Vol 52, No 1 (2018)

A series of new coumarin-6-sulfonamides have been synthesized as potential antibacterial agents. The reaction of coumarin with chlorosulfonic acid was found to yield the corresponding coumarin sulfonyl chloride (1). In the next step, coumarin sulfonyl chloride, was reacted with various amines in the presence of K₂CO₃ under solvent-free conditions to produce coumarine sulfonamides (2a – 2s) in good to excellent yields. The chemical structures of the products were elucidated by IR, ¹H NMR, and ¹³C NMR spectroscopy and elemental analysis. All the synthesized compounds have been screened for their in vitro anti-bacterial activities against Escherichia coli and Staphylococcus aureus bacteria.

P-glycoprotein (P-gp) mediated efflux affects the pharmacokinetics of several drugs. By analogy to verapamil, 1,4-dihydropyridines (DHPs) have been widely studied as P-gp inhibitors. Previously, we have reported on two new DHPs: IA₁(A) and IIA₅(B) as inhibitors of human MRP1, an efflux protein closely related to P-gp. The aim of the present study was to investigate the inhibitory effects of these two compounds on intestinal P-gp using the method of in situ single-pass intestinal perfusion (SPIP) in rat. According to this, the intestinal absorption of zidovudine (a P-gp substrate) was studied in anaesthetized rat jejunum in the absence and presence of DHPs IA₁(A) and IIA₅(B) (2 mg/kg). Verapamil (0.8 mg/kg), a well-known P-gp inhibitor, was employed as a standard. Zidovudine solution (200 ig/mL) in phosphate buffer (pH 7.4) was perfused through the jejunal segment, the perfusate concentrations were quantified by HPLC, and the permeability coefficient (P_eff) and fraction absorbed (F_abs) were calculated. Phenol red was used as a non-absorbable marker to correct water flux through the segment. In rats pretreated with compounds IA₁ and IIA₅, P_eff and F_abs of zidovudine were found to be 0.1669 ± 0.12 cm/sec, 0.2035 ± 0.18 and 0.2798 ± 0.12 cm/sec, 0.3015 ± 0.14, respectively, and were comparable to those of the standard (P_eff = 0.462713 ± 0.3 cm/sec, F_abs = 0.511835 ± 0.14). The differences between IA₁, IIA₅ and the standard were evaluated using ANOVA and found to be statistically significant (P < 0.05). Compounds IA₁ and IIA₅ have a modulating effect on intestinal P-gp. Compound IIA₅ was relatively more potent P-gp inhibitor and, quite interestingly, the results were in agreement with our earlier in silico and in vitro studies.

Hydrophobic β-cyclodextrin polymer nanofibers were obtained by the electrospinning of peracetyl-β-cyclodextrin polymer (AcβCDP) from acetone : DMF (3 : 2 v/v) solution. The morphology of AcβCDP nanofibers was studied by scanning electron microscopy. The proposed novel hydrophobic β-CD polymer was synthesized through reaction of water-soluble β-CD polymer crosslinked with epichlorohydrin (β-CD-ECH polymer) and acetic anhydride in the presence of pyridine. The peracylation of β-CD-ECH polymer is verified by FT-IR and solubility data. The final part of this study is focused on incorporating vitamin B₂ (VB₂) into the AcβCDP nanofiber. In vitro release of VB₂ from AcβCDP/VB₂ nanofiber in model physiological media was investigated; the results exhibited initial burst and then slow drug release. The release of VB₂ from AcβCDP/VB₂ nanofiber is slower than from AcβCDP/VB₂.

We present here the synthesis of 3- and 4-benzoylpyridine oxime derivatives with potential anticonvulsant action. The most active compound in the maximum electric shock test was 4-benzoylpyridine O-2-morpholinoethyloxime oxalate (1a), i.p. doses of 60 – 150 mg/kg of which increased the survival of mice to 100%. The best effect in the corasol antagonism test was obtained with 4-benzoylpyridine O-(isonicotinoyl)oxime (2c), i.p. doses of 12.5 mg/kg of which increased the survival of mice to 67% and the latent period of onset of generalized tonic-clonic convulsions to 52 sec. Compound 1a had low toxicity (the i.p. LD₅₀ in mice was 316 mg/kg) and a therapeutic index of 21.

In this study, chemical compositions of the essential oil and antioxidant activities of four Satureja species, namely S. hortensis (SH), S. bachtiarica (SB), S. laxiflora (SL), and S. intermedia (SI) were evaluated. GC and GC/MS were employed to analyze the essential oil samples extracted via hydrodistillation. DPPH and FRAP assays were used to evaluate the radical scavenging and antioxidant properties as well as antimicrobial activities. The GC and GC/MS analysis revealed and identified a total of 25 compounds. The most abundant chemical constituents were ρ-cymene (13.07 – 17.50%) in all four species, γ-terpinene in SL, SH, and SI (11.35 – 37.60%), thymol in SL, SB, and SI (24.54 – 38.75%), and carvacrol in SB and SH (32.07 – 42.51%). The FRAP assay showed that none of the methanol and dichloromethane extracts possessed significant antioxidant activity as compared to quercetin. In addition, the radical scavenging activity of SB and SI methanol extracts were higher than that of SL and SH (DPPH assay). However, all extracts did not show potent radical scavenging activities. It should be noted that this study was the first to evaluate the possible antioxidant or radical scavenging properties of SI and SL. The antimicrobial assay demonstrated a potent activity of all samples against Escherichia coli, Staphylococcus aureus, Candida albicans, Aspergillus fumigatus, and Epidermophyton floccosum (minimum inhibitory concentrations, MIC = 0.06 – 8 μg/mL). Due to rich content of thymol and carvacrol isomers in Satureja species, they can be suggested for use in various pharmacological applications.

On the basis of WHO recommendations and the principles developed for the standardization of erythropoietins we selected one epoetin alfa pharmaceutical substances included in the State Register of Medicines as a candidate reference sample. The results of the manufacturer’s monitoring of this pharmaceutical substance complied with the requirements of the normative documentation and additional verification of identity by capillary zone electrophoresis demonstrated the presence of eight isoforms, which corresponded to the requirements of the European Pharmacopeia. Conditions for the preparation of an industrial reference sample in lyophilized form were developed. The industrial reference sample was attested in interlaboratory tests and the value of the attested property - specific activity - was 2400 IU/ampule, with confidence limits of 94.5% to 105.8%. Studies of the stability of the industrial reference sample developed here gave a shelf life of five years at a storage temperature of -20°C, with potential to extend this on the basis of stability monitoring results.

The effects of original Russian 3-hydroxypyridine and succinic acid derivatives (emoxypine, Reamberin, and Mexidol) on monoamine oxidase (MAO-A and MAO-B) activity in rat liver were studied in vitro. The study drugs used in vitro at concentrations in the pharmacokinetic range (10 9 to 10 6 M), were found to have MAO-modulating actions, the directions depending on their chemical structural properties. The isolated 3-hydroxypyridine derivative emoxypine decreased MAO-A activity by 34 – 44% and MAO-B activity by 9 – 10% (p < 0.05 in both cases). The succinic acid derivative Reamberin increased MAO-A activity by 2-3% and MAO-B activity by 14% (p < 0.05 in both cases). Mexidol, which is a derivative of both 3-hydroxypyridine and succinic acid, decreased MAO-A activity by 13% and MAO-B activity by 4% (p < 0.05 in both cases). The 2-ethyl-3-methyl-3-hydroxypyridinium cation and the succinate anion were antagonists in terms of their MAO-modulating actions. Combining these antagonist ions into the structure of Mexidol led to complete loss of the MAO-stimulating effect of the succinate part and a significant reduction in the MAO-inhibiting action of the 3-hydroxypyridine component.

We present here a review of published data mostly from the last 10 years on the antitumor activity of substances from the fungus Ganoderma lucidum. Its main biologically active components are described, particularly triterpenes, polysaccharides, glycoproteins, and proteoglycans. The mechanisms of the antitumor actions of these compounds in vitro and in vivo are discussed, these including blockade of the cell cycle, induction of apoptosis, decreases in the metastatic potential, suppression of angiogenesis, and immunomodulatory activity. The potential of using substances from G. lucidum for the treatment of oncological patients is assessed.

The effects of acetylsalicylic acid, ibuprofen, 6-methyluracil, and chondroitin sulfate impregnated in poly-(lactide-co-glycolide) scaffolds of different chemical compositions and molecular weights using supercritical carbon dioxide on the processes of scaffold degradation in phosphate-buffered saline pH 7.4 were studied and the rate constants of these processes were determined. Incorporation of acetylsalicylic acid and ibuprofen into poly(lactide-co-glycolide) scaffolds was found to produce significant increases in the rate of hydrolysis of the polymer base, while the presence of methyluracil and chondroitin sulfate had virtually no effect.

One element of ensuring the quality and safety of medicines consists of normalizing and controlling elemental impurities (heavy metals). The sources and causes of the presence of elemental impurities (heavy metals) in medicines are discussed. Changes in approaches to assessment of elemental impurities in medicines in the State Pharmacopeia and leading non-Russian pharmacopeias are discussed. A risk-oriented approach to assessing elemental impurities used in international practice is presented.