Vol 51, No 2 (2017)

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.

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.

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.

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.

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.

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.

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.

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.