Pharmaceutical Chemistry Journal (v.51, #2)

Web Resources for Discovery and Development of New Medicines by V. M. Bezhentsev; D. S. Druzhilovskii; S. M. Ivanov; D. A. Filimonov; G. N. Sastry; V. V. Poroikov (91-99).
Modern drug discovery is based on the analysis of information about disease mechanisms, molecular targets, and pharmacological substances, the action of which helps to normalize pathological processes. Existing chemical and biomedical databases have recently been supplemented with many specialized computational resources that provide the means to estimate physicochemical properties, biological activity, toxicity, metabolism, and other characteristics of organic molecules in the early stages of drug development. Easy access to this information via the Internet expands significantly the opportunities for an investigator and, at the same time, poses the problem of selecting the information and computational resources most appropriate to the tasks at hand. This paper provides an overview of biomedical and chemical web resources freely available via the Internet and gives recommendations on their optimal use at various stages in the research and development of safer and more effective medicines.
Keywords: new drugs; drug discovery and development; biomedical and chemical databases; computational web resources; Internet

The substituted carbazole drug PLX01107 is being developed for the treatment of invasive pulmonary aspergillosis. A synthetic method for PLX01107 drug substance was developed in order to produce the required amount of drug substance of a quality suitable to support preclinical trials. An analytical method using HPLC-MS/MS was employed to determine the drug concentration in whole blood and internal organs. Preclinical trials of the new drug found that PLX01107 possessed linear pharmacokinetics in the i.v. dose range 5 – 20 mg/kg in CD-1 mice. Pharmacokinetic modeling determined the optimum i.v. dose regime for attaining the maximum effective concentration as a loading dose of 5 mg/kg with a maintenance dose of 5 mg/kg every 12 h. Analysis of the PLX01107 content in various organs found that lungs of test animals had the maximum concentrations after both i.v. and oral administration. This gave the developed drug a considerable advantage with respect to targeted delivery of the active ingredient.
Keywords: PLX01107; carbazole derivatives; synthesis; pharmacokinetics; biodistribution

Synthesis and Pharmacological Activity of Some α-Aminoketone Hydrochlorides by G. A. Gevorgyan; N. K. Gasparyan; O. A. Papoyan; D. A. Avakimyan; A. A. Tatevosyan; H. A. Panosyan (107-110).
New α-bromoethanones were synthesized by bromination of 1-[4(3,4)-substituted phenyl]-2-phenyl[3(4)-substituted phenyl]ethanones and were reacted with various amines in Et2O to produce the corresponding 1-[4-alkoxyphenyl(3-bromophenyl)]-2-phenyl-[3(4)-halophenyl]-2-aminoethanones. It was shown that the synthesized compounds possessed moderate antibacterial and pronounced peripheral n-cholinolytic activity.
Keywords: bromination; α-bromoethanones; α-aminoketones; antibacterial and peripheral n-cholinolytic activity

Preparation and Antiproliferative Activity of Glucose – Acetylsalicylic Acid Conjugate by Gangliang Huang; Hui Gao; Chengkun Yi; Yanqiu Ai; Dan Huang (111-114).
In this work, acetylsalicylic acid was used as the lead compound and its structure was modified by glycosylation. Glucose-based acetylsalicylic acid conjugate was prepared by using α-D-glucopyranosyl bromide as glycosyl donor and acetylsalicylic acid as acceptor. The proposed experimental procedure is simple and reproducible, providing a high yield and having great practical value. It is shown by MTT method that the glycosylated acetylsalicylic acid can inhibit in dose-dependent manner the proliferation of cancer cells.
Keywords: acetylsalicylic acid; glycosylation; conjugate preparation; antiproliferative activity

Synthesis, Characterization and Antibacterial Screening of Diorganotin(IV) Complexes Derived From 2-[(4-Dimethylamino-Benzylidene)Amino]Phenol by Wajid Rehman; Sirajul Haq; Fazal Rahim; Salimullah Khan; Muhammad Waseem; Mohsan Nawaz; Obaid-Ur-Rahman Abid; Muhammad Tauseef Qursehi; Cun-Yue Guo (115-118).
Five organotin complexes have been derived from a Schiff base, 2-[(4-dimethylamino-benzylidene)amino] phenol. The synthesis of target compounds is confirmed by spectroscopic techniques: IR, 1H NMR, and 13C NMR. Activity of the initial Schiff base and its complexes has been tested with respect to various bacterial strains, and the results obtained are quite promising against both Gram-positive and Gram-negative bacteria.
Keywords: 2-aminophenol; 4-(dimethylamino)benzaldehyde; Schiff base, antibacterial activity

New Flavonoids from Serratula coronata L. by A. V. Myagchilov; L. I. Sokolova; P. G. Gorovoi; P. S. Dmitrenok (119-123).
The composition of flavonoids (glycosides) isolated from leaves of Serratula coronata L. s. l. (crowned saw-wort) growing in Primorsky Krai was investigated. Liquid extraction and preparative column chromatography isolated for the first time the flavonoids 3-methylquercetin-3′-O-β-D-glucuronopyranoside [5-(5,7-dihydroxy-3-methoxy-4-oxo-4H-chromen-2-yl)-2-hydroxyphenylhexopyranosideuronic acid] and quercetin- 3′-O-β-D-glucuronopyranoside [2-hydroxy-5-(3,5,7-trihydroxy-4-oxo-4H-chromen-2-yl)phenylhexopyranosideuronic acid]. The structures of the isolated compounds were elucidated and proved using UV and NMR spectroscopy and mass spectrometry with electrospray ionization. The flavonoid 3-methylquercetin-3′-O-β-D-glucuronopyranoside was new and not previously described in the literature. S. coronata grows abundantly in Primorsky Krai and could be considered a renewable and promising source for producing flavonoids.
Keywords: Serratula coronata ; flavonoids; UV spectroscopy; NMR spectroscopy; mass spectrometry

Flavonoid Content in the Aerial Part of Saussurea Controversa DC (Asteraceae) by E. Yu. Avdeeva; E. A. Krasnov; A. A. Semenov (124-125).
A method for spectrophotometric determination of the flavonoid content in the aerial part of Saussurea controversa DC was developed. The amount of flavonoids calculated as rutin varied from (0.37 ± 0.07) to (0.73 ± 0.02)% depending on the collection year and storage time.
Keywords: Saussurea controversa DC; rutin; spectrophotometric determination

Determination of Organic Impurities in Combination Drugs by O. A. Matveeva; E. L. Kovaleva (126-129).
Methodological approaches to the control of organic impurities in drugs containing two and more active pharmaceutical ingredients are reviewed. Approaches of leading foreign pharmacopoeias (British, USA, Japanese) to assessing impurity profiles in combination drugs are analyzed. The methods for assessing impurities that carry the largest safety risks for combination drugs are determined. It is demonstrated that a unified approach to the control of organic impurities in combination drugs is needed.
Keywords: impurity profile; combination drugs; leading foreign pharmacopoeias

Development of Analytical Methods for Peroral Prolonged-Release Nimesulide Gel by E. O. Bakhrushina; M. N. Anurova; V. V. Smirnov; N. B. Demina (130-135).
Analytical methods were developed and results were presented for the authenticity, quantitation, and dissolution test of the new nimesulide dosage form peroral prolonged-release gel. The validation and metrological characteristics of the quantitative analytical methods for nimesulide were described.
Keywords: nimesulide; HPLC; dissolution test

Establishment of Pharmacopoeial Quality Standards for the State Pharmacopoeia of the Russian Federation by E. I. Sakanyan; T. B. Shemeryankina; I. G. Osipova; T. M. Kargina; L. I. Shishova; A. V. Barmin; A. P. Orlov; M. N. Lyakina; N. S. Tereshina (136-141).
Scientific research enabled the formulation of methodological approaches to the standardization of biological, herbal, and homeopathic drugs and their analytical methods included in the Russian Federation State Pharmacopoeia XIIIth Ed. The developed General Pharmacopoeial Articles and Pharmacopoeial Articles are fundamental elements of the standardization of medicines circulated on the Russian Federation pharmaceutical market.
Keywords: pharmacopoeia; pharmacopoeial monograph; analytical methods

An HPLC method with mass-spectrometric detection was developed for simultaneous quantitative determination of chlormadinone acetate and ethinyl estradiol in human blood plasma. The sample preparation method included liquid—liquid extraction using hexane—Et2O. The method was validated for selectivity, linearity, accuracy, precision, cross-transfer, and stability. The developed method enabled simultaneous determination of the chlormadinone acetate and ethinyl estradiol blood concentrations in volunteers and could be used for pharmacokinetics studies.
Keywords: chlormadinone acetate; ethinyl estradiol; HPLC; validation

Asimple, rapid isocratic liquid chromatography method was developed for the simultaneous determination of diphenhydramine, promethazine, chlorpheniramine, and ephedrine in cold-cough syrups commonly available in the Kenyan market. The influence of the percentage of organic modifier, ion pairing agent, buffer concentration as well as pH and column temperature on the selectivity with respect to analytes was investigated. Optimum chromatographic separation was achieved using a C18 Gemini® NX column (250 mm × 4.6 mm, 5 μm) maintained at 40°C and a mobile phase comprising methanol – triethylamine – 0.2 M ammonium acetate pH 5.0 – water mixture (50 : 0.15 : 40 : 9.85, v/v) delivered at a flow rate of 1.0 mL/min. Upon validation, the proposed liquid chromatography method satisfied the International Committee on Harmonization acceptance criteria for linearity, sensitivity, precision, and robustness. The method was applied in the analysis of commercial samples obtained from Nairobi County, Kenya. The method can be used in routine analysis of cold-cough syrups containing the specified compounds.
Keywords: diphenhydramine; promethazine; chlorpheniramine; ephedrine, cold-cough syrups

Validation of HPLC Method for Quantitative Determination of Gefitinib in Polymeric Nanoformulation by Navya Sree KS; Girish Pai K; Ruchi Verma; Padiyar Ananthakrishna; Lalit Kumar (159-163).
Gefitinib was determined quantitatively in a nanoformulation using the proposed HPLC method. Effective elution was achieved by using a stationary phase of HyperClone (Phenomenex®) C18 column (250 mm × 4.6 mm i.d., 5 μm, BDS 130 Å) and a mobile phase composed of acetonitrile and 40 mM ammonium formate buffer pH 2.5 (30 : 70, %v/v) at a flow rate of 1.0 mL/min. The samples were measured at 248 nm using UV detector. The column temperature was kept at 25°C; the run time was 7 min; the injection volume was 20 μL. Gefitinib was separated within 4.476 min. The correlation coefficient for the obtained calibration curve was found to be 0.998. The method was validated according to ICH Q2 (R1) guidelines for linearity, sensitivity, robustness, accuracy and precision. The LOD and LOQ were found to be 37.852 and 114.702 ng/mL, respectively.
Keywords: gefitinib; polymeric nanoformulation; HPLC; method development; method validation