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1. Estimation of lipophilicity data for derivatives of alkandiamine-N,N’-di-2-(3-cyclohexyl) propanoic acid with potential antineoplastic activity, by UHPLC-MS method

Author

Tubić, Biljana, Marković, Bojan, Vladimirov, Sote, Savić, Aleksandar, Poljarević, Jelena, Sabo, Tibor, Magjarevic, Ratko, Editor-in-chief, Ładyżyński, Piotr, Series editor, Ibrahim, Fatimah, Series editor, Lacković, Igor, Series editor, Rock, Emilio Sacristan, Series editor, and Badnjevic, Almir, editor

Published
2017
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4. Development and validation of liquid chromatography method for determination of acetylsalicylic and salicylic acid in dosage forms

Author

Damnjanović Danijela, Dobričić Vladimir, Čudina Olivera, and Vladimirov Sote

Subjects
acetylsalicylic acid, salicylic acid, liquid chromatography, validation of method, Pharmacy and materia medica, RS1-441
Abstract

Acetylsalicylic acid belongs to nonsteroidal anti-inflammatory drugs with antiinflammatory, analgesic and antipyretic properties. The aim of this work was development and validation of HPLC method for qualitative and quantitative analysis of acetylsalicylic acid and its major degradation product, salicylic acid, in dosage forms. The optimal separation was achived using Zorbax Eclipse XDB-C18 Analytical column (4,6x150 mm, particle size 5 μm) thermostated at 35°C. Mobile phase consisted of eluents A and B in ratio 65:35 (V/V). As the eluent A, water of HPLC purity and 85% phosphoric acid in ratio 80:0.5 (V/V) were used, while acetonitrile was used as the eluent B. The flow rate was 1.0 mL/min and UV detection was performed at 240 nm. The method was validated in terms of selectivity, linearity, precision, accuracy and robustness for both analytes, as well as limits of detection and quantification for salicylic acid. The obtained results meet the requirements of analytical procedures validation. The proposed HPLC method was applied in qualitative and quantitative analysis of acetylsalicylic and salicylic acids in six different forms of drugs. All obtained results meet the requirements of manufacturer specifications. The established HPLC method was found to be rapid, simple, accurate and selective for simultaneous determination of acetylsalicylic and salicylic acids in dosage forms.

Published
2018
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5. Lipophilicity determination of β-hydroxy-β-arilalkanoic acids by reversed phase liquid chromatography under high pressure

Author

Savić Jelena, Dilber Sanda, Crevar-Sakač Milkica, Vladimirov Sote, and Brborić Jasmina

Subjects
partition coefficient, logp, anti-inflammatory compounds, rp-hplc, kowwin, Pharmacy and materia medica, RS1-441
Abstract

Lipophilicity parameters (logP) were determined for thirteen synthesized β-hydroxy-β-arilalkanoic acids using reversed phase high performance liquid chromatography. Anti-inflammatory activity and potential selectivity towards cyclooxygenase-2 inhibition of synthetized compounds was assessed. Stationary phase was octadecyl modified (C-18) silicagel, and four used mobile phases contained different amount of methanol. Both synthetized and standard compounds with known logP values (aspirin, ibuprofen, ketoprofen, naproxen and phenanthrene) were tested in a chromatographic system. Using retention times for each standard and synthesized compound logk values (logarithm of capacity factor) were calculated. Intercept on a graph showing dependency of logk from methanol amount in the mobile phase for each compound represents logKw(capacity factor when organic solvent amount is zero). Graph showing linear dependency of logP of standard compounds from experimentally obtained logKw values was plotted. LogP values for synthetized compounds were obtained by interpolation from the plotted graph. Obtained values are in a range from 2.901 to 3.847. The best correlation between experimentally obtained and predicted logP values was using KOWWIN software (R2=0.8864), which makes this software appropriate for predicting logP values of this type of compounds.

Published
2018
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6. A modified RP-HPLC method for the determination of the pKa values of synthesized β-hydroxy-β-arylalkanoic acids

Author

Savić Jelena S., Dilber Sanda P., Vujić Zorica B., Vladimirov Sote M., and Brborić Jasmina S.

Subjects
dissociation constant, anti-inflammatory compounds, ibuprofen, liquid chromatography, carboxylic acids, Chemistry, QD1-999
Abstract

The pKa values of twelve β-hydroxy-β-arylalkanoic acids and ibuprofen were determined using a modified RP-HPLC method. The stationary phase was octadecyl modified (C-18) silica gel, and the mobile phases were mixtures of methanol and one of ten different buffers (60:40 volume ratio). The mean retention time of each compound was plotted against the pH of each of the ten used mobile phases. The inflection point of the obtained sigmoidal curve represents the s w pKa of a compound. Using s w pKa in previously established equations for the specific methanol/buffer mixture, the w w pKa values (in pure water) were calculated. The obtained w w pKa values for the synthesized compounds were in a range from 3.40 to 3.74, and the w w pKa for ibuprofen was 4.27. The Predicted pKa values for this type of compounds in the MarvinSketch 5.11.5. Program were in poor correlation with the experimental results, while in ACD/ /I-Labs pKa values were calculated as a wide range. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 172041]

Published
2018
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10. Development and validation of an LC-MS/MS method for the determination of adapalene in pharmaceutical forms for skin application

Author

Dobričić Vladimir, Bubić-Pajić Nataša, Marković Bojan, Vladimirov Sote, Savić Snežana, and Vuleta Gordana

Subjects
adapalene, MS/MS analysis, LC-MS/MS determination, pharmaceutical forms for skin application, Chemistry, QD1-999
Abstract

Development and validation of a liquid chromatography - tandem mass spectrometry (LC-MS/MS) method for the determination of adapalene in pharmaceutical forms for skin application were presented. The MS/MS analysis of adapalene was performed by use of three mobile phases, consisted of acetonitrile and (a) 0.1 % formic acid, (b) 0.1 % trifluoroacetic acid and (c) 20 mM ammonium acetate. The strongest signals of parent ion and dominant product ion were obtained in negative mode by use of the mobile phase (c). Validation of this method was performed according to the ICH guidelines. Small variations of selected chromatographic parameters (concentration of ammonium acetate, mobile phase composition, column temperature and flow rate) did not affect qualitative and quantitative system responses significantly, which proved method’s robustness. The method is specific for the determination of adapalene. Linearity was proved in the concentration range 6.7 - 700.0 ng mL-1 (r = 0.9990), with limits of detection and quantification 2.0 ng mL-1 and 6.7 ng mL-1, respectively. Accuracy was confirmed by calculated recoveries (98.4 % - 101.5 %). Precision was tested at three levels: injection repeatability, analysis repeatability and intermediate precision. Calculated relative standard deviations were less than 1, 2 and 3 %, respectively. [Projekat Ministartsva nauke Republike Srbije, br. OI172041 i br. TR34031]

Published
2016
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11. Synthesis and RP-TLC lipophilicity evaluation of a novel fluocinolon acetonide soft drug derivative

Author

Dobričić Vladimir, Vladimirov Sote, and Čudina Olivera

Subjects
cortienic acid, amide, lipophilicity, RP-TLC, Science
Abstract

Cortienic acid was obtained by periodic acid oxidation of fluocinolone acetonide, whereas corresponding amide was synthesized from the cortienic acid and ethyl ester of b-alanine by dicyclohexylcarbodiimide - hydroxybenzotriazole coupling procedure. Lipophilicity of the amide was evaluated by using reversed-phase thin-layer chromatography systems, consisting of ethanol and water in various ratios, and was higher in comparison to fluocinolone acetonide and cortienic acid.

Published
2016
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15. Synthesis, crystal structure and local anti-inflammatory activity of the L-phenylalanine methyl ester derivative of dexamethasone-derived cortienic acid

Author

Dobričić Vladimir, Francuski Bojana M., Jaćević Vesna, Rodić Marko V., Vladimirov Sote, Čudina Olivera, and Francuski Djordje

Subjects
17β-carboxamide steroids, X-ray diffraction, biological activity, ear edema test, Chemistry, QD1-999
Abstract

L-phenylalanine methyl ester derivative of dexamethasone - derived cortienic acid (DF) was synthesized and its crystal structure was characterized by X-ray diffraction method. The crystal system is orthorhombic with space group P212121 and cell constants a = 8.2969 (3) Å, b = 18.9358 (8) Å, c = 20.0904 (6) Å, V = 3156.4 (2) Å3 and Z = 4. Ring A of the steroid nucleus and phenyl ring in the 17β-side chain are almost planar. Rings B and C have a slightly distorted chair conformation, whereas ring D has an envelope conformation. The packing of DF is characterized by a network of intermolecular hydrogen bonds involving the O4 atom from one side of the steroid nucleus and O1 and F1 atoms from the other side as hydrogen bond acceptors. Apart from the intermolecular hydrogen bonds in the crystal packing, there are also numerous intramolecular hydrogen bonds of the N-H...O, C-H...O and C-H...F type. Local anti-inflammatory activity of DF was evaluated by use of croton oil-induced ear edema test. This derivative achieved maximal inhibition of ear edema at significantly lower concentration in comparison with dexamethasone. [Projekat Ministarstva nauke Republike Srbije, br. 172041, 172014 i 172035]

Published
2015
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18. Testing of newly synthesized propafenone derivatives antiarrhythmic activity in aconitic model of cardiac arrhythmia in rats

Author

Ivković Branka, Gojković-Bukarica Ljiljana, Novaković Radmila, Ćupić Vitomir, Vladimirov Sote, Živanović Vladimir, and Šćepanović Radisav

Subjects
antiarrhythmics, aconitic test, ion channels, Veterinary medicine, SF600-1100
Abstract

By applying of aconitic test in in vivo experiments in rats under deep anesthesia, there was investigated the antiarrhythmic potential of newly synthetized fluorinated derivatives of propafenone. The animals were divided into four experimental groups. The first (aconitine group) was treated with aconitine at a dose of 60μg/kg, which led to pronounced cardiac rhythm disorder in a short period of time. The appearance of ventricular extrasystole (VES) was taken as a parameter for ascertainment of cardiac rhytm disorder. The remaining three animal groups were taken for testing the potential of propafenone and propafenone fluorinated derivatives to stop the arrhythmia, and which was induced by i.v. aconitine injection (60|jg/kg). Propafenone, as well as 5OF derivative, did not convert the disturbed cardiac rhythm (survival of animals was 0%). By applying 5PF derivative in a dose of 6 mg/kg, the animals survived with occasional establishment of sinus rhythm. [Projekat Ministarstva nauke Republike Srbije, br. TR 31020 i br. OI 172041]

Published
2014
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19. Development and validation of RP-HPLC method for analysis of multicomponent cough-cold syrup formulation

Author

Ivković Branka, Marković Bojan, and Vladimirov Sote

Subjects
rp-hplc, validation of the method, cough-cold syrup formulation, Pharmacy and materia medica, RS1-441
Abstract

In this study a reversed phase HPLC method for rapid and simultaneous identification and quantification of doxylamine succinate, ephedrine sulfate, dextrometorphane hydrobromide, paracetamole and sodium benzoate in cough-cold syrup formulation was described. Separation was carried out on XTerraTM RP 18, Waters (150 mm x 4.6 mm column, 5 μm particle size). For the analysis of investigated substances gradient elution was used employing water, pH adjusted at 2.5 with 85 % ortophosphoric acid as the mobile phase A and acetonitrile as the mobile phase B. Detection was carried out by UV absorbance at 210 nm for doxylamine succinate, ephedrine sulfate, dextromethorphane hydrobromide and sodium benzoate and at 270 nm for paracetamole. The method was validated statistically for selectivity, linearity, precision, accuracy.

Published
2014
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20. The application of chromatography techniques for the purification process optimization of amide of hydrocortisone-derived cortienic acid and ethyl ester of L-glycine

Author

Dobričić Vladimir, Vladimirov Sote, and Čudina Olivera

Subjects
17(-carboxamide derivatives of hydrocortisone, analytical tlc, rp-hplc, column chromatography, preparative tlc, Pharmacy and materia medica, RS1-441
Abstract

Soft ('antedrug') glucocorticoids are pharmacologically active compounds which are biotransformed in a predictable and controllable way to inactive and non-toxic metabolites. Amides of cortienic acids (17(-carboxamide derivatives of glucocorticoids) are potential soft drugs with fewer side effects than traditional glucocorticoids. The purification of 17(- carboxamide derivatives of hydrocortisone was explained using the amide of hydrocortisonederived cortienic acid and ethyl ester of L-glycine as an example and performed by use of column chromatography and preparative thin-layer chromatography (TLC). The optimization of purification process was performed employing analytical TLC and reversed-phase highperformance liquid chromatography (RP-HPLC). The mobile phase that enables best chromatographic separation of the amide from impurities on TLC plate (chloroform-methanol (95:5 V/V)) was selected and modified (reduction of polarity and addition of glacial acetic acid) to be used for the column chromatography and preparative TLC purification. It was confirmed by use of RP-HPLC that purification procedures applied in this study resulted in pure (96.2 %) amide.

Published
2014
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22. Evaluation of ACE inhibitors lipophilicity using in silico and chromatographically obtained hydrophobicity parameters

Author

Odović Jadranka V., Marković Bojan D., Trbojević-Stanković Jasna B., Vladimirov Sote M., and Karljiković-Rajić Katarina D.

Subjects
lipophilicity, ACE inhibitors, hydrophobicity parameters, Reversed-phase thin-layer chromatography, computed logP, Chemical technology, TP1-1185
Abstract

The aim of this study was to compare different calculation methods to determine lipophilicity, expressed as logP value, of seven ACE inhibitors (enalapril, quinapril, fosinopril, lisinopril, cilazapril, ramipril, and benazapril) with significantly different structure. Experimentally determined n-octanol/water partition coefficients, logPO/W values, were obtained from relevant literature. The correlations between all collected logP values were studied and the best agreements between calculated logP and experimentally determined logPO/W values, were observed for KOWWINlogP or MilogP values (r = 0.999 or r = 0.974, respectively). The correlations between all collected logP values and chromatographically (reversed-phase thin-layer chromatography) obtained hydrophobicity parameters, RM0 and C0, were established. The good correlations (r > 0.90) were obtained in the majority of relationships. The KOWWINlogP was established as the most suitable hydrophobicity parameter of investigated group of ACE inhibitors with r = 0.981 for correlation with RM0 and r = 0.977 for correlation with C0 parameters (water-methanol mobile phase). Using multiple linear regressions, it was established that application of two selected logP, calculated by different mathematical approaches, led to very good correlation due to the benefits of both calculation methods. The good relationships indicate that the computed logP, with careful selection of method calculation, can be useful in ACE inhibitors lipophilicity evaluation, as high-throughput screening technique.

Published
2013
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23. Monitoring of the photochemical stability of carvedilol and its degradation products by the RP-HPLC method

Author

Stojanović Jelena, Vladimirov Sote, Marinković Valentina, Veličković Dragan, and Sibinović Predrag

Subjects
carvedilol, 4-hydroxycarbazole, rp-hplc, stability, Chemistry, QD1-999
Abstract

A sensitive, selective, precise and stability-indicating, new high-performance liquid chromatographic method for the analysis of carvedilol both as a bulk drug and in formulations was developed and validated. As the method could effectively separate the drug from its degradation products, it can be employed as a stability-indicating one. The method was validated for linearity, selectivity, precision, robustness, LOD, LOQ and accuracy. The chromatographic separation was achieved on a Chromolit RP8e, 100x4.6 mm, analytical column. The mobile phase consisted of a mixture of acetonitrile and water (45:55, V/V) (pH 2.5), pH adjusted with formic acid. The absorbance was monitored with a UV detector at 280 nm and the temperature of the analyses was 40°C. The flow rate was 0.5 mL/min. The linearity (r≥ 0.999), reproducibility (0.68-1.27 %) and recovery (99.71-101.58) were found to be satisfactory. This method enables the simultaneous determination of carvedilol and its degradation products, as well as stability. .

Published
2007
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24. Acid-base equilibria of 2,4-diiodo-6-methylphenylcarbamoylmethyl iminodiacetic acid and its labeling with technetium-99m

Author

Brborić Jasmina S., Jovanović Mirjana S., Popović Gordana V., Kapetanović Vera P., and Vladimirov Sote M.

Subjects
iminodiacetic acid analogues, acidity constants, hepatobiliary agent, technetium-99m, Chemistry, QD1-999
Abstract

The acid-base equilibria of a novel hepatobiliary imaging agent, 2,4-diiodo-6-methylphenylcarbamoylmethyl iminodiacetic acid (DIIODIDA) were studied. The potentiometrically determined acidity constants of the second carboxylic group, amino and amide groups were pK2 = 2.52 ± 0.02; pK3 = 5.86 ± 0.06 and pK4 = 10.9 ± 0.1. The determinations were performed at 25 ºC and an ionic strength of 0.1 mol/dm3 (NaCl). The acidity constants (pK1 = 1.3 ± 0.4) corresponding to the first carboxylic group was determined indirectly, on the basis of equilibrium constants obtained in a heterogeneous system, at 25 ºC and an ionic strength 1 mol/dm3 (HCl, NaCl). DIIODIDA was labeled with technetium-99m, and the influence of pH on the yield of labeling was investigated. It was found that labeling within the pH range from 5.5 to 6.5 provided a radiopharmaceutical of high radiochemical purity (>98 %).

Published
2006
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26. RP-HPLC determination of vitamins, folic acid and B12 in multivitamin tablets

Author

Amidžić Rada, Brborić Jasmina S., Čudina Olivera A., and Vladimirov Sote M.

Subjects
rp-hplc, vitamin b1, b3, b6, b12, folic acid, multivitamin preparation, Chemistry, QD1-999
Abstract

A simple and sensitive reversed-phase, ion-pair HPLC method was developed and validated for the simultaneous determination of B-group vitamins, thiamine chloride hydrochloride (B1), nicotinamide (B3), pyridoxine hydrochloride (B6) and folic acid in Pentovit® coated tablets. The cyanocobalamine (B12) was determined separately, because of its low concentration in the investigated multivitamin preparation. RP-HPLC analysis was per- formed with a LKB 2150 HPLC system, equipped with a UV/VIS Waters M 484 detector. The procedures for the determination of B1, B2, B6 and folic acid were carried out on a Supelcosil ABZ+ (15 cm 4.6 mm; 5 m) column with methanol-5mM heptanesulphonic acid sodium salt 0.1 % triethylamine TEA (25:75 V/V); pH 2.8 as the mobile phase. For the determination of B12 a Suplex pKb-100 (15 cm 4.6 mm; 5 m) column and methanol–water (22:78 V/V) as the mobile phase were used. The column effluents were monitored at 290 nm for B1, B3, B6 and folic acid, and at 550 nm for B12. The obtained results and statistical parameters for all the investigated vitamins of the B-group in Pentovit® coated tablets were satisfactory and ranged from 90.4 % to 108.5 % (RSD. from 0.5 % to 4.1 %). The parameters for the validation of the methods are given.

Published
2005
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27. Spectrophotometric determination of fluocortolone in tablets using 1,4-dihydrazinophthalazine

Author

Čudina Olivera, Vladimirov Sote, Živanov-Stakić Dobrila, and Agbaba Danica

Subjects
fluocortolone, 1,4-dihydrazinophthalazine, tablets, spectrophotometry, Chemistry, QD1-999
Abstract

The proposed method for the determination of fluocortolone is based on the formation of a stable, yellow coloured hydrazone product with 1,4-dihydrazinophthalazine as the reagent. Heating at 85°C for 2 h was found to be necessary to ensure optimal hydrazone formation in acidified 1-propanol as the solvent. The detection limit was 1.2 µg/ml. This method when applied for the determination of fluocortolone in pharmaceutical formulations gave precise and reproducible results.

Published
2000
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33. Estimation of lipophilicity and design of new 17β-carboxamide glucocorticoids using RP-HPLC and quantitative structure-retention relationships analysis.

Author

DOBRIČIĆ, VLADIMIR, BOŠKOVIĆ, JELENA, VUKADINOVIĆ, DRAGANA, VLADIMIROV, SOTE, and ČUDINA, OLIVERA

Subjects
LIPOPHILICITY, HIGH performance liquid chromatography, CHROMATOGRAPHIC analysis, GLUCOCORTICOIDS, BEHAVIORAL assessment, DRUG design
Abstract

Eight 17β-carboxamide glucocorticoids with local anti-inflammatory activity were selected and their retention behavior tested in six RP-HPLC systems (I-VI). logkw, a, and φ0 parameters were calculated and correlation with previously determined logPo/w values was examined. RP-HPLC system IV, which consisted of cyano column and methanol-water mobile phases (50:50, 60:40, 70:30, and 80:20, v/v), was selected as the most reliable for lipophilicity prediction and used for the analysis of chromatographic behavior of remaining fourteen 17β-carboxamide glucocorticoids. Quantitative structure-retention relationships analysis was performed and PLS(logkw) model was selected as the most statistically significant. On the basis of selected model and interpretation of corresponding descriptors, new derivatives with higher logkw values and higher expected lipophilicity were designed. [ABSTRACT FROM AUTHOR]

Published
2022
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40. Development and validation of liquid chromatography method for determination of acetylsalicylic and salicylic acid in dosage forms

Author

Damnjanović, Danijela, Damnjanović, Danijela, Dobričić, Vladimir, Čudina, Olivera, Vladimirov, Sote, Damnjanović, Danijela, Damnjanović, Danijela, Dobričić, Vladimir, Čudina, Olivera, and Vladimirov, Sote

Abstract

Acetylsalicylic acid belongs to nonsteroidal anti-inflammatory drugs with antiinflammatory, analgesic and antipyretic properties. The aim of this work was development and validation of HPLC method for qualitative and quantitative analysis of acetylsalicylic acid and its major degradation product, salicylic acid, in dosage forms. The optimal separation was achived using Zorbax Eclipse XDB-C18 Analytical column (4,6x150 mm, particle size 5 μm) thermostated at 35°C. Mobile phase consisted of eluents A and B in ratio 65:35 (V/V). As the eluent A, water of HPLC purity and 85% phosphoric acid in ratio 80:0.5 (V/V) were used, while acetonitrile was used as the eluent B. The flow rate was 1.0 mL/min and UV detection was performed at 240 nm. The method was validated in terms of selectivity, linearity, precision, accuracy and robustness for both analytes, as well as limits of detection and quantification for salicylic acid. The obtained results meet the requirements of analytical procedures validation. The proposed HPLC method was applied in qualitative and quantitative analysis of acetylsalicylic and salicylic acids in six different forms of drugs. All obtained results meet the requirements of manufacturer specifications. The established HPLC method was found to be rapid, simple, accurate and selective for simultaneous determination of acetylsalicylic and salicylic acids in dosage forms., Acetilsalicilna kiselina pripada grupi nesteroidnih antiinflamatornih lekova koji ispoljavaju antiinflamatorno, analgetičko i antipiretičko delovanje. Cilj ovog rada je bio razvoj i validacija HPLC metode za kvalitativnu i kvantitativnu analizu acetilsalicilne kiseline i njenog degradacionog proizvoda, salicilne kiseline, u doziranim oblicima. Optimalno razdvajanje ispitivanih analita postignuto je na koloni Zorbax Eclipse XDB-C18 Analytical (4,6x150 mm, veličina čestica 5 μm) na temperaturi od 35°C. Mobilnu fazu čine smeša A i B u odnosu 65:35 (V/V). Smeša A je voda HPLC čistoće i 85% fosforna kiselina u odnosu 80:0,5 (V/V), a B je acetonitril. Protok je bio 1,0 mL/min, a talasna dužina detekcije 240 nm. Metoda je validirana i ispitani su sledeći parametri validacije: selektivnost, linearnost, preciznost, tačnost i robusnost za oba analita, kao i limiti detekcije i kvantifikacije za salicilnu kiselinu. Dobijene vrednosti su u skladu sa definisanim kriterijumima za validaciju metode. Predložena HPLC metoda je primenjena za kvalitativnu i kvantitativnu analizu acetilsalicilne i salicilne kiseline u šest različitih komercijalnih preparata. Svi rezultati ispitivanja su u dozvoljenim granicama specifikacija proizvođača. Predložena HPLC metoda pod datim eksperimentalnim uslovima predstavlja brz, jednostavan, tačan i selektivan postupak za istovremeno određivanje acetilsalicilne i salicilne kiseline u doziranim oblicima.

Published
2018

41. Lipophilicity determination of β-hydroxy-β-arilalkanoic acids by reversed phase liquid chromatography under high pressure

Author

Savić, Jelena, Savić, Jelena, Dilber, Sanda, Crevar-Sakač, Milkica, Vladimirov, Sote, Brborić, Jasmina, Savić, Jelena, Savić, Jelena, Dilber, Sanda, Crevar-Sakač, Milkica, Vladimirov, Sote, and Brborić, Jasmina

Abstract

Lipophilicity parameters (logP) were determined for thirteen synthesized β-hydroxy-β-arilalkanoic acids using reversed phase high performance liquid chromatography. Anti-inflammatory activity and potential selectivity towards cyclooxygenase-2 inhibition of synthetized compounds was assessed. Stationary phase was octadecyl modified (C-18) silicagel, and four used mobile phases contained different amount of methanol. Both synthetized and standard compounds with known logP values (aspirin, ibuprofen, ketoprofen, naproxen and phenanthrene) were tested in a chromatographic system. Using retention times for each standard and synthesized compound logk values (logarithm of capacity factor) were calculated. Intercept on a graph showing dependency of logk from methanol amount in the mobile phase for each compound represents logKw(capacity factor when organic solvent amount is zero). Graph showing linear dependency of logP of standard compounds from experimentally obtained logKw values was plotted. LogP values for synthetized compounds were obtained by interpolation from the plotted graph. Obtained values are in a range from 2.901 to 3.847. The best correlation between experimentally obtained and predicted logP values was using KOWWIN software (R2=0.8864), which makes this software appropriate for predicting logP values of this type of compounds., Parametri lipofilnosti (logP) su određeni za trinaest sintetisanih β-hidroksi-β-arilalkanskih kiselina primenom reverzno fazne tečne hromatografije. Ispitivanje je urađeno na derivatima kojima je tokom prethodnih istraživanja okarakterisana antiinflamatorna aktivnost i pretpostavljena je potencijalna selektivnost prema inhibiciji ciklooksigenaze-2. Oktadecil-modifikovani (C-18) silikagel je predstavljao stacionarnu fazu, a korišćene su četiri mobilne faze u kojima je variran udeo metanola. Hromatografski su testirana jedinjenja sa poznatim logP vrednostima (aspirin, ibuprofen, ketoprofen, naproksen i fenantren) i sintetisana jedinjenja. Na osnovu retencionog vremena za svako standardno i sintetisano jedinjenje izračunate su vrednosti logk (logaritam faktora kapaciteta). Odsečak na y osi grafika zavisnosti logk od udela metanola u mobilnoj fazi za svako jedinjenje predstavlja vrednost logKw (vrednost retencionog faktora za hromatografski sistem u kome je sadržaj organske komponente nula) za dato jedinjenje. Konstruisan je grafik zavisnosti logP za standardna jedinjenja od njihovih eksperimentalno dobijenih logKw vrednosti i uspostavljena je linearna zavisnost. Interpolacijom logKw sa grafika su očitane vrednosti logP za sintetisana jedinjenja. Dobijene vrednosti su u opsegu od 2,901 do 3,847. Za predviđanje logP vrednosti korišćeni su računarski programi: AlogPS, Molinspiration, MarvinSketch i KOWWIN. Najbolja korelacija između eksperimentalno određenih i predviđenih rezultata je u programu KOWWIN (R2=0,8864), što čini ovaj program pogodnim za predviđanje logP vrednosti ovog tipa jedinjenja.

Published
2018

42. Derivati etilendiamin-N,N'-di-2-(3-cikloheksil) propanske kiseline sa potencijalnim citotoksičnim dejstvom - in silico/in vitro fizičko-hemijska i ADME karakterizacija

Author

Tubić, Biljana K., Marković, Bojan, Vladimirov, Sote, Sabo, Tibor, Stojisavljević Šatara, Svjetlana, Dobričić, Vladimir, Tubić, Biljana K., Tubić, Biljana K., Marković, Bojan, Vladimirov, Sote, Sabo, Tibor, Stojisavljević Šatara, Svjetlana, Dobričić, Vladimir, and Tubić, Biljana K.

Abstract

Estri (S,S)-1,2-etandiamin-N,N'-di-2-(3-cikloheksil)propanske kiseline(EDCP) sa metanolom (DM-EDCP), etanolom (DE-EDCP), propanolom (DPEDCP),butanolom (DB-EDCP) i izobutanolom (DIB-EDCP) i estri (S,S)-1,3-propandiamin-N,N'-di-2-(3-cikloheksil)propanske kiseline (PDCP) sametanolom (DM-PDCP), etanolom (DE-PDCP), propanolom (DP-PDCP),butanolom (DB-PDCP), izobutanolom (DIB-PDCP), pentanolom (DPE-PDCP) iizopentanolom (DIPE-PDCP) dizajnirani su kao ligandi za Pt(IV) komplekse. Uin vitro ispitivanjima utvrđena je značajna citotoksična aktivnost za navedenekomplekse, ali i za ligande u nevezanom obliku. Ispitivana supstanca DE-EDCPpokazala je najveću citotoksičnu aktivnost.U ovoj doktorskoj disertaciji opisan je razvoj i validacija savremenebioanalitičke metode - ultra visoko efikasne tečne hromatografije u sprezi samasenom detekcijom (UHPLC-MS/MS). Metoda je razvijena i validirana zapotrebe pretkliničkih ispitivanja, odnosno za određivanje ispitivane supstanceDE-EDCP u biološkom materijalu, kao i njenog potencijalnog metabolita EDCP.Kao interni standard primenjen je strukturni analog DB-PDCP.Tokom in vitro fizičko-hemijske biofarmaceutske karakterizacije ispitivanihsupstanci određena je i ocenjena njihova rastvorljivost u vodenom rastvoru,lipofilnost i permeabilnost na veštačkim membranama. Profili rastvorljivostikiselina i njihovih estara se značajno razlikuju, dok su profili rastvorljivosti obekiseline (EDCP i PDCP) slični, kao i profili rastvorljivosti svih estara. Kiseline sedobro rastvaraju u izrazito kiseloj sredini i u izrazito baznoj sredini, dok jerastvorljivost estara najveća u izrazito kiseloj sredini..., Esters of (S,S)-1,2-ethanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid(EDCP) with methyl alcohol (DM-EDCP), ethyl alcohol (DE-EDCP), n-propylalcohol (DP-EDCP), n-butyl-alcohol (DB-EDCP) and isobutyl-alcohol (DIBEDCP),and esters of (S,S)-1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid (PDCP) with methyl alcohol (DM-PDCP), ethylalcchol (DE-PDCP), n-propyl alcohol (DP-PDCP), n-butyl alcohol (DB-PDCP),and isobutyl alcohol (DIB-PDCP), n-pentyl alcohol (DPE-PDCP) and isopentylalcohol (DIPE-PDCP) were designed as ligand of Pt(IV) complexes. During the invitro investigation it was found significantly cytotoxic activity of thesecomplexes, and also it was found cytotoxic activity of ligand without complexes.Investigated substance DE-EDCP was exerted the strongest cytotoxic activity.In this doctoral dissertation, there is presented a development and validationof a new ultra-high-performance liquid chromatography tandem massspectrometry bioanalytical method (UHPLC-MS/MS). The developed method issupposed for determination of DE-EDCP and its potential metabolit EDCP inbiological materials during non-clinical and clinical studies. The structuralanalogue DB-PDCP was used as an internal standard.During the in vitro biopharmaceutical characterization of the investigatedsubstances, there was performed a determination of solubility, lipophilicity andmembrane permeability. Profiles of solubility of the observed acids and theircorresponding esters are significantly different, while the profiles of solubility fortwo acids (EDCP and PDCP) are similar as well as the profiles of solubility for allthe esters...

Published
2018

43. Derivati etilendiamin-N,N'-di-2-(3-cikloheksil) propanske kiseline sa potencijalnim citotoksičnim dejstvom - in silico/in vitro fizičko-hemijska i ADME karakterizacija

Author

Marković, Bojan, Vladimirov, Sote, Sabo, Tibor, Stojisavljević Šatara, Svjetlana, Dobričić, Vladimir, Tubić, Biljana K., Marković, Bojan, Vladimirov, Sote, Sabo, Tibor, Stojisavljević Šatara, Svjetlana, Dobričić, Vladimir, and Tubić, Biljana K.

Abstract

Estri (S,S)-1,2-etandiamin-N,N'-di-2-(3-cikloheksil)propanske kiseline (EDCP) sa metanolom (DM-EDCP), etanolom (DE-EDCP), propanolom (DPEDCP), butanolom (DB-EDCP) i izobutanolom (DIB-EDCP) i estri (S,S)-1,3- propandiamin-N,N'-di-2-(3-cikloheksil)propanske kiseline (PDCP) sa metanolom (DM-PDCP), etanolom (DE-PDCP), propanolom (DP-PDCP), butanolom (DB-PDCP), izobutanolom (DIB-PDCP), pentanolom (DPE-PDCP) i izopentanolom (DIPE-PDCP) dizajnirani su kao ligandi za Pt(IV) komplekse. U in vitro ispitivanjima utvrđena je značajna citotoksična aktivnost za navedene komplekse, ali i za ligande u nevezanom obliku. Ispitivana supstanca DE-EDCP pokazala je najveću citotoksičnu aktivnost. U ovoj doktorskoj disertaciji opisan je razvoj i validacija savremene bioanalitičke metode - ultra visoko efikasne tečne hromatografije u sprezi sa masenom detekcijom (UHPLC-MS/MS). Metoda je razvijena i validirana za potrebe pretkliničkih ispitivanja, odnosno za određivanje ispitivane supstance DE-EDCP u biološkom materijalu, kao i njenog potencijalnog metabolita EDCP. Kao interni standard primenjen je strukturni analog DB-PDCP. Tokom in vitro fizičko-hemijske biofarmaceutske karakterizacije ispitivanih supstanci određena je i ocenjena njihova rastvorljivost u vodenom rastvoru, lipofilnost i permeabilnost na veštačkim membranama. Profili rastvorljivosti kiselina i njihovih estara se značajno razlikuju, dok su profili rastvorljivosti obe kiseline (EDCP i PDCP) slični, kao i profili rastvorljivosti svih estara. Kiseline se dobro rastvaraju u izrazito kiseloj sredini i u izrazito baznoj sredini, dok je rastvorljivost estara najveća u izrazito kiseloj sredini..., Esters of (S,S)-1,2-ethanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid (EDCP) with methyl alcohol (DM-EDCP), ethyl alcohol (DE-EDCP), n-propyl alcohol (DP-EDCP), n-butyl-alcohol (DB-EDCP) and isobutyl-alcohol (DIBEDCP), and esters of (S,S)-1,3-propanediamine-N,N'-di-2-(3- cyclohexyl)propanoic acid (PDCP) with methyl alcohol (DM-PDCP), ethyl alcchol (DE-PDCP), n-propyl alcohol (DP-PDCP), n-butyl alcohol (DB-PDCP), and isobutyl alcohol (DIB-PDCP), n-pentyl alcohol (DPE-PDCP) and isopentyl alcohol (DIPE-PDCP) were designed as ligand of Pt(IV) complexes. During the in vitro investigation it was found significantly cytotoxic activity of these complexes, and also it was found cytotoxic activity of ligand without complexes. Investigated substance DE-EDCP was exerted the strongest cytotoxic activity. In this doctoral dissertation, there is presented a development and validation of a new ultra-high-performance liquid chromatography tandem mass spectrometry bioanalytical method (UHPLC-MS/MS). The developed method is supposed for determination of DE-EDCP and its potential metabolit EDCP in biological materials during non-clinical and clinical studies. The structural analogue DB-PDCP was used as an internal standard. During the in vitro biopharmaceutical characterization of the investigated substances, there was performed a determination of solubility, lipophilicity and membrane permeability. Profiles of solubility of the observed acids and their corresponding esters are significantly different, while the profiles of solubility for two acids (EDCP and PDCP) are similar as well as the profiles of solubility for all the esters...

Published
2018

44. A modified RP-HPLC method for the determination of the pK(a) values of synthesized beta-hydroxy-beta-arylalkanoic acids

Author

Savić, Jelena, Savić, Jelena, Dilber, Sanda, Vujić, Zorica, Vladimirov, Sote, Brborić, Jasmina, Savić, Jelena, Savić, Jelena, Dilber, Sanda, Vujić, Zorica, Vladimirov, Sote, and Brborić, Jasmina

Abstract

The pK(a) values of twelve beta-hydroxy-beta-arylalkanoic acids and ibuprofen were determined using a modified RP-HPLC method. The stationary phase was octadecyl modified (C-18) silica gel, and the mobile phases were mixtures of methanol and one of ten different buffers (60: 40 volume ratio). The mean retention time of each compound was plotted against the pH of each of the ten used mobile phases. The inflection point of the obtained sigmoidal curve represents the (s)(w)pK(a) of a compound. Using (s)(w)pKa in previously established equations for the specific methanol/buffer mixture, the (w)(w)pK(a) values (in pure water) were calculated. The obtained wwpKa values for the synthesized compounds were in a range from 3.40 to 3.74, and the (w)(w)pK(a) for ibuprofen was 4.27. The Predicted pK(a) values for this type of compounds in the MarvinSketch 5.11.5. Program were in poor correlation with the experimental results, while in ACD//I-Labs pK(a) values were calculated as a wide range.

Published
2018

45. Development of a Reversed-Phased Thin-Layer Chromatography Method for the Lipophilicity Prediction of 17 beta-Carboxamide Glucocorticoid Derivatives

Author

Dobričić, Vladimir, Dobričić, Vladimir, Stanisić, Aleksa, Vladimirov, Sote, Čudina, Olivera, Dobričić, Vladimir, Dobričić, Vladimir, Stanisić, Aleksa, Vladimirov, Sote, and Čudina, Olivera

Abstract

Octanol-water partition coefficients (log Po/w) of fifteen previously synthesized 17 beta-carboxamide glucocorticoid derivatives and prednisolone were determined using shake-flask method. The retention behavior of selected compounds was tested in five reversed-phased thin-layer chromatography (RP-TLC) systems, consisting of water and organic solvent (acetonitrile, acetone, ethanol 96%, methanol, or tetrahydrofuran), and chromatography parameters (R-M(0), S, and C-0) were calculated. Simple linear regression (SLR) analysis was performed, and the correlation between log Po/w and chromatography parameters was tested. The most appropriate RP-TLC system for log Po/w prediction was that consisting of water and ethanol 96% as the mobile phase. Statisitical evaluation of the quality of models created using this system proved their reliability for log Po/w prediction of new 17 beta-carboxamide glucocorticoid derivatives, and the model with the most favorable statistical parameters was underlined.

Published
2018

46. Evaluation of Biological Activity and Computer-Aided Design of New Soft Glucocorticoids

Author

Dobričić, Vladimir, Jaćević, Vesna, Vučićević, Jelica, Nikolić, Katarina, Vladimirov, Sote, and Čudina, Olivera

Abstract

Soft glucocorticoids are compounds that are biotransformed to inactive and non-toxic metabolites and have fewer side effects than traditional glucocorticoids. A new class of 17-carboxamide steroids has been recently introduced by our group. In this study, local anti-inflammatory activity of these derivatives was evaluated by use of the croton oil-induced ear edema test. Glucocorticoids with the highest maximal edema inhibition (MEI) were pointed out, and the systemic side effects of those with the lowest EC50 values were significantly lower in comparison to dexamethasone. A 3D-QSAR model was created and employed for the design of 27 compounds. By use of the sequential combination of ligand-based and structure-based virtual screening, three compounds were selected from the ChEMBL library and used as a starting point for the design of 15 derivatives. Molecular docking analysis of the designed derivatives with the highest predicted MEI and relative glucocorticoid receptor binding affinity (20, 22, 24-1, 25-1, 27, VS7, VS13, and VS14) confirmed the presence of interactions with the glucocorticoid receptor that are important for the activity.

Published
2017

48. Dizajniranje, sinteza, fizičko-hemijske i biološke karakteristike ß-hidroksi-ß-arilalkanskih kiselina

Author

Savić, Jelena, Brborić, Jasmina, Dilber, Sanda, Vladimirov, Sote, Milenković, Marina, Dobrić, Silva, Savić, Jelena, Savić, Jelena, Brborić, Jasmina, Dilber, Sanda, Vladimirov, Sote, Milenković, Marina, Dobrić, Silva, and Savić, Jelena

Abstract

Nesteroidni antiinflamatorni lekovi (NSAIL) se koriste za ublažavanje simptomaakutne i hronične inflamacije već više od pedeset godina. Grupa NSAIL je veomabrojna i obuhvata različite hemijske strukture. Potreba za pronalaženjem novih NSAIL idalje postoji jer neselektivni NSAIL često izazivaju neželjene gastrointestinalne efekte,a neki noviji selektivni lekovi se dovode u vezu sa ozbiljnim neželjenimkardiovaskularnim efektima.U ovoj disertaciji opisani su dizajniranje, sinteza, ispitivanje fizičko-hemijskih ibioloških osobina β-hidroksi-β-arilalkanskih kiselina. U doking studijama je ispitanuticaj α supstitucije jednom ili dvema metil grupama bočnog niza šest prethodno većsintetisanih β-hidroksi-β-arilalkanskih kiselina koje su derivati β-hidroksi-β-bifenilbuterne kiseline ili β-hidroksi-β,β-difenilpropionske kiseline na inhibiciju enzimaciklooksigenaze kao i na selektivnost prema izoformi ciklooksigenaza-2. Dokingstudijama je ispitan uticaj različitih supstituenata (nitro, trifluorometil, metil, metoksi,dimetilamino grupe i hlora) na benzenovom prstenu sedam derivata 3-hidroksi-3,3-difenilpropanske kiseline na inhibiciju i selektivnost prema COX-2 izoformi. Izračunatesu molekulske zapremine za sva dokovana jedinjenja i utvrđeno je da ispunjavaju uslovda su za minimalno 15 Å3 veće od molekulske zapremine ibuprofena, što znači da suove kiseline potencijalno selektivne za COX-2.Modifikovanom Reformatski reakcijom sintetisano je sedam derivata 3-hidroksi-3,3-difenilpropanske kiseline. Tri planirana jedinjenja nije bilo moguće sintetisati naovaj način, kao ni korišćenjem indijuma kao katalizatora, niti klasičnom Reformatskireakcijom. Modifikovana Reformatski reakcija se sastoji iz dve faze. U prvoj fazi sesintetišu α-bromo alkil 1-etoksiestri iz α-bromsirćetne kiseline i etilvinil etra...

Published
2017

49. Dizajniranje, sinteza, fizičko-hemijske i biološke karakteristike ß-hidroksi-ß- arilalkanskih kiselina

Author

Brborić, Jasmina, Dilber, Sanda, Vladimirov, Sote, Milenković, Marina, Dobrić, Silva, Savić, Jelena S., Brborić, Jasmina, Dilber, Sanda, Vladimirov, Sote, Milenković, Marina, Dobrić, Silva, and Savić, Jelena S.

Abstract

Nesteroidni antiinflamatorni lekovi (NSAIL) se koriste za ublažavanje simptoma akutne i hronične inflamacije već više od pedeset godina. Grupa NSAIL je veoma brojna i obuhvata različite hemijske strukture. Potreba za pronalaženjem novih NSAIL i dalje postoji jer neselektivni NSAIL često izazivaju neželjene gastrointestinalne efekte, a neki noviji selektivni lekovi se dovode u vezu sa ozbiljnim neželjenim kardiovaskularnim efektima. U ovoj disertaciji opisani su dizajniranje, sinteza, ispitivanje fizičko-hemijskih i bioloških osobina β-hidroksi-β-arilalkanskih kiselina. U doking studijama je ispitan uticaj α supstitucije jednom ili dvema metil grupama bočnog niza šest prethodno već sintetisanih β-hidroksi-β-arilalkanskih kiselina koje su derivati β-hidroksi-β- bifenilbuterne kiseline ili β-hidroksi-β,β-difenilpropionske kiseline na inhibiciju enzima ciklooksigenaze kao i na selektivnost prema izoformi ciklooksigenaza-2. Doking studijama je ispitan uticaj različitih supstituenata (nitro, trifluorometil, metil, metoksi, dimetilamino grupe i hlora) na benzenovom prstenu sedam derivata 3-hidroksi-3,3- difenilpropanske kiseline na inhibiciju i selektivnost prema COX-2 izoformi. Izračunate su molekulske zapremine za sva dokovana jedinjenja i utvrđeno je da ispunjavaju uslov da su za minimalno 15 Å3 veće od molekulske zapremine ibuprofena, što znači da su ove kiseline potencijalno selektivne za COX-2. Modifikovanom Reformatski reakcijom sintetisano je sedam derivata 3-hidroksi- 3,3-difenilpropanske kiseline. Tri planirana jedinjenja nije bilo moguće sintetisati na ovaj način, kao ni korišćenjem indijuma kao katalizatora, niti klasičnom Reformatski reakcijom. Modifikovana Reformatski reakcija se sastoji iz dve faze. U prvoj fazi se sintetišu α-bromo alkil 1-etoksiestri iz α-bromsirćetne kiseline i etilvinil etra...

Published
2017

50. Application of biopartitioning micellar chromatography and QSRR modeling for prediction of gastrointestinal absorption and design of novel beta-hydroxy-beta-arylalkanoic acids

Author

Dobričić, Vladimir, Dobričić, Vladimir, Savić, Jelena, Nikolić, Katarina, Vladimirov, Sote, Vujić, Zorica, Brborić, Jasmina, Dobričić, Vladimir, Dobričić, Vladimir, Savić, Jelena, Nikolić, Katarina, Vladimirov, Sote, Vujić, Zorica, and Brborić, Jasmina

Abstract

Gastrointestinal absorption of thirteen novel beta-hydroxy-beta-arylalkanoic acids (HAA) with anti-inflammatory activity was predicted by use of biopartitioning micellar chromatography and compared to ibuprofen. All tested HAA have lower retention factors (k) and lower expected gastrointestinal absorption than ibuprofen, whereas derivatives with the highest values of k are 1C, 2APTF and 2C. Quantitative structure-retention relationship (QSRR) analysis was performed in order to identify molecular descriptors with the highest influence on k and ANN(k) model was selected as optimal. Descriptors which form this model (nBM, P VSA_LogP_8 and Eta_L) indicate that replacement of phenyl ring with a saturated or partially unsaturated one, as well as presence of halogens and nitro group should positively affect k values. On the basis of these conclusions, six novel HAA were designed and selected QSRR model was used for the prediction of their k values.

Published
2017

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