Supplementary material for the article: Lazić, A. M.; Mašulović, A. D.; Lađarević, J. M.; Valentić, N. V. Assessing the pharmacological potential of selected xanthene derivatives. Journal of the Serbian Chemical Society 2023, 88(9), 811-824. https://doi.org/10.2298/JSC230131035L

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.Related to: [https://technorep.tmf.bg.ac.rs/handle/123456789/6809]Supplementary material for: [https://doi.org/10.2298/JSC230131035L

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 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

ANTIOXIDATIVE AND IMMUNOMODULATING POTENTIAL OF THE MUSHROOM Phellinus linteus

Phellinus linteus is a popular medicinal mushroom that is widely used in Asian countries. A number of studies have confirmed that P. linteus possesses exceptional biological potential useful for pharmacological applications, including anticancer and anti-inflammatory activities, as well as antidiabetic, hepatoprotective, and neuroprotective effects. The objective of the present study was to evaluate antioxidant and immunomodulatory activities of hot water polysaccharide extract obtained from the medicinal mushroom Phellinus linteus (Berk. et Curt.) Teng. FT-IR was used to study the polysaccharide profile of the extract. Its antioxidant potential was measured by the conjugated diene method in the linoleic acid model system. Immunomodulation was tested in vitro by measuring the synthesis of interferon-gamma (IFN-γ) in healthy human peripheral blood mononuclear cells (PBMCs) using enzyme linked immunosorbent assay (ELISA). The FT-IR spectrum of P. linteus hot water extracted polysaccharides showed a typical carbohydrate pattern. A small amount of proteins was also observed with characteristic absorptions at 1635, 1540 and 1412 cm-1 . Measurements of antioxidant properties in linoleic acid model system revealed relatively high antioxidant activity with EC50 value of 7.11 mg/mL. After 48 h of P. linteus polysaccharide extract incubation, the IFN-γ titer displayed immunosuppressive effect, 32.6 pg/mL. The IFN-γ titer for the suspension of PBMCs in PBS, which was used as a positive control, was found to be 135.2 pg/mL. Differences in IFN- γ contents in P. linteus extract vs. model control were strongly significant (p < 0.05). The results of this study suggest that the polysaccharide extract of P. linteus acts as a natural antioxidant and possesses immunomodulatory properties. Therefore, it can be a suitable raw material for the development of antioxidant food additives. In addition, due to the possible immunosuppressive effect P. linteus polysaccharide extract is particularly interesting and could find application in suppression of autoimmune diseases such as rheumatoid arthritis

Sinteza i karakterizacija 1-(4-supstituisanih benzil)-3’,4’-dihidro-2’H-spiro[imidazolidin-4,1’-naftalen]-2,5-diona potencijalnih antikonvulzivnih agenasa

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

In vitro antioxidant activity evaluation of selected xanthene derivatives

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

Synthesis, structure and properties of 7,8-benzo-1,3-diazaspiro[4.5]decane-2,4-dione and its derivatives

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

The influence of the structure on the antiproliferative activity of the cycloalkanespiro-5-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

Design, synthesis and antiproliferative evaluation of novel cycloalkane-spiro-5-hydantoin derivatives: A structure-activity relationship study

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

Supramolecular architectures of selected xanthenedione derivatives

The wide range of pharmacological activities (e.g. antiviral, antifungal, antibacterical, antiinflamatory, leishmanicidal and antidepresant) has already been attributed to the xanthenediones, a group of synthetic heterocyclic compounds possessing a pyran nucleus fused on either side with cyclohex-2-enone rings [1]. In this work, two 3,3,6,6- tetramethyl-9-substituted-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-diones (Figure 1) were synthesized and their crystal stuctures were determined by single crystal X-ray diffraction. The main structural feature in compound 1 is a supramolecular chain along the a-axis formed by O4–H4···O2 hydrogen bond and C13–H13···O4 and Br1···Br2 interactions between the adjacent asymmetric units, while the formation of supramolecular network is further achieved by C–H···π interactions between the adjacent chains. The main motif in 2 is a dimer formed via O4–H4···O2 hydrogen bond and Cl1···π interactions. The neighbouring dimers are connected through strong C7– H7A···π interactions, thus resulting in formation of a zigzag chain parallel to the c-axis. Weak C–H···π interactions link the adjacent chains into a supramolecular layer. This work may provide a basis for design of new biologically active xanthenediones both at the molecular and supramolecular level

Chemometric analysis of lipophilicity parameters of newly synthesized spiro hydantoin derivatives determined by RP-TLC and protic solvents

Predmet ovog rada je ispitivanje lipofilnosti novosintetisanih derivata cikloalkilspiro-5-hidantoina. Parametri lipofilnosti (RM0) za ispitivana jedinjenja dobijeni su primenom reversno fazne hromatografije na tankom sloju C-18 modifikovanog slikagela. Kao pokretne faze korišćene su dvokomponentne smeše vode i protičnih organskih rastvarača (metanola, etanola, n-propanola, i-propanola i t-butanola). Linearna zavisnost između RM vrednosti i zapreminskog udela organskog modifikatora u pokretnoj fazi, φ, omogućava izračunavanje RM0 ispitivanih jedinjenja. Uticaj supstituenata, kao modifikatora pokretne faze na RM0 vrednosti procenjen je primenom hemometrijskih metoda, hijerarhijske kalster analize (HCA) i analize glavnih komponenata (PCA). Ove metode omogućavaju grupisanje ispitivanih derivata spirohidantoina, kao i primenjenih pokretnih faza prema njihovoj polarnosti.The subjects of this paper are newly synthesized derivatives of cycloalkylspiro-5- hydantoins and the analysis of their lipophilicity. The parameters of lipophilicity (RM0) were determined by reverse phase thin layer chromatography on C-18 modified silica gel. Mobile phases were two-component mixtures of water and protic organic solvents (i.e. methanol, ethanol, n-propanol, i-propanol and t-butanol). Linear relationship between RM values and volume fraction of organic solvent, φ, allows calculation of RM0 for investigated compounds. The effect of the substituents in the molecule as well as mobile phase modifier on RM0 value was assessed using chemometric methods, hierarchical cluster analysis (HCA) and principal component analysis (PCA). This allows clustering of spiro hydantoin derivatives as well as applied mobile phases according to their polarity