Pharmaceutical Chemistry Journal (v.52, #5)

Synthesis and Pharmacological Activity of Trifluoromethyl-Containing Imidazo[1,2-A]Benzimidazoles by O. N. Zhukovskaya; A. A. Spasov; T. A. Kuz’menko; A. S. Morkovnik; A. F. Kucheryavenko; V. A. Anisimova; O. A. Salaznikova; K. A. Gaidukova; V. A. Kuznetsova; D. A. Babkov; O. Yu. Grechko; N. V. Eliseeva; A. I. Rashchenko (385-391).
A series of 2-(4-trifluoromethylphenyl)- and 2-trifluoromethyl-9-dialkylaminoalkylimidazo[1,2-a]benzimidazoles were synthesized for the first time by reacting 2-amino-1-dialkylaminoalkylbenzimidazoles and 2-bromo-1-[(4-trifluoromethyl)phenyl]ethanone or 1-bromo-3,3,3-trifluoroacetone and were tested for analgesic and antiplatelet activity, glycogen phosphorylase and dipeptidyl peptidase-4 inhibitory activity, and in vitro glycation of bovine serum albumin.
Keywords: 2-(4-trifluoromethylphenyl)- and 2-trifluoromethylimidazo[1,2-a]benzimidazoles; antiplatelet; analgesic; and antidiabetic activity

Synthesis and Neuropsychotropic Activity of Indole-Containing Gamma-Aminobutyric Acid Derivatives by V. M. Berestovitskaya; O. S. Vasil’eva; E. S. Ostroglyadov; S. M. Aleksandrova; I. N. Tyurenkov; O. V. Merkushenkova; V. V. Bagmetova (392-396).
A series of indole-containing γ-aminobutyric acids (GABA) were synthesized via alkaline hydrolysis of 4-(indol-3-yl)-2-pyrrolidones. Their structures were confirmed by IR, PMR, and 13C NMR spectroscopy. Studies of the pharmacological properties of 4-amino-3-indolylbutanoic acids (GABA derivatives) showed that they possessed neuropsychotropic activity, the spectrum of which depended on the acid molecular structure. Nootropic properties prevailed for 4-amino-3-(indol-3-yl)butanoic acid; anxiolytic activity, for 4-amino-3-(1-benzylindol-3-yl)butanoic acid.
Keywords: 2-pyrrolidones; 4-aminobutyric acids; γ-aminobutyric acids; GABA; neuropsychotropic activity

Antidepressant Effect of a Dipeptide Brain-Derived-Neurotrophic-Factor Mimetic (GSB-106) in a Generic Oral Dosage Form by A. V. Tallerova; P. Yu. Povarnina; E. V. Blynskaya; V. V. Bueva; K. V. Alekseev; T. A. Gudasheva; S. B. Seredenin (397-399).
A deficiency of brain-derived neurotrophic factor (BDNF) has now been demonstrated in many studies to play a central role in the pathogenesis of depression. The dimeric dipeptide BDNF-mimetic bis(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide or GSB-106 was discovered at Zakusov State Institute of Pharmacology. Previously, the antidepressant properties of GSB-106 at doses of 0.1 – 1 mg/kg i.p. were established in mice in the Porsolt forced swim test. An oral dosage form of GSB-106 was developed. The present research focused on the antidepressant activity of the GSB-106 dosage form in mice in the Porsolt forced swim test. It is established that GSB-106 in the oral dosage form possesses antidepressant activity for 14 d at doses of 0.05, 0.1, and 1 mg/kg.
Keywords: BDNF; low-molecular-mass mimetic; GSB-106; antidepressant activity; dosage form

Synthesis and Biological Activity of 1-Chloromethyl- and 1-Dichloromethyl-3,3-Dialkyl-3,4-Dihydroisoquinolinium Chlorides by A. G. Mikhailovskii; O. V. Gashkova; I. P. Rudakova; S. V. Chashchina; A. S. Yusov (400-403).
1-Chloromethyl- and 1-dichloromethyl-3,3-dialkyl-3,4-dihydroisoquinolines were synthesized via cyclo-condensation of dialkylbenzylcarbinols with chloroacetonitrile or dichloroacetonitrile. Their hydrochlorides were tested for antiarrhythmic, anticonvulsant, and analgesic activity. Water-soluble 1-chloromethylisoquinoline hydrochlorides showed antiarrhythmic activity with a maximum antiarrhythmic index of 14.8. These same compounds were active against corazole-induced convulsions. 1-Dichloromethylisoquinolines had analgesic effects comparable with that of metamizole sodium.
Keywords: cyclocondensation of dialkylbenzylcarbinols with chloroacetonitrile and dichloroacetonitrile; 1-chloromethyl- and 1-dichloromethyl-3,3-dialkyl-3,4-dihydroisoquinolinium chlorides; antiarrhythmic activity; maximum antiarrhythmic index of 14.8; anticonvulsant and analgesic effects

New 3-(4-Propoxybenzyl)-5-Sulfanyl-Substituted (4H)-1,2,4-Triazoles and Their Antitumor Activity by T. R. Ovsepyan; S. V. Dilanyan; F. G. Arsenyan; R. E. Muradyan; N. S. Minasyan; R. G. Melik-Ohanjanyan (404-407).
3,4-Substituted-(4H)-1,2,4-triazole-5-thiols were synthesized and used for S-alkylation, cyanoethylation, and aminomethylation to produce a series of new 1,2,4-triazole derivatives of interest as biologically active compounds. The antitumor properties of several of the 1,2,4-triazole derivatives were studied.
Keywords: thiosemicarbazide; aminomethylation; cyclization; S-alkylation; cyanoethylation; sarcoma 180

Synthesis and Antinociceptive and Anti-Inflammatory Activity of Monomethyl Esters of Oxodicarboxylic Acids by N. F. Kirillov; R. R. Makhmudov; P. M. Kashkin; E. A. Nikiforova; L. G. Mardanova (408-410).
Reformatsky reactions of dicarboxylic acid anhydrides formed monomethyl esters of oxodicarboxylic acids with antinociceptive and anti-inflammatory activity.
Keywords: oxodicarboxylic acids; methyl esters; antinociceptive and anti-inflammatory activity; Reformatsky reaction; carbocyclic Reformatsky reagents; Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 52, No. 5, pp. 26 – 28, May, 2018.

Molecular docking of 22 N-aroyl-substituted halo(H)anthranilic acid amides and hydrazides with cyclooxygenase 1 (COX1) is described. The dependence of anti-inflammatory activity (AIA) on scoring functions (BeCOX1, ImeCOX1, KiCOX1) and lipophilicity constant (log P calc) is studied. The optimal regression equations for discovering biologically active compounds were AIAcalc = –42.1907 – 1.1029·BeCOX1–7.9806·ImeCOX1 + 8.7036·log P calc (R = 0.902, F = 26.32, S = 8.14, N = 22, QLOO2 $$ {Q}_{mathrm{LOO}}^2 $$ = 0.73). The predicted AIAcalc values were checked for six compounds and were found to be related to the experimental AIAexp values (R = 0.909).
Keywords: anthranilic acid; molecular docking; docking energy; lipophilicity constant (log P); anti-inflammatory activity

Synthesis and Biological Activity of 4-ARYL-2-[(2-OXO-1,2-Diphenylethylidene)-Hydrazinyl]-4-Oxobut-2-Enoic-Acid Amides by R. A. Bykov; N. N. Trapeznikova; S. Yu. Balandina; O. A. Komarova; R. R. Makhmudov; N. A. Pulina; F. V. Sobin; A. E. Rubtsov (415-418).
4-Aryl-2-[(2-oxo-1,2-diphenylethylidene)hydrazinyl]-4-oxobut-2-enoic-acid amides were produced via decyclization of 3-[(2-oxo-1,2-diphenylethylidene)hydrazono]-5-arylfuran-2(3H)-ones by the corresponding amines and via reaction of 4-aryl-2-hydroxy-4-oxobut-2-enoic-acid hetarylamides with 2-hydrazono-1,2-diphenylethanone. Their analgesic and antibacterial activities were studied. Compounds with low toxicities and activities comparable to and exceeding those of reference drugs were discovered.
Keywords: 4-aryl-2-[(2-oxo-1,2-diphenylethylidene)hydrazinyl]-4-oxobut-2-enoic-acid amides; analgesic and antimicrobial activity

Synthesis and Conversions of Polyhedral Compounds. 32. Synthesis and Antibacterial Activity of Azaadamantane-Containing Azomethine Dihydrochlorides by G. L. Arutyunyan; A. D. Arutyunyan; K. A. Gevorkyan; S. P. Gasparyan; R. V. Paronikyan; G. M. Stepanyan; N. S. Minasyan (419-423).
New azomethines (Schiff bases) containing azaadamantane groups on one side and several biologically active compounds on the other were synthesized. The antibacterial activity of their dihydrochlorides showed that azomethines containing a nitrofuryl group were most active.
Keywords: 1,3-diazaadamantane; 1,3,5-triazaadamantane; azomethines; Schiff bases; condensation; antibacterial activity

Microwave-Assisted Synthesis, In Vivo Anti-Inflammatory and In Vitro Anti-Oxidant Activities, and Molecular Docking Study of New Substituted Schiff Base Derivatives by Muhammad Hanif; Mubashir Hassan; Muhammad Rafiq; Qamar Abbas; Ansa Ishaq; Saba Shahzadi; Sung-Yum Seo; Muhammad Saleem (424-437).
In view of considerable interest in the design and synthesis of new heterocyclic compounds with promising biological activities for medical and biological applications, a series of eight imine derivatives have been synthesized through microwave-assisted Schiff base formation by reacting 2-(4-methoxyphenyl)acetohydrazide (3) and 4-amino-3-(4-methoxybenzyl)-1H-1,2,4-triazole-5(4H)-thione (6) with various substituted aldehydes. Structures of the newly synthesized compounds were characterized by FT-IR, 1H NMR and 13C NMR spectral analysis. All the synthesized derivatives were screened for their in vivo anti-inflammatory and in vitro anti-oxidant activities using carrageenan induced rat paw edema test and DPPH free radical scavenging assay, respectively. In addition, molecular docking experiment was also performed to check the actual binding affinity of ligand against target protein. Compounds 4a, 4c, 7a, and 7c screened as potent anti-inflammatory drugs significantly lowered the volume of rat paw edema (P < 0.05). In case of anti-oxidant assay, compound 7a with ferrocenyl group as substituent R and 3,4-disubstitued 1,2,4-triazole as side coupled group exhibited IC50 value of 7.2 ± 2.7 μg/mL comparable with that of the reference ascorbic acid (2.61 ± 0.29 μg/mL) and was the most active compound among the series. However, no prominent results were obtained in case of aralkanoic acid hydrazide substituted Schiff base derivatives 4a – 4d. It is believed that the synthesized Schiff base derivatives can be used for the development of potent anti-inflammatory and anti-oxidant drugs with considerable advantages of convenient synthetic strategy possessing high product yield, short reaction time, and convenient handling. The molecular docking results were found in good correlation with experimental IC50 values.
Keywords: microwave assisted synthesis; Schiff base derivatives; in vivo anti-inflammatory activity; in vitro anti-oxidant activity

Flavones can play a potential role in estrogen dependent breast cancer due to greater reactivity of imidazole and triazole heterocycles which have been investigated in this work. We emphasized on synthesis of flavones derivatives with imidazole (2a, 2b, 2c) and triazole (3a, 3b, 3c) nucleus as a fundamental hetero-aromatic system with modifications, which have been confirmed by TLC, IR, NMR and mass spectrometry data. The synthesized compound were studied as non-steroidal aromatase inhibitors and evaluated for in vitro anti-breast cancer activity against MCF-7 cell line through SRB assay. The triazole derivative 3a with nitro substitution (H-bond accepting group) was found to be more active in comparison to standard drug letrozole.
Keywords: aromatase; aromatase Inhibitors; flavones; flavonoids; imidazole; triazole; SRB assay; MCF-7 cell line

Synthesis, Antimicrobial Activity and QSAR Studies of Some New Sparfloxacin Derivatives by Ayush Kumar; Ajmer Singh Grewal; Vikramjeet Singh; Rakesh Narang; Deepti Pandita; Viney Lather (444-454).
The increasing global health problem of bacterial resistance to the major classes of antibiotics is driving scientists to search for newer antimicrobial agents. The present work was designed to synthesize and evaluate the antimicrobial activities of a new series of sparfloxacin derivatives. Aseries of 22 new sparfloxacin derivatives (1 – 22) were synthesized followed by their spectral characterization and antimicrobial evaluation using serial dilution method. QSAR studies were performed to relate their antimicrobial activity and structure. The results of antimicrobial activity testing against all the three selected bacterial strains (Bacillus subtilis, Staphylococcus aureus, and Escherichia coli) indicated that compounds 21 and 22 exhibited maximum antibacterial potential among all the synthesized sparfloxacin derivatives. Compounds 6, 17, and 22 exhibited maximum antifungal potential against two fungal strains (Candida albicans and Aspergillus niger). The results of QSAR studies revealed the fact that topological parameters, particularly the valence third-order molecular connectivity index, are the major factor in influencing the antibacterial potential of the synthesized molecules. These new derivatives can offer new avenues in the design of better antimicrobial molecules active against drug-resistant bacterial and fungal strains.
Keywords: antimicrobial activity; Mannich bases; quinolones; QSAR, sparfloxacin derivatives

Amethod for quantitative determination of total saponins in Aralia elata (Miq.) Seem. (A. mandshurica Rupr. et Maxim.) roots was developed using spectrophotometry at 510 nm of products from the reaction of the analytes with conc. H2SO4 as recalculated for saparal (total ammonium salts of aralia saponins) or the average specific absorption coefficient of saparal. The total saponin contents in the raw material varied from 9.41 ± 0.18 to 10.46 ± 0.15%. The error of a single determination using the developed method with confidence probability 95% was less than ± 1.43%.
Keywords: Manchurian aralia; A. elata (Miq.) Seem.; Aralia mandshurica Rupr. et Maxim.; roots; saparal; saponins; aralosides; spectrophotometry

Alkaloid Content, Antioxidant and Cytotoxic Activities of Various Parts of Papaver somniferum by Farukh Sharopov; Abdujabbor Valiev; Isomiddin Gulmurodov; Mansour Sobeh; Prabodh Satyal; Michael Wink (459-463).
Poppy (Papaver somniferum) is a traditional source of isoquinoline alkaloids, especially morphine, codeine and papaverine that exhibit a wide spectrum of therapeutic effects. Due to beneficial properties, poppy has been used by humankind for several thousand years and is still being used around the world. The present study was aimed to investigate alkaloid composition and biological activity of various parts of the plant (leaves, stems, roots, capsules, flowers, seeds) in an ornamental variety of P. somniferum. The alkaloid content rangedwithin 0.16 – 6.5 mg/g fresh weight of raw plant material. The major components of the alkaloid fraction were papaverine (37.7 – 2062.9 μg/g), codeine (7.4 – 1280.5 μg/g) and morphine (3.25 – 929.3 μg/g). The P. somniferum alkaloid extract produced a strong antioxidant effect, which was evaluated using the radical-scavenging DPPH, ABTS and FRAP assays. The antioxidant properties were characterized by IC50 values ranging within 35.1 – 157.6 μg/mL for DPPH radical and 138.5 – 306.3 μg/mL for ABTS∙•+ radical scavenging. The ferric reducing antioxidant power (FRAP) values varied from 59.75 to 1348.71 mM FeSO4/g extract. The alkaloid extract was active against all human tumor cell lines studied (HeLa, Caco-2, MCF-7, CCRF-CEM and CEM/ADR 5000). The methanol extract exhibited a pronounced cytotoxicity against most of cancer cell lines studied, especially those with a low expression of ABC transporters.
Keywords: Papaver somniferumextract; alkaloids; morphine; antioxidant; cytotoxicity

Immobilization of Benzocaine in Polymeric Nanocontainers. Pharmacokinetic Modeling by G. Yu. Shkurenko; S. Yu. Lyrshchikov; A. A. Gorlov; O. G. Al’tshuler; G. N. Al’tshuler (464-466).
The possibility of immobilizing benzocaine in polymeric nanocontainers made of sulfonated cation exchangers, i.e., sulfonated polycalixarene and KU-23 30/100, was studied. The desorption kinetics of neutral and cationic benzocaine from the polymeric nanocontainers provided the desired drug-release pharmacokinetics upon peroral administration.
Keywords: polymeric nanocontainer; immobilized benzocaine; sulfonated cation-exchange resins

The influence of the isomalt mass fraction in a mixture with glucose on the flowability, density, and elastic-plastic properties of the tableting mass and the quality of the obtained 1-g tablets (14 mm diameter) was studied. The flowability of the mixture decreased by 0.6 ± 0.06 g/c if the isomalt ST-PF content was increased by 10%. The curve for the bulk density had a distinct maximum near an isomalt–glucose ratio of 50:50. The tablet strength increased linearly by 55 ± 7 and 51 ± 7 N; the density, by 0.0036 ± 0.0002 and 0.076 ± 0.003 g/cm3; and the disintegration time, by 1.2 ± 0.2 and 1.7 ± 02 min if the isomalt ST-PF concentration in the mixture was increased to 35% and the compaction pressure to 350 N/cm2, respectively.
Keywords: direct pressing; 3D-modeling; tablets; excipients; isomalt; glucose; ascorbic acid

Technological Aspects of Ensuring the Specific Safety of Human Immunoglobulin and Albumin Preparations by O. G. Kornilova; M. A. Krivykh; É. Y. Kudasheva; I. V. Borisevich (473-477).
Modern technological approaches to ensuring the specific safety of human immunoglobulin and albumin preparations are analyzed. Introduction into human immunoglobulin preparation technology of donor screening for group- and rhesus-affiliations and chromatographic purification steps to reduce the contents of anti-A and anti-B hemagglutinins and anti-D antibodies are shown to be promising. Technological capabilities for reducing the anticomplementary activity and thrombogenic potential of immunoglobulin preparations and decreasing the contents of prekallikrein activator in human i.v. immunoglobulin and albumin preparations are discussed.
Keywords: human immunoglobulin preparations; human albumin preparations; specific safety; anticomplementary activity; anti-A and anti-B hemagglutinins; anti-D antibodies; prekallikrein activator; manufacturing technology; plasma fractionation

A gas-chromatographic method for quantitative determination of phenol in biological drugs was developed. The optimal chromatography conditions were a DB-WAX column (30 m × 0.25 mm × 0.25 μm, Agilent Technologies); injector temperature 250°C; split ratio 40:1; sample volume 0.5 μL; He carrier gas; constant pressure mode; flow rate 1.4 mL/min; furnace temperature profile: initial 160°C (constant for 3 min), ramp at 40°C/min to 200°C (constant for 0.6 min), ramp at 40°C/min to 220°C; analysis time 7.133 min; and detector temperature 250°C. The method was validated. The analytical range of the method was phenol concentrations from 1 to 5 mg/mL. The accuracy and specificity of the method were confirmed. The precision was evaluated. The results allowed this method to be considered an alternative for quantitative determination of phenol in biologicals.
Keywords: phenol; gas chromatography; biologicals; quantitative determination

Development and Validation of a Liquid Chromatography Method for the Analysis of Rivaroxaban and Determination of Its Production Related Impurities by Basima Arous; Mohammad Amer Al-Mardini; Francois Karabet; Manal Daghestani; Fida Al-Lahham; Alyamama Al-Askar (483-490).
The purpose of this work was to develop a sensitive and validated HPLC method for analysis of rivaroxaban and estimation of related impurities in parent drug substance and pharmaceutical dosage forms. The analysis was carried out on a Macherey-Nagel Nucleodur C18 column (250 × 4.6 mm, 5 μm particle size) with a mobile phase containing acetonitrile and water in gradient program at a flow rate of 1.5 mL/min, the column oven temperature 55°C, and the UV detector wavelength set at 254 nm. The method was validated according to USP38-NF33 guideline recommendations and to the ICH guidelines for validation. The linearity, selectivity, accuracy, precision, robustness, LOD and LOQ characteristics of the proposed method showed acceptable values. The method is suitable for practical routine analysis of drug substance and pharmaceutical dosage forms, and it was successfully used to analyze Rovaltro (Syrian product) and Xarelto (brand product). All the analysis results were acceptable according to pharmaceutical requirements.
Keywords: rivaroxaban; product related impurities; HPLC; validation