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A Quantitative structure-retention relationship (QSRR) analysis has been performed on the chromatography parameters of lipophilicity of selected spirohydantoins. Multiple linear regression (MLR) was applied to construct the QSRR models. The chromatographic parameters of lipophilicity were determined by reversed-phase thin-layer chromatography. Chromatographic analyses were performed on C-18 modified silica gel with a two-component mobile phase consisting of water and protic organic solvent (ethanol, n-propanol, i-propanol, or t-butanol) in different ratios. QSRR models were also created for additional four aqueous mobile phases: acetone-water, acetonitrile-water, tetrahydrofuran-water, and 1,4-dioxane-water (results published before). In total, chromatographic lipophilicity parameters obtained for two types of organic solvents were subject of the QSRR. The predictive ability of each model was evaluated using internal and external validation. The best QSRR model for predicting the chromatographic parameter of lipophilicity was obtained for tetrahydrofuran as an organic solvent.

Xanthendiones (1,8-dioxooctahydroxanthenes) are a special class of oxygenincorporating tricyclic compounds bearing as a basic feature a pyran nucleus fused on either side with cyclohex-2-enone rings. They are often found as a structural motif in natural products with a wide range of biological activities, such as: antioxidant, antimicrobial, trypanocidal, antiinflammatory, antiproliferative and anticancer. A convenient and efficient approach toward the synthesis of seven aromatically substituted xanthendiones 1‒7 and one structurally-related xanthenone 8 through condensation of dimedone and the appropriate aromatic aldehyde is reported. The relationship between the chemical structure and pharmacological activity was determined empirically using appropriate software packages and in vitro using the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) method. The results of the ABTS assay indicate that five compounds possess the ability to scavenge the ABTS•+ radical cation. Based on the comparison of the IC50 values, the activity of the compounds was found to be as follows: 6 > 1 > 7 > 2 > 8.

A convenient and efficient approach toward the synthesis of seven aromatically substituted xanthendiones 1‒7 and one structurally-related xanthenone 8 through condensation of dimedone and the appropriate aromatic aldehyde is reported. Further, their chemical structure was confirmed by melting points, elemental analysis, FT-IR, 1H-, 13C-NMR and UV–Vis spectroscopic methods. The relationship between the chemical structure and pharmacological activity was determined empirically using appropriate software packages and in vitro using the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) method. The results of in silico prediction suggested that all investigated compounds possess good oral bioavailability. The results of the ABTS assay indicate that five compounds possess the ability to scavenge the ABTS•+ radical cation. Based on the comparison of the IC50 values, the activity of the compounds was found to be as follows: 6 > 1 > 7 > 2 > 8. The effects of solvent dipolarity/polarizability and solute solvent–hydrogen-bonding interactions on the shifts of the absorption maxima were rationalized by means of the linear solvation energy relationship concepts proposed by Kamlet–Taft and Catalán.

A convenient and efficient approach toward the synthesis of seven aromatically substituted xanthendiones 1‒7 and one structurally-related xanthenone 8 through condensation of dimedone and the appropriate aromatic aldehyde is reported. Further, their chemical structure was confirmed by melting points, elemental analysis, FT-IR, 1H-, 13C-NMR and UV–Vis spectroscopic methods. The relationship between the chemical structure and pharmacological activity was determined empirically using appropriate software packages and in vitro using the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) method. The results of in silico prediction suggested that all investigated compounds possess good oral bioavailability. The results of the ABTS assay indicate that five compounds possess the ability to scavenge the ABTS•+ radical cation. Based on the comparison of the IC50 values, the activity of the compounds was found to be as follows: 6 > 1 > 7 > 2 > 8. The effects of solvent dipolarity/polarizability and solute solvent–hydrogen-bonding interactions on the shifts of the absorption maxima were rationalized by means of the linear solvation energy relationship concepts proposed by Kamlet–Taft and Catalán., U ovom radu, predstavljena je jednostavna metoda u dva koraka za sintezu sedam derivata ksantendiona i jednog derivata ksantenona koji sadrže različite aromatične supstituente, polazeći od dimedona i odgovarajućih aromatičnih aldehida. Karakterizacija sintetisanih jedinjenja izvršena je određivanjem temperature topljenja, kao i primenom elementalne analize, FT-IR, 1 H-NMR i 13C-NMR spektroskopskih metoda. Veza između hemijske strukture ovih jedinjenja i njihove farmakološke aktivnosti uspostavljena je empirijski korišćenjem odgovarajućih softverskih paketa (za predikckciju farmakološke aktivnosti) i in vitro određivanjem njihove antioksidativne aktivnosti primenom ABTS metode. Rezultati ABTS metode pokazuju da od celokupne serije testiranih jedinjenja, pet jedinjenja pokazuje značajnu antioksidativnu aktivnost. Na osnovu međusobnog poređenja IC50 vrednosti ispitivanih jedinjenja pokazano je da njihova antioksidativna aktivnost opada u sledećem nizu: 6 > 1 > 7 > 2 > 8. Jedinjenje 6 je najaktivnije u analiziranoj seriji i ima IC50 vrednost približne vrednosti kao askorbinska kiselina. Rezultati solvatohromnih jednačina koje su razvili Kamlet (Kamlet), Taft (Taft) i Katalan (Catalán), ukazuju da položaj apsorpcionih maksimuma proučavanih jedinjenja zavisi od prirode (polarnosti i kiselo-baznih svojstava) upotrebljenih rastvarača. Sa visokim vrednostima antioksidativne aktivnosti i dobrom oralnom bioraspoloživošću, derivati ksantendiona i ksantenona sa aromatičnim supstituentima, predstavljaju dobru polaznu osnovu za sintezu novih farmakološki aktivnih jedinjenja i bolje razumevanje uticaja strukture na farmakološku aktivnost.

The quantitative assessment of intermolecular interactions and their cooperative effects has been performed in spirohydantoin-based model compounds, 3-benzoyl-1,3-diazaspiro[4.5]decane-2,4-dione (1) and 3-(4-fluorobenzoyl)-1,3-diazaspiro[4.5]decane-2,4-dione (2), through single crystal X-ray crystallography and quantum chemical studies. In both crystal structures, molecules generate the same hydrogen-bonded centrosymmetric R22(8) synthon. The extended supramolecular architectures depend on the C-HO, C-Hπ, stacking interactions and parallel interactions at large offsets, which lead to molecular sheets and further, with the assistance of the C-HF interaction in the case of2, to three-dimensional networks. Electrostatic potential maps have indicated that formation of the intermolecular FF interaction in the crystal structure of2results in a new region with a larger surface area and a higher negative potential in comparison to the individual fluorine atoms. Establishment of this interaction leads to strengthening of the interaction of one of the fluorine atoms with a third molecule from the environment which does not interact with both of them. When this third molecule interacts with both fluorine atoms simultaneously, the calculations have shown that the effect of strengthening of the individual interactions due to formation of the FF interaction is absent.

Sintetisan je racemski derivat spirohidantoina, koji poseduje tetralinsku i 4- metoksibenzil-grupu, a zatim je određena njegova kristalna struktura. Hijerarhijski razvoj kristalnog pakovanja diskutovan je sa aspekta kooperativnosti homo- i heterohiralnih dimernih motiva koji odražavaju različite intermolekulske interakcije. Specifična strukturna karakteristika proučavanog jedinjenja jesu naizmenično postavljeni dvostruki slojevi. Veliki broj kontaktnih fragmenata u okruženju tetralinske grupe predstavlja posledicu veće kontaktne površine. Sa druge strane, 4-metoksibenzil-grupa obezbeđuje veći doprinos ukupnoj stabilizaciji. Što se tiče farmakološkog potencijala proučavanog jedinjenja, izvršena je simulacija vezivanja molekula za dopaminski receptor D3 i enzim IRAK 4 (eng. Interleukin-1 Receptor-Associated Kinase 4). Ukupan broj aminokiselinskih ostataka koji stupaju u interakciju sa 4-metoksibenzil-grupom je nešto veći od broja aminokiselinskih ostataka u okruženju tetralinske grupe. Usled veće fleksibilnosti, 4-metoksibenzil-grupa se lakše adaptira za uspostavljanje interakcija sa biološkim ciljevima., Sintetisan je racemski derivat spirohidantoina, koji poseduje tetralinsku i 4- metoksibenzil-grupu, a zatim je određena njegova kristalna struktura. Hijerarhijski razvoj kristalnog pakovanja diskutovan je sa aspekta kooperativnosti homo- i heterohiralnih dimernih motiva koji odražavaju različite intermolekulske interakcije. Specifična strukturna karakteristika proučavanog jedinjenja jesu naizmenično postavljeni dvostruki slojevi. Veliki broj kontaktnih fragmenata u okruženju tetralinske grupe predstavlja posledicu veće kontaktne površine. Sa druge strane, 4-metoksibenzil-grupa obezbeđuje veći doprinos ukupnoj stabilizaciji. Što se tiče farmakološkog potencijala proučavanog jedinjenja, izvršena je simulacija vezivanja molekula za dopaminski receptor D3 i enzim IRAK 4 (eng. Interleukin-1 Receptor-Associated Kinase 4). Ukupan broj aminokiselinskih ostataka koji stupaju u interakciju sa 4-metoksibenzil-grupom je nešto veći od broja aminokiselinskih ostataka u okruženju tetralinske grupe. Usled veće fleksibilnosti, 4-metoksibenzil-grupa se lakše adaptira za uspostavljanje interakcija sa biološkim ciljevima.

A racemic spirohydantoin derivative with two aromatic substituents, a tetralin and a 4-methoxybenzyl unit, was synthesized and its crystal structure was determined. To define the relationship between molecular stereochemistry and spatial association modes, development of the crystal packing was analyzed through cooperativity of intermolecular interactions. Homo and heterochiral dimeric motifs were stabilized by intermolecular N−H⋅⋅⋅O, C−H⋅⋅⋅O, C−H⋅⋅⋅π interactions and parallel interactions at large offsets (PILO), thus forming alternating double layers. The greatest contribution to the total stabilization came from a motif of opposite enantiomers linked by N−H⋅⋅⋅O bonds (interaction energy=−13.72 kcal/mol), followed by a homochiral motif where the 4-methoxybenzyl units allowed C−H⋅⋅⋅π, C−H⋅⋅⋅O interactions and PILO (interaction energy=−11.56 kcal/mol). The number of the contact fragments in the environment of the tetralin unit was larger, but the 4-methoxybenzyl unit had greater contribution to the total stabilization. The statistical analysis of the data from the Cambridge Structural Database (CSD) showed that this is a general trend. The compound is a potential inhibitor of kinase enzymes and antigen protein-coupled receptors. A correlation between the docking study and the results of the CSD analysis can be drawn. Due to a greater flexibility, the 4-methoxybenzyl unit is more adaptable for interactions with the biological targets than the tetralin unit.

A racemic spirohydantoin derivative with two aromatic substituents, a tetralin and a 4-methoxybenzyl unit, was synthesized and its crystal structure was determined. To define the relationship between molecular stereochemistry and spatial association modes, development of the crystal packing was analyzed through cooperativity of intermolecular interactions. Homo and heterochiral dimeric motifs were stabilized by intermolecular N-H...O, C-H...O, C-H...pi interactions and parallel interactions at large offsets (PILO), thus forming alternating double layers. The greatest contribution to the total stabilization came from a motif of opposite enantiomers linked by N-H...O bonds (interaction energy=-13.72 kcal/mol), followed by a homochiral motif where the 4-methoxybenzyl units allowed C-H...pi, C-H...O interactions and PILO (interaction energy=-11.56 kcal/mol). The number of the contact fragments in the environment of the tetralin unit was larger, but the 4-methoxybenzyl unit had greater contribution to the total stabilization. The statistical analysis of the data from the Cambridge Structural Database (CSD) showed that this is a general trend. The compound is a potential inhibitor of kinase enzymes and antigen protein-coupled receptors. A correlation between the docking study and the results of the CSD analysis can be drawn. Due to a greater flexibility, the 4-methoxybenzyl unit is more adaptable for interactions with the biological targets than the tetralin unit.

Spirohidantoins represent a pharmacologically important class of compounds. Many of them display activities against a wide range of biological targets1 . A recent study shows that a wide range of biological activities of spirohydantoin derivatives strongly depends upon their structure. Hence it is important to understand their properties, particularly the properties of newly synthesized derivatives. One of the most important properties for biological activity is lipophilicity. Lipophilicity is responsible for pharmacokinetics, and hence important for further development of potentially active compounds. The aim of this study is to determine the chromatographic retention parameter of the new synthesized spirohydantoin derivatives as a measure of their lipophilicity. Chromatographic retention parameters of investigated compounds have been determined by reversed-phase thin-layer chromatography on C-18 modified silica gel. Mobile phases were two-component mixtures of water and aprotic organic solvents (i.e. acetonitrile, acetone, dioxane, and tetrahydrofuran). Quantitative structure-retention relationship2 (QSRR) was used for assessment of relationships between chromatographic retention parameters, RM 0 , and calculated partition coefficients of the molecule, log P. For the calculation of log P and additional molecular descriptors were used several software packages (Dragon and ChemDraw) in addition to online internet modules Molinspiration (https://www.molinspiration.com/) and ADMETlab (http://admet.scbdd.com/).

Among the diverse pharmacological activity reported for spirohydantoin and the closely related spirosuccinimides, their anticonvulsant and antiproliferative activities are commonly encountered. Of all cyclic ureide derivatives, Phenytoin (5,5-diphenylhydantoin) is one of the well-known commercially available anticonvulsants, which is also widely used as an antiarrhythmic agent. However, the clinical use of 5,5-diphenylhydantoin is limited by its central nervous adverse effects in addition to a wide variety of drug interactions [1]. With the aim of developing new analogs with a more efficient therapeutic effect, a series of 1-(4-substitutedbenzyl)-3’,4’-dihydro-2’H-spiro[imidazolidine-4,1’-naphtalene]-2,5-diones, have been synthesized, characterized by melting points, FT-IR, 1H and 13C NMR spectroscopic techniques, and evaluated for anticonvulsant activity. The objective of the present investigation is to identify the pharmacological impact of the spirocyclic attachment of a semi-rigid tetralin residue at C-5 of the imidazolidine-2,4-dione ring and to explore the effect of substitution at N-3 on anticonvulsant activity.

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.

U okviru proučavanja uticaja strukture na biološku aktivnost derivata cikloalkanspiro-5-hidantoina, u radu je testirana citotoksičnost novih serija jedinjenja: 3-(4-supstituisanih benzil)-1,3- -diazaspiro[4.5]dekan-2,4-diona i 3-(4-supstituisanih benzil)-1,3-diazaspiro[4.6] undekan-2,4- diona. Citotoksična aktivnost određena je MTT testom prema ćelijskoj liniji humanog karcinoma dojke (MDA-MB-231). Strukturne karakteristike jedinjenja su određene rendgenskom strukturnom analizom kao i odgovarajućim spektroskopskim metodama. Testirana jedinjenja su pokazala statistički značajnu antiproliferativnu aktivnost prema ćelijskoj liniji MDA-MB-231 u proučavanom opsegu koncentracija. Naročito su se istakli derivati koji u okviru svoje strukture sadrže kao supstituente atome halogena i nitro-grupu. Rezultati su upoređeni sa prethodno određenom antiproliferativnom aktivnošću za 3-(4-supstituisane benzil)-5,5-difenilhidantoine. Diskutovan je uticaj strukture na antiproliferativnu aktivnost proučavanih jedinjenja., In order to investigate the influence of the structure on the antiproliferative activity of the cycloalkanespiro-5-hydantoine derivatives, the cytotoxity of the new series of compounds: 3-(4- substituted benzyl)-1,3-diazaspiro[4.5]decane-2,4-dione and 3-(4-substituted benzyl)-1,3- -diazaspiro[4.6]undecane-2,4-dione has been tested. Cytotoxic activity was determined by the MTT assay againist the cell line of human breast cancer (MDA-MB-231). The structural characteristics of the compounds are determined by X-ray structural analysis, as well as by appropriate spectroscopic methods. The tested compounds showed statistically significant antiproliferative activity to the MDA-MB-231 cell line in the studied concentration range. Among the most active are derivatives containing as substituents halogen atoms and a nitro group. The results were compared with a predetermined antiproliferative activity for 3-(4-substituted benzil)-5,5- -diphenylhydantoines. The influence of structure on the antiproliferative activity of the studied compounds is also discussed.

Derivati tetrantoina (7,8-benzo-1,3-diazaspiro[4.5]dekan-2,4-diona) (Slika ) su jedinjenja širokog spektra biološke aktivnosti. Mnogi od njih su poznata antikonvulzivna, antivirusna i antikancerogena jedinjenja, a uspešno se koriste i u lečenju dijabetesa. U okviru ovog rada, sintetizovan je tetrantoin i njegovi derivati koji u položaju 3 hidantoinskog prstena sadrže supstituisanu benzil grupu (supstituent X: H, CH3, OCH3, Cl, Br, CN). Struktura navedenih jedinjenja potvrđena je temperaturama topljenja, 1 H i 13 C NMR, Ft-IR i UV spektroskopskim metodama. Na osnovu strukturnih i lipofilnih karakteristika diskutovana je potencijalna biološka aktivnost sintetizovanih jedinjenja., Derivatives of tetrantoin (7,8-benzo-1,3-diazaspiro[4.5]decane-2,4-dione) (Figure) are the compounds of a wide range of biological activities. Many of them are known anticonvulsant, anticancer and antiviral compounds, and are successfully used in the treatment of diabetes. In this work, was synthesized tetrantoin and its derivatives which in the 3-position of the hydantoin ring containing a substituted benzyl group (the substituent X: H, CH3, OCH3, Cl, Br, CN). The structure of these compounds was confirmed by melting point, 1H and 13C NMR, FT-IR and UV spectroscopic methods. Based on structural lipophilic characteristics is discussed the potential biological activity of the synthesized compounds.

Spirohidantoini pripadaju grupi jedinjenja koja ispoljavaju širok spektar biološke aktivnosti. Do sada su derivati spirohidantoina identifikovani kao antikonvulzivi, antiaritmici, antidijabetici i antitumorni agensi. U cilju ispitivanja biološke aktivnosti, testirana je citotoksičnost novih serija jedinjenja: 3-(4-supstituisanih benzil)-1,3-diazaspiro[4.5]dekan-2,4-diona, 3-(2-(4-supstituisanih fenil)-2-oksoetil)-1,3-diazaspiro-[4.5]-dekan-2,4-diona, 3-(4-supstituisanih benzil)-1,3-diazaspiro[4.6]undekan-2,4-diona i 3-(2-(4-supstituisanih fenil)-2-oksoetil)-1,3-diazaspiro[4.6]undekan- -2,4-diona. Citotoksična aktivnost određena je MTT testom prema ćelijskim linijama humane mijeloidne leukemije (K562), raka debelog creva (HCT-116) i raka dojke (MDA-MB-231). Testirana jedinjenja pokazala su značajnu citotoksičnost prema svim ćelijskim linijama, a naročito su se istakli derivati koji u okviru svoje strukture sadrže halogene kao supstituente. Uticaj sternih i elektronskih svojstava supstituenata na aktivnost proučavanih jedinjenja, analiziran je primenom QSAR modela., Spiroydantoins belong to a group of compounds exhibiting a wide range of biological activities. Until now, the spirohydantoin derivatives are identified as anticonvulsants, antiarrhythmic drugs, antidiabetic agents and antitumor agents. In order to investigate the biological activity was tested on the cytotoxicity of the new series of compounds: 3-(4-substituted benzyl)-1,3-diazaspiro[4.5]decane-2,4-dione, 3-(2-(4-substituted phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane2,4-dione, 3-(4-substituted benzyl)-1,3--diazaspiro-[4.6]undecane-2,4-dione and 3-(2-(4-substituted phenyl)-2-oxoethyl)-1,3-diazaspiro[4.6]-undecane-2,4-dione. Cytotoxic activity was assessed by MTT assay cell lines of human myeloid leukemia (K562), colon (HCT-116) and breast cancer cells (MDA-MB-231). The test compounds showed a significant cytotoxicity to all cell lines, and in particular the derivatives containig within its structure halogens as substituents. The effect of steric and electronic properties of the substituents on activity of studed compounds, was analyzed by QSAR models.

U radu je sintetizovana serija 3-(4-supstituisanih benzil)-1,3-diazaspiro4.4nonan-2,4-diona čija je struktura određena temperaturama topljenja, FT-IR, 1H i 13C NMR i UV/Vis spektroskopijom. Uticaj supstituenata na apsorpcione spektre spirohidantoina, u različitim rastvaračima, proučavan je Hametovom jednačinom. Eksperimentalni rezultati su pokazali zadovoljavajuću saglasnost sa rezultatima kvantnohemijskih proračuna dobijenih primenom DFT metode. Pokazano je da supstituenti značajno utiču na intramolekulski transfer naelektrisanja (ICT) kao i na reaktivnost proučavanih hidantoina razmatranu na osnovu molekulskog elektrostatičkog potencijala (MEP)., In this work, a series of 3(4-substituted benzyl)-1,3-diazaspiro4.4nonane-2,4-dione was synthesized and fully characterized by melting points, FT-IR, 1H, and 13C NMR and UV/Vis spectroscopy. The Hammett equation was used to quantitatively evaluate the effects of substituents on the absorption frequencies in different solvents. The experimental results showed very good agreement with quantum chemical calculations obtained using DFT method. It was shown that substituents change the extent of conjugation, and affect intramolecular charge transfer (ICT) character. To estimate chemical reactivity of the molecules, the molecular electrostatic potential (MEP) surface maps were calculated for the optimized geometries of the investigated molecules.

U radu je sintetizovano dvadeset novih 3-(supstituisanih benzil)-5,5'-cikloalkan-spirohidantoina čija je struktura određena temperaturama toplenja, FT-IR, 1H i 13C NMR i UV spektroskopijom. Solvatohromizam ovih jedinjenja je proučavan metodom linearne korelacije energija solvatacije. Kvantitativna procena uticaja rastvarača na pomeranje apsorbcionih maksimuma je nedvosmisleno ukazala na vezu između lipofilnosti i relevantnih farmakoloških karakteristika proučavanih jedinjenja sa njihovim proton-akceptorskim svojstvima., In this work twenty novel 3-(substituted benzyl)-5,5'-cycloalkanespirohydantoins have been synthesized and fully characterized by melting point, FT-IR, 1H and 13C NMR and UV spectroscopy. Solvatochromism of these compounds have been analysed by means of linear solvation energy relationships (LSER) concept. The quantitative relationships beetwen hydrogen bonding interaction and the correspodenting pharmacologically relevant propereties of the studied compounds have been discussed.