Pharmaceutical Chemistry Journal (v.50, #12)

Prediction and Study of Anticonvulsant Properties of Benzimidazole Derivatives by P. M. Vasil’ev; K. Yu. Kalitin; A. A. Spasov; O. Yu. Grechko; V. V. Poroikov; D. A. Filimonov; V. A. Anisimova (775-780).
Anticonvulsive activities of some condensed imidazo[1,2-a]benzimidazole derivatives were predicted using PASS software. Benzimidazoles as a class showed promise as sources of anticonvulsants. Several compounds demonstrated various levels of anticonvulsive activity in the corazole-induced seizure model (75 mg/kg, s.c.). The most promising compounds (laboratory codes RU-1205, RU-285, RU-1204, and RU-1203) at a dose of 10 mg/kg (i.p.) showed high levels of anticonvulsive activity comparable with that of reference valproic acid (130 mg/kg, i.p.) at a molar ratio of ~1:30. The Free—Wilson model was used to describe quantitative structure—activity relationships in order to evaluate contributions of substituents or structural fragments to the anticonvulsive activity of the parent structure. Four pharmacophore patterns that favored high anticonvulsive activity among imidazo[1, 2-a]benzimidazole derivatives were found using IT Microcosm.
Keywords: benzimidazole; corazole; screening; anticonvulsive activity; anticonvulsants; valproic acid; epilepsy; PASS system; IT Microcosm; Free—Wilson method; pharmacophores

Potential Synthetic Adaptogens. II. Synthesis and Pharmacological Activity of New Conformationally Labile Bromantane Analogs, N-[(Adamantan-1-YL)Methyl]-4-Bromoanilines by A. S. Babushkin; M. B. Navrotskii; I. A. Novakov; B. S. Orlinson; M. D. Robinovich; D. S. Sheikin; S. N. Voloboev (781-787).
New structural analogs of bromantane with greater conformational lability than the prototype were synthesized. Their physiological activity profiles were assessed in vivo. It was found that the analogs could be prepared under much milder conditions than bromantane and that their biological activity profiles dependedstrongly on the nature of adamantane substitution.
Keywords: synthetic adaptogens; bromantane; N-[(adamantan-1-yl)methyl]-4-bromoanilines

Synthesis and Pharmacological Properties of Linear Poly(Ethylene Glycol)s Conjugated to Interferon α-2b by Azo Coupling by S. V. Sheremet’ev; D. V. Lonshakov; S. A. Korovkin; E. M. Belosludtseva; A. V. Katlinskii; A. V. Semchenko; O. V. Borisova (788-793).
A method for the preparation of pharmacologically active conjugates of interferon α-2b with poly(ethylene glycol)s that absorbed in the visible spectral range was proposed. New covalent conjugates of linear poly(ethylene glycol)s with interferon α-2b were prepared via diazotization of 4-aminobenzoic acid poly(ethylene glycol) esters followed by azo coupling of the obtained diazonium salts with histidine imidazoles and tyrosine phenols of the protein amino-acid chain. The synthesized conjugates retained a high degree of interferon α-2b antiviral activity in vitro and had longer blood circulation times than a foreign analog and very low acute toxicity and immunogenicity.
Keywords: interferon α-2b; pegylation; diazotization; azo coupling; pharmacokinetics

1-R-3-Methyl-6-methoxy-7-(n-propoxy)-3,4-dihydroisoquinolines were synthesized via cyclocondensation of O-n-propyleugenol with various nitriles. It was shown that the hydrochlorides of the synthesized compounds exhibited anthelmintic and weak insecticidal activity. The isoquinoline containing a 1-benzyl radical had the greatest anthelmintic activity and was more potent than pyrantel and imidacloprid.
Keywords: cyclocondensation of O-n-propyleugenol with nitriles; 1-R-3-methyl-6-methoxy-7-(n-propoxy)-3,4-dihydroisoquinoline hydrochlorides; anthelmintic and insecticidal activity

Antiproliferative Activity of Cyano-Substituted Pyrans and 1,2,5,6,7,8-Hexahydroquinoline-3,3,4,4-Tetracarbonitriles by M. A. Mar’yasov; V. P. Sheverdov; V. V. Davydova; O. E. Nasakin (798-799).
The antiproliferative activity of methyl-6-amino-3-acyl-4-aryl-5-cyano-4H-pyran-2-carboxylates, 9-aryl-12-imino-10,11-dioxatricyclo[5.3.2.01, 6]dodecane-7,8,8-tricarbonitriles, and 1,2,5,6,7,8-hexahydroquinoline-3,3,4,4-tetracarbonitriles was investigated.
Keywords: methyl-6-amino-3-acyl-4-aryl-5-cyano-4H-pyran-2-carboxylates; 9-aryl-12-imino-10,11-dioxatricyclo[5.3.2.01 ; 6]dodecane-7,8,8-tricarbonitriles; and 1,2,5,6,7,8-hexahydroquinoline-3,3,4,4-tetracarbonitriles; tetracyanoethylene; arylidenemalononitriles; antiproliferative activity

Binary Classification of CNS and PNS Drugs by D. E. Polianchik; V. Yu. Grigor’ev; G. I. Sandakov; A. V. Yarkov; S. O. Bachurin; O. A. Raevskii (800-804).
Stable classification predictive models of 626 drugs acting on the central (CNS) and peripheral (PNS) nervous systems were constructed based on linear discriminant analysis, logistic regression, random forest, and support vector machine methods with physicochemical descriptors characterizing the steric factors, electrostatic interactions, and H-bonding features. Internal cross-validations demonstrated that these models possessed satisfactory statistical properties.
Keywords: QSAR; CNS; PNS; binary classification; HYBOT

Phytochemical and Pharmacological Vectors from Malva Sylvestris L. for application in Dermatological Practice by I. I. Terninko; O. D. Nemyatykh; Z. B. Sakipova; E. V. Kuldyrkaeva; U. E. Onishschenko (805-809).
The composition of phenolic constituents from common mallow leaves was studied by HPLC. Total flavonoids and hydroxycinnamic acids were determined quantitatively as 2.97 ± 0.08% and 2.84 ± 0.03%, respectively. Luteolin (96.12 mg/100 g) and chlorogenic acid (51.04 mg/100 g) dominated the extracted phenolic compounds. Pharmacological tests (acute exudative inflammation model, wound-tensiometry on linear incised wound model, Nesterov test) were conducted. It was established that a gel with mallow extract applied to animals with inflammatory pathologies decreased statistically significantly as compared with a control the inflammation index and exudation rate. The complex of phenolic compounds may have been responsible for this. Reparative, capillary-protective, and hydrating effects of the plant extract were also found. The obtained results provided experimental justification for treating inflammatory pathologies with mallow leaves and using this plant to treat dermatological diseases. The prerequisites for developing dosage forms from common mallow extract and introducing it into official medicine have been created.
Keywords: common mallow leaves; phenolic constituent composition; pharmacological research; dermatology

The carbohydrate compositions of the hydrophilic fractions of homeopathic matrix tinctures of two snowdrop species were studied. The qualitative compositions and quantitative contents of free (D-sucrose, D-glucose, D-fructose) and bound (D-arabinose, D-galactose, D-xylose, D-glucose, D-mannose) sugars in homeopathic matrix tinctures of Galanathus woronowii Losinsk. and G. nivalis L. were determined.
Keywords: homeopathic matrix tincture; Galanthus woronowii L; Galanthus nivalis L; carbohydrates

Planning Bioequivalence Studies of Drugs with Narrow Therapeutic Indices by D. P. Romodanovskii; D. V. Goryachev; Yu. V. Olefir; N. D. Bunyatyan (814-816).
The principles for assessing therapeutic equivalence based on bioequivalence studies as accepted in Russia are significantly different from those adopted abroad, in particular with respect to drugs with narrow therapeutic indices (NTI). Certification of these drugs based on bioequivalence studies with commonly recognized limits is unacceptable in practice because drugs in this concentration range can cause serious adverse side effects and be more dangerous than the reference drug. The situation becomes especially critical when the reference drug is replaced by a generic. This circumstance creates the need to develop stricter regulations for NTI drugs. This article analyzes possible approaches to planning bioequivalence investigations for NTI drugs as adopted by leading world regulatory institutions in order to harmonize them with bioequivalence studies of NTI drugs in the Russian Federation. General recommendations for planning bioequivalence studies of NTI drugs were formulated based on the analysis.
Keywords: bioequivalence; generic drugs; narrow therapeutic index; narrow therapeutic index drugs

Electrochemical Synthesis of Cellulose Mesylates by Sh. Sh. Khidirov; Kh. S. Khibiev; M. A. Akhmedov (817-819).
Results of voltammetric measurements and analysis of cellulose electrochemical oxidation products from preparative electrolysis established that esters, i.e., cellulose mesylates, were formed.
Keywords: cellulose; mesylates; electrochemical oxidation

Gelatin is usually used as an excipient in drug preparations and more rarely as an active ingredient. Domestic quality standards regulating gelatin used in drug production were enacted over 20 years ago. A comparative analysis of quality requirements for gelatin in domestic and foreign pharmacopoeias seemed timely in order to justify national pharmacopoeial quality requirements for gelatin (quality parameters, analysis methods, norms) and to compose a pharmacopoeial monograph for gelatin in the RF State Pharmacopoeia.
Keywords: gelatin; pharmacopoeial quality standards; gelatin quality control methods

Crystal and Molecular Structures of Methylcytisine Nitro-Derivatives by A. F. Smol’yakov; V. A. Karnoukhova; S. V. Osintseva; P. R. Petrova; A. V. Koval’skaya; I. P. Tsypysheva (826-832).
Crystal structures of the two isomers N-methyl-11-nitro- and N-methyl-9-nitrocytisine (I and II) were investigated in detail using a combination of x-ray crystal structure analysis and quantum-chemical calculations. The unit cells of both isomers contained two symmetrically independent molecules. This fact was explained and reasons for the very substantial differences in the densities and melting points of crystals of the isomers were discussed.
Keywords: nitromethylcytisine; crystal packing; x-ray crystal structure analysis; quantum chemistry

Certification of Human Immunoglobulin Standard Samples for Determination of Anticomplementary Activity by M. A. Krivykh; O. G. Kornilova; N. D. Bunyatyan; E. V. Paramonova; É. Yu. Kudasheva; E. V. Novikova; O. B. Ustinnikova; R. A. Volkova; O. V. Fadeikina (833-836).
An evaluation and stability study of the original Russian human immunoglobulin standard intended for determining the anticomplementary activity and assessing the stability and acceptability of test results are reported. The certified values of the experimental anticomplementary activity of the negative control standard fell in the range 37.9 – 45.1%; of the positive control, 73.6 – 82.8% (for P = 0.95). Ashelf life of 1.5 years was justified based on the stability data of the standard sample. Introduction of the certified reference materials into the analysis of human immunoglobulin pharmaceutical preparation for intravenous administration during evaluation and quality control under government projects and confirmation of compliance with regulatory requirements will ensure that the determined anticomplementary properties are accurate.
Keywords: standard sample; certification; human immunoglobulins; anticomplementary activity

Drug Development and Analysis Review by SK Manirul Haque; Elaref S. Ratemi (837-850).
The drug discovery has now evolved into a much more scientific and rational process due to better understanding of biological processes and the underlying chemistry, owing to the progress made due to advances in high throughput experimental techniques and availability of high performance computation resources. The process has matured to the stage where drugs are designed rather than being discovered. The development and validation of analytical methods play important roles in the discovery, development, and manufacture of pharmaceuticals. Method development is the process of proving that an analytical technique is acceptable for use to measure the concentration of an active pharmaceutical ingredient (API) in a particular compound dosage form. This allows simplified procedures to verify that a proposed analytical method will accurately and consistently perform reliable measurements of APIs in a given drug preparation. The validation of analytical method is essential for its development, whereby it is extensively tested for specificity, linearity, accuracy, precision, range, limit of detection, limit of quantitation, and robustness. Thus, the development and validation of analytical methods allows one to confirm that accurate and reliable measurement of the potency a pharmaceutical preparation can be performed. The present review highlights the process of drug development, its phases, and analytical methods, including chromatographic, spectroscopic, and electrochemical techniques, which have been applied in the analysis of pharmaceuticals.
Keywords: drug discovery; drug analysis

Studying Newly Synthesized and Developed 4-Hydroxy-3-Methoxybenzaldehyde Schiff Bases by UV Spectrophotometry and High Performance Liquid Chromatography by Sridevi Chigurupati; Selvadurai Muralidharan; Lim Sue Cin; Wei Yin Raser; Kumaraswamy Santhi; Krishnan Selvarajan Kesavanarayanan (851-856).
Green synthesis is the design of chemical products and processes that reduces or eliminates the use and generation of hazardous substances. Schiff bases of 4-hydroxy-3- methoxybenzaldehyde (vanillin) were prepared using various aromatic amines and base catalyst in the presence of aqueous media. High performance liquid chromatography (HPLC) and ultraviolet (UV) spectrophotometry methods were developed for qualitative study of the synthesized 4-hydroxy-3- methoxybenzaldehyde Schiff bases. HPLC was carried out by reversed phase on a C18 column with a mobile phase composed of acetonitrile and 0.5% triethyl amine (pH 4.5 adjusted with orthophosphoric acid (60:40, v/v)). UV measurements were performed at λmax 286 nm for compound V1 ((E)-4-(4-hydroxy-3-methoxybenzylideneamino)benzoic acid), λmax 336 nm for compound V2 ((E)-4-(4-hydroxy-3-methoxybenzylideneamino)phenol), and λmax 320 nm for compound V3 ((2-methoxy-4-(E)-(phenylimino)methyl)phenol). Both the HPLC and UV methods showed good reproducibility and precision and were successfully applied to study 4-hydroxy-3- methoxybenzaldehyde derivatives. The standard de-viations of relative peak area and retention times for 4-hydroxy-3-methoxybenzaldehyde derivatives were within 2% indicating the suitability of the system. The proposed economical methods can be applied for rou-tine analysis of 4-hydroxy-3-methoxybenzaldehyde derivatives of any type.
Keywords: benzaldehyde derivatives; green synthesis; vanillin; Schiff bases; UV; HPLC, method development

This work was aimed to study the controlled drug delivery behavior of phthalic anhydride based hyperbranched polyesteramide (PA-HBPEA) synthesized by self-polycondensation method under nitrogen atmosphere. Drug-loaded microspheres were prepared by oil-in-water (o/w) emulsion solvent evaporation methodology using acetaminophen as a model drug and PA-HBPEA as the matrix. The polymer and microspheres were characterized by UV-Vis, FTIR and 1H NMR spectroscopy techniques. The morphology was observed by scanning electron microscopy (SEM) and optical microscopy. The drug loading capacity, drug entrapment efficiency, and percentage drug release were also measured by the UV-Vis spectroscopy. FTIR and NMR results confirmed the formation of drug-loaded PA-HBPEA microspheres. An in-vitro drug release study was carried out to understand the nature of transport of drug-containing solution through the polymeric material. The potential of high content of HBPEA formulation (HBPEA-M2) was controlled drug release more (up to 60.3%) than HBPEA-M1 (up to 76.8%) with acidic and phosphate buffer medium at 37°C at various time intervals. Drug release kinetics of zero order Higuchi and Korsmeyer – Peppas models were found to be satisfactory with exponent n > 0.6, which shows non-fickian diffusion release. The average size of microspheres was found to be 50 μm. In-vitro drug release data showed that HBPEA has potential of controlled drug release in phosphate buffer medium.
Keywords: hyperbranched polyesteramide; self-polycondensation; microspheres; in-vitro drug release; acetaminophen