoma cells were evaluated to determine structure-activity relationships. Almost all of the compounds exhibited statistically significant antiproliferative effects at a concentration of 100 μM, while the derivative bearing a benzyl group was active even at lower concentrations. Moreover, their in vitro antibacterial activities against Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 and clinical isolates of Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Enterococcus faecalis and Staphylococcus aureus were evaluated. Only the 3-isopropyl and 3-benzyl derivatives showed weak antibacterial activities against the Gram-positive bacterium E. faecalis and the Gram-negative bacteria E. coli ATCC 25922 and E. coli. Sintetisana je serija od dvanaest 3-supstituisanih-5,5-difenilhidantoina, koja obuhvata neke od derivata čije su antikonvulzivne aktivnosti poznate u literaturi. Određena je njihova antiproliferativna aktivnost prema ćelijskoj liniji humanog karcinoma kolona, kako bi se utvrdio uticaj strukture na aktivnost. Skoro sva jedinjenja ispoljavaju antiproliferativan efekat u koncentraciji od 100 μM, dok je derivat sa benzil grupom aktivan i u nižim koncentracijama. Dodatno je određena i antibakterijska aktivnost proučavanih jedinjenja prema Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 i kliničkim izolatima Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Enterococcus faecalis i Staphylococcus aureus. 3-Izopropil i 3-benzil derivati pokazuju slabu aktivnost prema gram-pozitivnoj bakteriji E. faecalis i gram-negativnim bakterijama E. coli ATCC 25922 i E. coli.

A series of 5-substituted 5-phenylhydantoins was synthesized and their UV absorption spectra were recorded in the region 200–400 nm in selected solvents of different polarity. The effects of solvent dipolarity/polarizability and solvent–solute hydrogen-bonding interactions were analyzed by means of the linear solvation energy relationship concept proposed by Kamlet and Taft. The lipophilicities of the investigated hydantoins were estimated by calculation of their log P values. The quantitative relationship between the ratio of the contributions of specific solvent interactions and the corresponding lipophilicity parameter is discussed. The correlation equations were combined with the corresponding ED50 values and different physicochemical parameters to generate new equations that demonstrate the reasonable relationships between solute–solvent interactions and the structure–activity parameters. In order to determine a spectroscopic assignment of the absorption bands in different solvents, quantum chemical calculations were done.

Hydantoin is a five-membered cyclic ureide that is present in numerous biologically active compounds including antiarrhytmics, anticonvulsants and antitumor agents. This paper describes different ways of synthesis of hydantoin-derivatives, their physical properties and reactivity. Also, the most widely used hydantoin anticonvulsants and the analysis of structureactivity relationships of anticonvulsant drugs in terms of lipophilicity and hydrogen bonding are presented here. Hidantoin je petočlani ciklični ureid koji je sadržan u brojnim biološki aktivnim jedinjenjima kao što su antiaritmici, antikonvulzivi i antitumor agensi. U ovom radu su opisani postupci dobijanja derivata hidantoina, njihova fizička svojstva i reaktivnost. Prikazani su najčešće korišćeni antikonvulzivi iz grupe hidantoina, a razmatran je i uticaj strukture na antikovulzivnu aktivnost različitih derivata sa aspekta lipofilnosti i mogućnosti uspostavljanja vodoničnih veza.

Several 5-methyl-5-(3- or 4-substituted phenyl)hydantoins were prepared and their ultraviolet absorption spectra were recorded in the region 200-400 nm in twelve solvents of different polarity. The effect 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. The lipophilic activity of the investigated hydantoins was estimated by calculation of log P values with Advanced Chemistry Development Software. The calculated values of log P were correlated with the contribution of hydrogen bond donor-solvent interactions. By employing the thus obtained linear dependence, the pharmacological activity of the studied hydantoin derivatives is discussed. U okviru proučavanja uticaja strukture na farmakološku aktivnost hidantoina, u ovom radu sintetizovano je četrnaest jedinjenja i određeni su njihovi UV apsorpcioni maksimumi u dvanaest rastvarača različite polarnosti. Apsorpcioni maksimumi su korelisani Kamlet-Taftovom (Kamlet-Taft) solvatohromnom jednačinom i izvršena je kvantitativna procena proton-donorskih i proton-akceptorskih karakteristika proučavanih jedinjenja, koje su od velikog značaja za njihovu fiziološku aktivnost. Izračunate vrednosti log P korelisane su sa udelom proton-donorskih karakteristika rastvarača i na osnovu dobijenih linearnih zavisnosti za molekule sa umerenim elktron-donorskim i elektron-akceptorskim supstituentima, diskutovana je veza između farmakološke aktivnosti hidantoina i interakcija sa molekulima rastvarača.

The rate constants for the reaction of 2-substituted cyclohex-1-enecarboxylic acids and the corresponding 2-substituted benzoic acids with diazodiphenylmethane were determined in various aprotic solvents at 30 ºC. In order to explain the kinetic results through solvent effects, the second order rate constants of the reaction of the examined acids were correlated using the Kamlet-Taft solvatochromic equation. The correlations of the kinetic data were carried out by means of multiple linear regression analysis and the solvent effects on the reaction rates were analyzed in terms of the contributions of the initial and transition state. The signs of the equation coefficients support the proposed reaction mechanism. The quantitative relationship between the molecular structure and the chemical reactivity is discussed, as well as the effect of geometry on the reactivity of the examined molecules. Konstante brzine za reakciju 2-supstituisanih cikloheks-1-enkarboksilnih i odgovarajućih 2-supstituisanih benzoevih kiselina sa diazodifenilmetanom su određene u nizu različitih aprotičnih rastvarača na temperaturi od 30 °S. Da bi se kinetički rezultati objasnili pomoću efekata rastvarača, dobijene konstante brzine reakcije drugog reda su korelisane Kamlet-Taftovom solvatohromnom jednačinom. Korelacije kinetičkih podataka su dobijene pomoću metode višestruke linearne regresione analize i efekti rastvarača su posebno analizirani u odnosu na osnovno i prelazno stanje. Aritmetički znaci ispred koeficijenata solvatohromnih parametara rastvarača odgovaraju pretpostavljenom mehanizmu ispitivane reakcije. Takođe je proučavan kvantitativni odnos molekulske strukture i reaktivnosti, kao i efekat geometrije molekula ispitivanih jedinjenja na njihovu reaktivnost.

In the framework of this research, the program Image Pro Plus was applied for determining the polymer-oxidizer interactions in HTPB-based composite propellants. In order to improve the interactions, different bonding agents were used, and their efficiency was analyzed. The determination of the quantity, area and radius of non-bonded oxidizer crystals is presented. The position of formed cracks in the specimen and their area have a great influence on the mechanical properties of composite propellant. The preparation of the composite propellant in order to enable the photographing of their structure by means of stereoscopic and metallographic microscopes with the digital camera is also described as well. . U okviru istraživanja program Image Pro Plus je primenjen za određivanje interakcija između polimera i oksidansa u kompozitnim gorivima na bazi HTPB. U cilju poboljšanja ovih interakcija, korišćeni su različiti vezujući agensi i analizirana je njihova efikasnost. U radu je takođe vršeno određivanje količine, udela, površine i prečnika čestica, koje nisu vezane za polimer. Površina formiranih pukotina i njihova raspodela u uzorku imaju veliki uticaj na mehanička svojstva kompozita. Priprema uzoraka kompozitnih goriva za snimanje njihove morfološke strukture pomoću stereomikroskopa i metalografskog mikroskopa sa digitalnom kamerom je takođe opisana. .

Composite propellants are non-homogenous propellants and comprise primarily crystalline oxidizer and metal fuels uniformly suspended in a resin binder. The strength of the bonds between the polymer matrix and the oxidizer determine the mechanical properties of composite propellants. In order to achieve good mechanical properties of the fuel, bonding agents are added to the mixture. The role of the bonding agents is to enable good interactions (interphase) between the polymer matrix and the oxidizer grains. The level of interconnection between the phases could be measured by using the surface obtained by cutting the composite material and observing the resulting surface. A problem in the visualization of such a material is to enable the visibility of the polymer matrix and the grains in the image as both phases are white. There are two possible ways to overcome this problem: to add a pigment into the matrix polymer and to color the matrix and make it different from the grain color. Another possibility is to find a solvent for one of the phases and to dissolve one of the phases in an appropriate solvent so that the remaining phase could be stained, photographed and analyzed using the image analysis program. The morphological characteristics of the image could be established and analyzed. The topic of this study was to establish the conditions of preparation of composite propellants containing ammonium per chlorate and HMX and RDX as oxidizers, and polymer of the polybutadiene type and 1,3,5-trisubstituted isocyanurates as bonding agents. The bonding phenomenon was investigated by optical microscopy. The established procedure of preparation will enable the visualization of the composite structure and the morphological characteristics of the surface will be obtained. From the morphological properties of the obtained composite, it will be possible to select a suitable polymer for the preparation of uniformly distributed composite propellant. Kompozitna goriva se mogu posmatrati kao kompozitni materijali koji sadrže kristalni oksidans, polimernu matricu i metalnu komponentu. Jačina interakcije između oksidansa i polimerne matrice određuje mehanička svojstva kompozitnih materijala. Da bi se dobila dobra mehanička svojstva goriva, u materijale se dodaje "bonding" agens, koji obezbeđuje dobru interakciju između polimerne matrice i oksidansa. Predmet ovog rada je utvrđivanje uslova pripreme uzoraka kompozitnih goriva za snimanje njihove morfološke strukture pomoću stereo mikroskopa i digitalne kamere. Dobijeni snimci su analizirani korišćenjem programa za analizu sliku i ukazuju na različito ponašanje uzoraka u zavisnosti od korišćenih komponenata.

A series of 1,3-bis-substituted-5,5-dimethylhydantoins was synthesized using the reaction of 5,5-dimethylhydantoin with the corresponding alkyl halide in the presence of trimethylamine as catalyst and sodium hydroxide, according to a modified literature procedure. The experimental investigation included modification of the synthetic procedure in terms of starting materials solvent, temperature, isolation techniques, as well as purification and identification of the products. The absorption spectra of the 1,3-bis-substituted-5,5-dimethylhydantoins were recorded in twelve solvents in the range 200–400 nm. The effects of the solvent polarity and hydrogen bonding on the absorption spectra were interpreted by means of linear solvation energy relationships using a general equation of the form ν = ν0 s¶* + aα + bβ and by two-parameter models presented by the equation ν = ν0 s¶* + aα, where ¶* is a measure of the solvent polarity/polarisability, α is the scale of the solvent hydrogen bond donor acidities and β is the scale of the solvent hydrogen bond acceptor basicities. The solvent and substituent effects on the electronic absorption spectra of the investigated hydantoins is discussed. U okviru rada je izvršena sinteza serije 1,3-bis-supstituisanih-5,5-dimetilhidantoina iz 5,5-dimetilhidantoina i odgovarajućeg alkilhalogenida u prisustvu trimetilamina kao katalizatora i natrijum-hidroksida, po modifikovanom postupku iz literature. Sintetizovani hidantoini su identifikovani na osnovu tačke topljenja, FTIR, 1H-NMR i UV spektroskopskih podataka. Apsorpcioni spektri 1,3-bis-supstituisanih-5,5-dimetilhidantoina su određeni u dvanaest rastvarača različite polarnosti u opsegu 200–400 nm. Uticaj polarnosti rastvarača kao i efekat vodonične veze proučavani su metodom linearne korelacije solvatacionih energija odnosno jednačinama oblika νmax = ν0 s¶*+aα + bβ i νmax = ν0 + s¶* + aα, u kojima je ν apsorpciona frekvencija ¶* mera efekata solvatacije vezana za polarnost rastvarača, α mera uspostavljanja vodonične veze sa proton-donorskim rastvarač ima, a β mera vodonične veze ostvarene sa protonakceptorskim rastvaračima. Rezultati prezentovani u ovom radu su veoma značajni za sagledavanje karakteristika 1,3-bis-supstituisanih- 5,5-dimetilhidantoina zbog njihove velike primene u kompozitnim materijalima kao vezujućih agenasa.

The rate constants for the reaction of diazodiphenylmethane with 1-cyclopentenecarboxylic, 1-cycloheptenecarboxylic, cyclopent-1-enylacetic and cyclohept-1-enylacetic acids were determined in eight alcohols at 30 ºC using the appropriate UV-spectroscopic method. In order to explain the kinetic results through solvent effects, the second order rate constants of the examined acids were correlated using a total solvatochromic equation, of the form: log k = A0+ s¶*+aα+ bβ, where ¶* is a measure of the solvent polarity, βrepresents the scale of solvent hydrogen bond acceptor basicities and β represents the scale of solvent hydrogen bond donor acidities. The correlations of the kinetic data were carried out by means of multiple linear regression analysis. The opposite sings of the electrophilic and the nucleophilic parameters are in agreement with the well-known reaction mechanism. The results presented in this paper were compared with the kinetic data for 1-cyclohexenecarboxylic and cyclohex-1-enylacetic acids obtained under the same experimental conditions. Konstante brzina za reakciju između diazodifenilmetana (DDM) i 1-ciklopentenkarbonske, 1-cikloheptenkarbonske, ciklopent-1-enilsirćetne i ciklohept-1-enilsirćetne kiseline su određene u osam alkoholnih rastvarača na 30 ºC odgovarajućim UV-spektrofotometrijskim metodom. Da bi se dobijeni kinetički rezultati objasnili kroz efekte rastvarača konstante brizna reakcije (k) su korelisane totalnom solvatohromnom jednačinom oblika: log k = A0+ s¶*+aα+ bβ, gde je ¶* mera polarnosti rastvarača, βpredstavlja skalu baznosti rastvarača kao akceptora protona u vodoničnoj vezi, a αskalu kiselosti rastvarača kao donora protona u vodoničnoj vezi. Korelacija kinetičkih parametara je izvršena metodom višestruke linearne regresione analize. Suprotni znaci uz elektrofilni i nukleofilni parametear u saglasnosti su sa izvedenim mehanizmom reakcije. Rezultati prikazani u ovom radu su upoređeni sa kinetičkim podacima za 1-cikloheksenkarbonsku i cikloheks-1-enilsirćetnu kiselinu, dobijenim pod istim eksperimentalnim uslovima.

Background A 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. Results The 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. Conclusions The 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.