Vol 4, No 1 (2013)

March 2013

Table of Contents


Hakan Arslan
Editorial Board
Hakan Arslan
Graphical Contents

Research Article

Uros Groselj, Georg Dahmann, Branko Stanovnik, Jurij Svete

2-Substituted 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidin-4(3H)-ones were synthesized in three steps from itaconic acid derivatives via cyclization with primary amines followed by Masamune-Claisen condensation, and cyclization of the newly formed β-keto esters with amidines. Preparation and/or isolation of β-keto esters with polar N-substituents failed, but the corresponding final products were obtained in a different way. 6-(1-(3-Hydroxypropyl)-5-oxopyrrolidin-3-yl)-2-phenylpyrimidin-4(3H)-one was obtained by hydrogenolytic o-deprotection of its o-benzyl derivative. Depending on reaction conditions, further mesylation of 6-(1-(3-(benzyloxy)propyl)-5-oxopyrrolidin-3-yl)-2-phenylpyrimidin-4(3H)-one followed by treatment with pyrrolidine gave either the monoaminated- or the diaminated product. The structures of novel compounds were determined by NMR.

Serife Selma Uras Gungor, Sevda Guzel Ozay, Ahmet Ilcim, Gamze Kokdil

The aqueous methanolic extracts obtained from aerial parts and seeds of T. isthmocarpa Boiss. & Bal. from Turkey were analyzed by reversed-phase HPLC for their phenolic acid and flavonoid composition. Total phenolic content was determined using the Folin-Ciocalteu assay, while total flavonoid content was measured spectrometrically with AlCl3 assay. Primary antioxidant activity in terms of free radical scavenging activities of both extracts was measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The highest total flavonoid and total phenolic content was determined in the extract of aerial parts (830.8 mg/100 g and 877.9 mg gallic acid equivalent/100 g, respectively). The extracts of aerial parts and seeds had the high antioxidant activity (87.2 % and 78.2%, respectively). Gallic acid, caffeic acid, luteolin, apigenin and kaempferol were detected as phenolic compounds in both extracts by HPLC methods. In addition, an isoflavone, formononetin was determined in the extract from aerial parts of the plant. The present results suggest that T. isthmocarpa have shown potential a source of natural antioxidants.

Ashraf Hassan Fekry Abd El-Wahab, Hany Mostafa Mohamed, Ahmed Mohamed El-Agrody, Mohamed Ahmed El-Nassag, Ahmed Hammam Bedair

A series of triazolophthalazine derivatives (4-22) were synthesized and characterized. The structures of the newly synthesized compounds were confirmed by spectral data. The newly synthesized compounds were also screened for their antimicrobial activity.

Siti Nuryanti, Sabirin Matsjeh, Chairil Anwar, Tri Joko Raharjo, Baharuddin Hamzah

Acid-base titration requires indicators to show color change at each pH interval. Synthetic indicators applied recently have some negatives, such as chemical pollution, availability and expensive production cost. Effort to obtain natural product-based-indicator from corolla of Roselle (Hibiscus sabdariffa L.) has been conducted. Firstly, anthocyanin contained in the Roselle’s corolla was identified. Then, the indicator was obtained by extracting the corolla consecutively with n-hexane, ethyl acetate and methanol-HCl 0.5%. Then the filtrate was evaporated at 65 oC. The obtained indicator was applied in weak base-strong acid and weak acid-strong base titrations. The comparison indicators used in this research were methyl orange and phenolphthalein. The results showed that the Roselle’s corolla indicator gave red color in acidic solution, while green in basic solution. Additionally, its performance is similar to that of methyl orange.

Emre Mentese, Fatih Islamoglu, Esra Bal, Bahittin Kahveci

A series of 2-substituted benzimidazole derivatives have been synthesized via microwave mediated process. Different benzimidazole derivatives were titrated with tetrabutylammonium hydroxide in four non-aqueous solvents (isopropyl alcohol, N,N-dimethylformamide,tert-butyl alcohol and acetonitrile), using potentiometric method. The half neutralization potential values and the corresponding pKa values were determined for all cases.

Ismail Salama, Mohamed Sayed Gomaa

Two new validated methods for the quantification of miconazole (MIC), nystatin (NYS), hydrocortisone acetate (HCA) and neomycin (NS) by high performance thin layer chromatography (HPTLC)-densitometry and reverse-phase high-performance liquid chromatography procedure coupled with photodiode array detector (RP-HPLC-DAD) were developed and compared. HPTLC separations were performed using a mobile phase, ethylacetate:methanol:glacial acetic acid (60:40:0.4, v:v:v) for MIC, NYS, HCA and ethylacetate for NS. For HPLC-DAD analysis, using an isocratic elution system, separation of all compounds was achieved. Good resolution and quantization were achieved, accuracy and precision, as well as detection and quantitation limits of the two methods, were evaluated and compared. Excellent linearity was observed for all of the standard calibration curves, and the correlation coefficients were above 0.9997. HPTLC limits of quantitation were 15.37×10-2, 9.8×10-2, 13.32×10-2 and 15.19×10-2 µg/mL for MIC, NYS, HCA and NS respectively, whereas HPLC limits were 6.80×10-2, 6.56×10-2, 1×10-1 and 10.16×10-2 µg/band for MIC, NYS, HCA and NS respectively. In comparison with HPLC, HPTLC is less expensive and faster procedure, requiring 2-3 h to analyse 10-12 samples on a single plate. The developed methods were proved to be specific, robust and accurate for the determination of cited drugs in pharmaceutical preparations.

Magda Mohamed Ayad, Hisham Ezzat Abdellatef, Mervat Mohamed Hosny, Yassmin Ahmed Sharaf

Several simple, sensitive, accurate and inexpensive spectrophotometric and spectrofluorimetric methods were developed for the determination of propafenone HCl and diltiazem HCl using 4-chloro-7-nitrobenzofurazan (NBD-Cl) accompanied with kinetic study, either in pure form or in pharmaceutical preparations. In this work, the cited drugs react with (NBD-Cl) in presence of borate buffer of pH = 7.6 at a fixed time of 30 minutes on thermostated water bath at (75-80 °C). The absorbance was measured using spectrophotometric technique at 489 and 481 nm for propafenone HCl and diltiazem HCl, respectively, or by using spectrofluorimetric technique after dilution at the specific wavelength of excitation and emission.The calibration curves were linear in the range of 4-44, 16-96 µg/mL when using spectrophotometric method, and 0.4-3.6, 1.6-8.8 µg/mL when spectrofluorimetric method was applied for propafenone HCl and diltiazem HCl, respectively. The limit of quantitation and the limit of detection were also calculated. The methods were applied successfully to commercial dosage form and can be further applied for their determination on a large scale in quality control laboratories. The obtained results statistically agreed with those obtained by reference methods. The determination of the studied drugs by the fixed concentration and rate constant methods is feasible with the calibration equations obtained, but the fixed time method proves to be more applicable.

Luciana Gavernet, Maria Luisa Villalba, Luis Bruno Blanch, Ileana Daniela Lick

In this investigation, a kinetic study of the thermolysis of N-(benzyl)-N´-(tert-butoxycarbonyl) sulfamide to yield benzylsulfamide in an efficient manner was performed. The thermolysis reaction was monitored in helium flow by thermogravimetry at different heating rates between 0.2 and 10 oC/min. The activation energy value was obtained from the Kissinger-Akahira-Sunose isoconversional method and theoretical calculations (from Transition State Theory). The reaction model of the process was studied by means of the master-plot method. Results obtained from experiments of thermolysis performed under the melting point temperature of N-(benzyl)-N´-(tert-butoxycarbonyl) sulfamide fit with an Avrami-Erofeev model whereas data found for experiments at higher temperatures fit with first order model. Isothermal experiments were simulated at 115, 120 and 130 oC using the model-free method, employing only the activation energy value.

Abdul Hameed, Ayaz Anwar, Khalid Mohammed Khan, Rizwana Malik, Fernaz Shahab, Sadia Siddiq, Fatima Zahra Basha, Muhammad Iqbal Choudhary

A novel series of tricyano substituted polyfunctional 5,6-dihydropyridine 8a-n bearing functionalized aromatic rings at C-4 and C-6 position have been prepared from (α-methylbenzylidene) malononitriles in good to excellent yields (52-98%) in solvent free conditions. All the synthesized compounds (8a-n) were evaluated for their in vitro urease inhibition and anticancer activity against prostate cancer (PC3) and Hela cell lines. Compound 8k (4,6-bis(4-methoxyphenyl)-5,6-dihydropyridin) showed slightly better urease inhibitory potential (IC50 = 20.47 µM) as compared to standard thiourea (IC50 = 21 µM). Whilst in the case of anticancer studies the compound 8a 2-(4,6-bis(4-bromophenyl)-6-methyl-5,6-dihydropyridin found to be most active (IC50 = 4.40 and 8.80 µM) among the series when compared with standard doxorubicin 4 (IC50 = 0.91 and 3.1 µM) in both cell lines respectively. A structure-activity relationship of this series has been established on the basis of electronic effects and position of different substituents (H, Br, Cl, I, F, Me, OMe, OH, and NO2) present on the C-4 and C-6 phenyl rings. The anticancer activity evaluation of these pyridine derivatives envisage that the compound 8a could be putatively linked with doxorubicin IV to developed new anticancer prodrugs for multidrug resistant (MDR) cancer cells. All the synthesized compounds were characterized by spectroscopic techniques.

Abdulaziz Alnajjar, Marzouq Alsaiedi, Morsy Ahmed El-Apasery

Ethyl 2-amino-3-cyano-4-phenylnicotinates (8), could be readily synthesized via reacting ethyl propiolate with benzylidenemalononitrile in the presence of L-proline as a catalyst and subsequent rearrangement of the so formed 2-aminopyran (7), with acetic acid in the presence of ammonium acetate. A series of 2-amino and 2-hydroxyarylazonicotinates monoazo disperse dyes (12a-c), were prepared in a good yields via condensation of arylhydrazonals (11a-c), with active methylene nitriles. The compound 9 was also characterized by single crystal X-ray diffraction studies. Crystal data for compound 9, C15H18O6 (M = 294.29): hexagonal, space group P65 (no. 170), a = 11.3311(5) Å, c = 19.5375(10) Å, V = 2172.42(18) Å3, Z = 6, T = 296(2) K, μ(MoKα) = 0.879 mm-1, Dcalc = 1.350 g/mm3, 4546 reflections measured (9.02 ≤ 2Θ ≤ 132.96), 2271 unique (Rint = 0.0921) which were used in all calculations. The final R1 was 0.0686 (>2σ(I)) and wR2 was 0.1691 (all data).

Tadjuddin Naid, Wahyu Rizandi Syukur, Amran Ilyas, Seniwati Dali, Baharuddin Hamzah

The study was conducted with the purpose to develop and validate a high performance liquid chromatography method with UV detector to determine ketoprofen content in tablet preparation using ethanol-phosphate buffer (pH = 6.0, 80:20, v:v). The method was validated toward parameters of accuracy, precision, linearity, selectivity, LOD and LOQ. The results obtained fulfill the validation requirement of the ketoprofen tablet in the form of LOD = 0.5302 ppm and LOQ = 1.7676 ppm.

Malavalli Basavaraju Sridhara, Ramesh Suhas, Dase Gowda Channe Gowda

A simple and efficient protocol for the synthesis of symmetrically substituted azoarenes from nitroarenes by using ammonium bromide as hydrogen donor and magnesium powder as catalyst at room temperature in methanol media is described. Various azoarenes containing few additional substituents such as halogen, methyl, hydroxyl, methoxy, ethoxy etc. functions have been synthesized in a single step by the use of this reagent. The conversion is clean, rapid, chemo-selective and high yielding.

Tiago Alexandre Dinis Pinto, Marilia Silva, Silvia Cunha, Ana Maria Ferreira Oliveira-Campos, Ligia Marona Rodrigues, Radim Hrdina, Ana Paula Esteves

2,3,4,6-Tetra-o-acetyl-1-[4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl]-β-D-glucopyranose was prepared and reacted with several acids, either commercially available or prepared. These included, aliphatic or aromatic acids (phenylacetic acid derivatives, benzoic derivatives), palmitic acid and the protected amino acids N-(benzyloxycarbonyl)glycine and N-(tert-butyloxycarbonyl)-phenylalanine. Two other acids, 2-(3-bromopropoxy)benzoic acid and 2-(5-bromopentoxy)benzoic acid (analogues of salicylic acid were synthesized), whose preparation is also described in this work. The esterification was performed either with N,N'-dicyclohexylcarbodiimide (DCC)/4-dimethylaminopyridine (DMAP) or by reacting the acyl chlorides with the alcohol in the presence of triethylamine. The products were isolated in fair yields and fully characterized by the usual analytical techniques.

Tahseen Abed Al Qader Alsalim, Bahjat Ali Saeed, Rita Sabah Elias, Hanna Sabeeh Abbo, Salam Jaber Titinchi

Two series of p-alkyl- and p-alkoxy-substituted curcuminoids were synthesized. The validity of the proposed structures was checked on the basis of their high resolution mass spectra as well as NMR, IR and electronic spectra. The spectra were essentially similar for both series. NMR, IR and electronic spectra showed that the compounds exist mainly or exclusively as the enolic tautomer in their solutions. Theoretical study for the electronic spectra was conducted to account for the origins of the electronic transitions that are responsible for the UV-VIS bands. The theoretical calculations were done at the B3LYP/6-31G(d) level of theory and predicted that the similarity of the electronic spectra is may be due to the close resemblance of their molecular orbitals.


Review Article

Juliana Ivanova, Yordanka Gluhcheva, Denitsa Tsanova, Angelina Piskova, Radostina Djaleva, Steliana Mokresheva, Dimitrina Kamenova, Mariana Mitewa

Cadmium (Cd) has been classified as a human carcinogen. The World Health Organization (WHO) reported that the concentration of Cd in the environment has rapidly increased in the last few years. In many epidemiological studies, the correlation between environmental exposure of humans to Cd and diseases such as stroke, ischemia, renal and hepatic dysfunction, anemia, osteoporosis and diabetes has been discussed. For the treatment of heavy metal intoxications a therapy with chelating agents has been applied. A chelating agent is a compound that binds the toxic metal ion thus promoting its excretion by the living organisms. Recently, it has been found that Cd-induced toxicity is a result of formation of reactive oxygen species (ROS). These results increased the interest towards the antioxidants as possible agents for the treatment of Cd-induced organ toxicity. Herein, we present summary and discussion of the literature data for the influence of chelating agents and antioxidants on Cd-induced pathological conditions in Cd-intoxicated animals.