Vol 53, No 6 (2019)

Dimeric dipeptide mimetic GK-2 or hexamethylenediamide bis-(N-monosuccinyl-L-glutamyl-L-lysine), which activated TrkA receptors and exhibited neuroprotective activity in vitro (10^–5 – 10^–9 M) and in vivo (0.05 – 5 mg/kg i.p.), was designed by us earlier based on the beta-turn of the nerve growth factor (NGF) fourth loop. The effect of dimerizing spacer length on the manifestation of neuroprotective activity was studied by synthesizing GK-2 (11 σ-bonds) analogs tetramethylenediamide bis-(N-monosuccinyl-L-glutamyl-Llysine) (GK-2c); pentamethylenediamide bis-(N-monosuccinyl-L-glutamyl-L-lysine) (GK-2b); and trimethylenediamide bis-(N-monosuccinyl-L-glutamyl-L-lysyl-6-aminohexanoic acid) (GK-2a) containing 9, 10, and 22 σ-bonds, respectively, between the lysine C_α-atoms of the dipeptide fragments. Neuroprotective activity was investigated in vitro using HT-22 mouse hippocampal neuronal cell culture under H₂O₂-induced oxidative stress and showed that the neuroprotective activity as measured by the minimum effective concentration was 104 times less if the distance between the dipeptide fragments increased from 11 to 22 σ-bonds. The neuroprotective activity decreased insignificantly if this distance was decreased from 11 to 10 σ bonds (GK-2b) and disappeared with 9 σ -bonds (GK-2c). Therefore, the hexamethylene spacer was optimal although the distance between the corresponding amino-acid moieties of natural NGF from an x-ray structure analysis was considerably greater at 33 σ-bonds. This contradiction could have arisen because two ionically bound mimetic molecules interacted with TrkA receptors. Another possible explanation was that TrkA molecules could approach closer in the presence of bis-dipeptide GK-2 than NGF.

Methods were developed for synthesizing new substituted piperazine derivatives from chloropyrano- [3,4-c]pyridines. Pharmacological screening of the synthesized compounds used the well-known corazole antagonism and open field tests. The rotating rod test was used to evaluate the neurotoxicity of the compounds. The tested compounds displayed neurotropic activity. Several compounds of this series exhibited pronounced anticonvulsant and anxiolytic activity.

[3,3-Dialkyl-3,4-dihydroisoqinolin-1(2H)-ylidene]-N-alkylacetamides were synthesized by reacting dialkylbenzylcarbinols with N-alkylcyanoacetamides. Hydrochlorides of the synthesized compounds existed in the imine form. All hydrochlorides showed antiarrhythmic and coagulant (hemostatic) effects. An amide with an unsubstituted amide N atom and a 3-spiro-cyclopentyl moiety was the most active compound with antiarrhythmic activity 2.8 times that of lidocaine and blood coagulation accelerated by 37.9%, which was 21.9% faster than etamsylate.

A series of esters of ferulic acid and alcohols were synthesized and characterized structurally. All tested synthetic compounds were more cytotoxic against HCT116 cell line (human colon carcinoma) than ferulic acid. Benzyl and phenylethyl esters of ferulic acid were the most active compounds (IC₅₀ = 0.0077 and 0.0065 g/L, respectively). Feruloylated wheat-bran oligosaccharides were less active than free ferulic acid against HCT116 tumor cells.

In this study, iron oxide (Fe₃O₄) nanoparticles were synthesized using the Massart co-precipitation method followed by surface coating with dextran. Next, coated magnetic nanoparticles (MNPs) were functionalized by diclofenac and dopamine attachment to the surface. The kinetics of release of these drugs was studied at various temperatures and pH of the medium. Concentrations of the released drugs were measured in vitro by spectrometric methods, and the mechanism of drug release from MNP carrier was analyzed in terms of the Korsmeyer – Peppas model. According to the results, the amount of released diclofenac and dopamine depended on the conditions, namely, temperature and pH of the medium. The values of the diffusion exponent n obtained for diclofenac suggest a Fickian diffusion mechanism, while the mechanism of dopamine diffusion was anomalous. These results were compared to those obtained previously for ibuprofen. The current results demonstrate differences in the mechanism of drug release under exposure to diverse environmental conditions.

We have evaluated the antiproliferative activity of (E)-3-(3,5-difluorophenyl)-1-(2,4,6-trimethoxyphenyl)- prop-2-en-1-one (chalcone 5) against MGC-803 cells. This chalcone analog displayed a potent antiproliferative activity with an IC₅₀ value of 0.23 μM against MGC-803 cells. It could induce apoptosis and regulate the apoptosis-related markers (Bax, Bcl-2, Bcl-xl, and Bid) in a concentration dependent manner. Treatment with NAC almost completely attenuated chalcone-induced cell inhibition and cell apoptosis in MGC-803 cells, indicating that the apoptotic mechanisms were related to ROS generation. Therefore, this chalcone derivative is a new apoptosis inducer for prevention and treatment of gastric cancer.

Modern antimicrobial preservatives authorized for use in dosage form technology are reviewed. The nomenclature and various classifications of preservatives according to chemical nature, mechanism and spectrum of antimicrobial action, optimum effective concentrations for antimicrobial activity, and separate factors affecting the activity of antimicrobial preservatives in various dosage forms, e.g., optimum solution pH values and specific adsorbents reducing preservative activity, are presented. Antimicrobial preservatives used widely in pharmaceutical technology, i.e., parabens, sorbic acid and its salts, benzoic acid and its salts, and benzalkonium chloride, are discussed in detail. Ascience-based approach to selecting antimicrobial preservatives is shown to produce the most stable and safest medicines.

A simple, selective, precise and stability-indicating high-performance liquid chromatography (HPLC) method for the determination of rifampicin in the parent drug substance and drug products was developed and validated as per the current ICH guidelines. The analysis was achieved isocratically on Phenomenex Luna C₁₈ column (5 μm; 250 × 4.6 mm) utilizing a mobile phase consisting of a mixture of formic acid buffer, pH adjusted to 4.5, and acetonitrile (55:45 v/v) at a flow rate of 1.5 mL min^-1 with UV detection at 235 nm. The retention time was 3.5 min. The linear regression analysis for calibration plot showed good linear relationship with r₂ = 0.9999 with respect to peak area in the concentration range 5 – 250 μg mL^-1. The limits of detection and quantification were 3.0 and 9.2 μg mL^-1, respectively. The method was validated for precision, accuracy, selectivity, recovery, robustness and ruggedness. The intra-day and inter-day accuracy expressed as % relative error were better than 2%. The precision determined and expressed as % relative standard deviation did not exceed 0.5%. Rifampicin was subjected to acid and alkali hydrolysis, oxidation, photo degradation and dry heat treatment. The drug was found to undergo complete degradation under acid-, base-, and oxidation-induced stress conditions, but was stable under other stress conditions. The method was applied to commercial drug capsules and showed highly satisfactory results.

The physicochemical and technological properties of Lycopus europaeus dry herbal extract were studied. Excipients were also selected. The technological characteristics of experimental samples containing L. europaeus dry herbal extract were studied. Stepwise mixing of drugs and excipients was proposed to prepare capsules. The results showed that a formulation in which lactose monohydrate, AEROSIL^® A380, and vegetable magnesium stearate were used as excipients had the optimal technological characteristics.

Various extraction methods are reviewed. Their advantages and disadvantages are discussed. Traditional and modern extraction methods are compared.

A potentiometric benzylpenicillin-sensitive sensor with a plasticized polyvinyl-chloride membrane was developed. The sensor contains a benzylpenicillin—rhodamine 6G ion pair. The response is linear for benzylpenicillin concentrations in the range 10^–3 – 10^–1M with an electrode-function slope characteristic of singly charged anions and a minimum detected concentration of (6.3 – 7.9) × 10^–4 M. This sensor could be used to detect and determine benzylpenicillin in pharmaceuticals.