Vol 53, No 9 (2019)

Efficacious antiviral analogs of viral nucleoside DNA-polymerase inhibitors are used to treat infections caused by herpes simplex virus (HSV) although their widespread use in clinical practice has caused drug-resistant HSV strains to develop. The drug substance pyrimidine-dispirotripiperazinium or 3,3-(2-methyl-5-nitropyrimidin-4,6-diyl)-bis-3,12-diaza-6,9-diazoniadispiro[5.2.5.2]hexadecane tetrachloride dihydrochloride (PDSTP) was previously synthesized by us and possessed high antiherpetic activity in vitro. The antiherpetic efficacy of the new drug substance was evaluated in vivo using a herpetic encephalitis mouse model and various treatment regimes (i.p. and peroral administration, monotherapy, combination therapy with acyclovir).

A group of new 1-(methoxybenzyl)-4-{2-[(methoxybenzyl)amino]ethyl}piperazines (1) were synthesized. The relationship of the structure of the triazaalkane linker and the cardiotropic activity in a series of these compounds was compared with that of previously studied linear and cyclic methoxyphenyltriazaalkanes. The most active compound in the group was 1e (1-(3,4,5-trimethoxybenzyl)-4-{2-[(3,4,5-trimethoxybenzyl)amino] ethyl}piperazine trihydrochloride) with statistically significant antiarrhythmic activity in aconitine and CaCl2 arrhythmia models.

Publications on the design, synthesis, pharmacological research, and clinical trials of the Russian original class III antiarrhythmic drugs nibentan {(RS)-4-nitro-N-[1-phenyl-5-(diethylamino)pentyl]benzamide hydrochloride} and niferidyl {4-nitro-N-[(1RS)-1-(4-fluorophenyl)-2-(1-ethylpiperidin-4-yl)ethyl]benzamide hydrochloride}are reviewed.

The present study was aimed at creating a combination between lower dose of sulfamethoxazole (S) as a broad-spectrum synthetic antibiotic and quercetin (Q), a natural polyphenol to decrease the antibiotic side effects and increase its antioxidant activity. Staphylococcus aureus infected animal model was studied both in vitro and in vivo in comparison to doxycycline (Dox) as standard antibiotic. The in vitro test results indicated that Q exhibited activity alone and in combination with S against tested bacterial strains, while S in low concentration was inactive. The in vivo results revealed that the S+Q combination in mice showed significant improvements in the liver and kidney functions as compared to those in the infected group or S- and Dox-treated groups. Moreover, malondialdehyde level was significantly decreased, while superoxide dismutase and catalase activities were significantly increased in the sera of (S+Q)-treated group in comparison to other treated groups. The spleen recovery in the (S+Q)-treated group was observed with the disappearance of S. aureus colonies as compared to the infected mice. In conclusion, the in vivo treatment of S. aureus infection with S+Q combination decreased the sulfamethoxazole side effects while increasing its antibacterial activity, which supported the therapeutic use of this combination in humans.

A new series of tetraoxanes were developed and screened for in vitro antimalarial activity against chloroquine sensitive strains of Plasmodium falciparum (3D7 and RKL-2) and chloroquine resistant strain of P. falciparum (RKL-9). Among the synthesized derivatives, few compounds showed mild to moderate activity against the parasites as compared to a standard drug. The test results revealed two compounds, 5a (3,3,6-trimethyl-1,2,4,5-tetraoxane) and 5k (3,3-dimethyl-6,6-diphenyl-1,2,4,5-tetraoxane) possessing significant activity against chloroquine sensitive 3D7 strain (IC₅₀ = 1.953 ± 0.020 μg/mL) and RKL-2 strain (IC₅₀ = 3.906 ± 0.010 μg/mL). At the same time, only compound 5j (3-methyl-3,6,6-triphenyl-1,2,4,5-tetraoxane) showed superior activity against chloroquine resistant RKL-9 strain (IC₅₀ = 3.906 ± 0.006 μg/mL) in in contrast to all other derivatives of the set studied. In order to elucidate the vital drug interaction with falcipain-2 (FP-2), docking studies of potent ligands were performed.

The esterification stage of low-molecular-mass heparin (enoxaparin) production by hydrolytic depolymerization of unfractionated heparin was studied and consisted of treating previously synthesized benzethonium heparinate with benzyl chloride. The content of benzyl moieties in the synthesized heparin benzylates and their degree of benzylation were determined using HPLC, PMR, and ¹³C NMR methods. A carboxylic-acid content of 0.13 ± 0.01 mol/g in the starting heparin was calculated from these results. A new method for estimating the degree of heparin benzylation from PMR and HPLC data was proposed. The benzyl content in the heparin benzylates increased with increasing molar excess of benzyl chloride.

A spectrophotometric method for determining sodium prodronate in tablets by measuring the absorption at 237 ± 2 nm of a Cu(II)—prodronate complex in acetate buffer was developed and validated. The method met applicable requirements of the SP RB for quantitative analysis methods for drugs and could be recommended for use by the State Drug Quality Control Inspection and technical control departments of chemical and pharmaceutical plants.

A phytochemical study of crude extracts obtained from Euphorbia atlantica Coss. led to the isolation and structure identification of ten known compounds by spectroscopic analysis including 1D and 2D NMR techniques (¹H, ¹³C, DEPT, COSY, HSQC, HMBC and NOESY), mass spectrometry (ESI-MS), measurements of optical rotation [α]_D, and by comparison with the literature data. The total phenolic content was estimated and the antioxidant activities of the petroleum ether and ethyl acetate extracts were evaluated using seven different methods, namely scavenging of the free radicals (ABTS and DPPH), ferric reducing antioxidant power (FRAP), total antioxidant capacity by phosphomolybdate assay (PPM), cupric reducing antioxidant capacity (CUPRAC), and metal chelate and ferrous ion chelating activities. The antibacterial activity of extracts was estimated by the agar disk diffusion assay against four bacterial strains including Staphylococcus albus, Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 35218 and Enterobacter sp.

The main development issues for pharmaceutical gels for peroral administration, a modern dosage form, are reviewed. Patent and literature searches for gel forms for peroral administration were performed. The main development issues for gels for peroral administration are the need for an experimental and science-based approach to correcting the taste, providing the optimal rheological characteristics that determine the stability to aggregation and release of active ingredients from the dosage form, and selecting the packaging and dispensing device for improved therapeutic efficacy. Principles for designing peroral formulations as gels with prolonged release are discussed.

Preclinical studies of a new octreotide derivative with a chelate (DPAH-octreotide) that binds 99mTc for radiological diagnosis of neuroendocrine tumors are currently in progress. A method for preparing DPAH-octreotide is based on forming an amide bond between the amine of D-phenylalanine and the bifunctional chelate succinimid-1-yl 6-[bis(pyridin-2-ylmethyl)amino]hexanoate. An HPLC method for determining the identity, impurities, and quantitative content is proposed for DPAH-octreotide quality assurance. The validation protocol established that the HPLC analytical method for determining DPAH-octreotide had quality parameters for specificity, detection limit, linearity, accuracy, precision, and intralaboratory precision that met requirements for analytical methods and could be used for quality control of the finished product during manufacturing of reagents for preparation of related radiopharmaceuticals.

Secondary patenting of organic compounds that can undoubtedly be used as active pharmaceutical ingredients (APIs) is discussed. As a rule, such compounds, their synthetic pathways, and potential applications as APIs are patented several years before official authorization to use medicines containing them is obtained. This time lag stimulates attempted illegal secondary patenting of such APIs by new applicants. These attempts can be successful because of the extremely low level of patent review. As a rule, secondary patents contain unconfirmed experimental data and numerous errors, indicating that the applicant and experts lack sufficient professional training. In order to draw the attention of the scientific community to the problem, various aspects of it are discussed below using as examples secondary patents granted for six vitally important drugs used as APIs: abacavir sulfate, darunavir, dasatinib, lenalidomide, apalutamide, and enzalutamide. The appearance of such patents is shown to be inadmissible from scientific, ethical, and legal viewpoints.