Pharmaceutical Chemistry Journal (v.49, #4)

An analytical review of widely discussed issues on the classification of drugs based on the methods/sources of their preparation and the complexity of their structures is presented. According to the classification, drugs are divided into three types: (A) low-molecular-weight synthetic “conventional” drugs that are completely characterized chemically; (B) biological complex drugs that are not fully characterized chemically (BCD); and (C) non-biological/synthetic complex drugs that are not fully characterized chemically (NBCD). This classification has both scientific and practical significance due to the fact that NBCDs (liposomal drugs, complex iron—carbohydrate complexes, glatiramoids, low-molecular-weight heparins) are similar to BCDs with respect to both structure (a mixture of strongly bound macromolecular fragments not amenable to isolation and complete identification) and biological/pharmacological effects (immunogenicity, insufficient information about the mechanism of action). Recent practice shows that NBCD generic versions in addition to biosimilar drugs are actually not identical to the original drugs because of differences in the manufacturing technology. For this reason, the expedited review and registration of these drugs, which is analogous to that used for conventional low-molecular-weight drugs, seems to be insufficient.
Keywords: non-biological/synthetic drugs; incompletely characterized chemical structure; liposomal drugs; iron–carbohydrate complexes; glatiramoids; review

Prospects for Using Gold, Silver, and Iron Oxide Nanoparticles for Increasing the Efficacy of Chemotherapy by T. A. Fedotcheva; A. Yu. Olenin; K. M. Starostin; G. V. Lisichkin; V. V. Banin; N. L. Shimanovskii (220-230).
Modern concepts about nanosized conjugates of gold, silver, and iron oxide nanoparticles with antitumor drugs that are intended for chemotherapy of oncological diseases are reviewed. The main possibilities for increasing the safety and efficacy of chemotherapy with the aid of such metal-nanoparticle—antitumor-drug conjugates are shown. Among these possibilities, the most important in practice are targeted drug delivery, controlled drug release, and suppression of multiple drug resistance of tumor cells. An analysis of the advantages and drawbacks of biomedical applications of various metal nanoparticles for antitumor therapy shows good prospects for using conjugates of iron oxide nanoparticles with antitumor drugs, in particular, with doxorubicin. The expediency of creating these nanocomplexes is justified by the possibility of their magnetic-driven delivery, controlled biodistribution, selective toxicity, and relatively simple synthesis.
Keywords: nanoparticles; gold; silver; mixed iron oxide; tumors; multiple drug resistance; targeted delivery; controlled release; targeted delivery systems; drug nanocarriers

Synthesis, Transformations, and Study of Some Biological Properties of New 3,4,5-Substituted 1,2,4-Triazoles by T. R. Hovsepyan; F. G. Arsenyan; L. E. Nersesyan; A. S. Agaronyan; I. S. Danielyan; R. V. Paronikyan; R. G. Melik-Ogandzhanyan (231-236).
A series of new 3,4,5-substituted 1,2,4-triazoles were synthesized. Their SH-alkylation by various alkylating compounds and aminomethylation leading to the formation of Mannich bases were studied. The influence of the synthesized compounds on the level of DNA methylation and their antitumor and antibacterial properties were investigated. Several compounds with pronounced demethylation and weak antitumor and antibacterial activities were identified. Correlations among the investigated biological properties were not found.
Keywords: synthesis; triazole; alkylation; aminomethylation; antibacterial and antitumor activity; DNA methylation

Synthesis and Antibacterial Activity of 3-Pyrrol-1-Ylthieno[2,3-b ]Pyridine-2-Carboxylic Acid [(Phenyl-,1,3-Benzodioxol-5-YL)Methylene]Hydrazides by E. S. Kostenko; E. A. Kaigorodova; V. I. Terekhov; S. I. Firgang; L. D. Konyushkin (237-242).
Aseries of 3-pyrrol-1-ylthieno[3,2-b]pyridine-2-carboxylic acid [(phenyl-, 1,3-benzodioxol-5-yl)methylene]- hydrazides were synthesized by reacting 3-pyrrol-1-ylthieno[2,3-b]pyridine-2-carbohydrazides with aromatic aldehydes. The synthesized hydrazides possessed antibacterial properties.
Keywords: 3-(1-pyrrolyl)thieno[2,3-b]pyridine derivatives; hydrazides; antibacterial activity

Tropylation of p-anisidine with tropylium perchlorate formed the salt 8-p-methoxyphenyl-8-azaheptafulvenium perchlorate, which converted in the presence of imidazole into N-benzylidene-4-methoxyaniline as a result of the contraction of the tropylium ring. Tropylation of 4-(7-cyclohepta-1,3,5-trienyl)aniline with tropylium perchlorate gave 4-(7-cyclohepta-1,3,5-triehyl)-N-(1-cyclohepta-2,4,6-trienyl)aniline, which showed antibacterial activity against Staphylococcus aureus 906 and Escherichia coli and antimycotic activity against five strains of yeast-like fungi of the genus Candida.
Keywords: tropylium perchlorate; aniline; p-anisidine; 4-(7-cyclohepta-1,3,5-trienyl)aniline; 4-(7-cyclohepta-1,3,5-trienyl)-N-(1-cyclohepta-2,4,6-trienyl)aniline; imidazole; antimicrobial; antibacterial; and antimycotic activity

Series of N,N′,2-triaryl-6-hydroxy-6-methyl-4-oxocyclohexane-1,3-dicarboxamides were synthesized in good yields via the reaction of N-arylacetoacetamides and aromatic aldehydes in EtOH in the presence of piperidine. The synthesized compounds were tested for antimicrobial activity.
Keywords: N,N′,2-triaryl-6-hydroxy-6-methyl-4-oxocyclohexane-1,3-dicarboxamides; synthesis; antimicrobial activity

Effect of Native Humic Acids from Tomsk Region Lowland Peat on Mitochrondrial Oxidative Phosphorylation Under Hypoxic Conditions by M. V. Belousov; R. R. Akhmedzhanov; M. V. Zykova; K. Yu. Vasil’ev; M. S. Yusubov (250-253).
Peat humic acids (PHAs) were found under experimental normobaric hypoxia with hypercapnia to normalize the activities of succinate- and NAD-dependent energy-production processes and to prevent disconnection of oxidative phosphorylation in mouse cerebral and hepatic mitochondria. The antihypoxic activity of PHAs was comparable with that of the reference antihypoxant dihydroquercetin in mouse brain and exceeded it in liver. The observed normalization by PHAs of oxidative phosphorylation in cerebral and hepatic mitochondria was probably related to their protective properties that prevented free-radical damage of cells and organelles under hypoxic conditions.
Keywords: peat humic acids; hypoxia; antihypoxic activity; oxidative phosphorylation

Efficient synthesis of a series of pyrazolylbiscoumarin (4a – 4e) and pyrazolylxanthenedione derivatives (5a – 5e) is described. The structures of the synthesized compounds were confirmed by their spectral data (IR, 1HNMR and 13CNMR). All the synthesized compounds 4 and 5 were screened for their antibacterial activity against Gram-positive bacteria S. aureus and Gram-negative bacteria K. pneumoniae. The tested compounds exhibited varying degree of antibacterial activity, showing the inhibition zone size ranging from 6 to 21 mm.
Keywords: biscoumarin; xanthenedione; 1H-pyrazole-4-carbaldehyde; antibacterial evaluation

The chemical composition of essential oil from Turkish oregano growing in southeastern Turkey was studied by gas chromatography/mass spectrometry. More than 70 constituents, of which 57 were identified, were detected. Oregano essential oil from this Turkish region was characterized by a high content of phenolic compounds including thymol and carvacrol (75.72% total) belonging to the menthane biosynthetic type. In addition, essential oil contained linalool (4.42%), p-cymene (3.36%), borneol (2.35%), 4-terpineol (1.74%), -bisabolene (1.24%), anethole (1.12%), caryophyllene oxide (1.10%), β-caryophyllene (0.68%), β-terpineol (0.55%), spathulenol (0.55%), carvone (0.51%), τ-terpinene (0.44%), o-acetylthymol (0.43%), etc. Taking into account the high contents of these compounds in essential oil, Turkish oregano could be recommended for further study as a promising aromatic plant for non-black-earth zones of the RF.
Keywords: Turkish oregano (Origanum onites L.); essential oil; thymol; carvacrol

Reproductive Toxicity of Cassia Absus Seeds in Female Rats: Possible Progesteronic Properties of Chaksine and b-Sitosterol by Azadeh Hamedi; Mohhamad Javad Khoshnoud; Nader Tanideh; Farzaneh Abbasi; Masood Fereidoonnezhad; Davood Mehrabani (268-274).
This study was designed to evaluate the reproductive toxicity of Cassia absus seeds, which have been used in Persian folk medicine. Female rats in treatment groups (N = 5) received C. absus n-hexane fraction (CAF) at oral doses of 100, 200, and 500 mg/kg b.wt./day, once per day on days one to five post-coitum (pc). The control group received 0.2 mL of olive oil (vehicle). Fertility, maternal index, hormone level, and teratogenicity were evaluated. Phytoconstituents of the seeds were detected by HPTLC and GC-MS. The presence of phytoprogesterones was evaluated by docking software. The fertility index and number of fetuses in treated groups decreased significantly. Missed abortion was 50% after administration of 500 mg/kg/day of CAF. The maternal body weight, uterine weight, and levels of FSH, LH, and estradiol exhibited insignificance changes. The serum concentration of progesterone also changed significantly in a dose-dependent manner. No teratogenic effect was found. Oleic acid (35.89%) and linoleic acid (24.22%) were the major constituents of the seed oil. In addition, chaksine and β-sitosterol showed potential phytoprogesteronic properties in docking studies. The reproductive toxicity of C. absus seeds may be related to a hormonal imbalance, a decline in the fertility index, and an increase in the rate of missed abortions of fetuses.
Keywords: anti-fertility; Cassia absus ; female; hormone; progesterone; β-sitosterol

Sterilization of Ocular Medical Inserts with Immobilized Proteins by S. S. Dekina; I. I. Romanovskaya; A. M. Ovsepyan; M. V. Balashova (275-279).
The influence of sterilization of ocular medicinal inserts with human serum albumin (HSA), lysozyme, papain, and urea on the preservation of their physicochemical properties was studied. It was found that the physicochemical properties of inserts with HSA and lysozyme preserved totally their physicochemical properties after sterilization by γ-irradiation in doses of 10, 17, and 28 kGy. The influence of γ-irradiation on the proteolytic activity of ocular medicinal inserts with papain and urea was dose-dependent and reduced the activity by 85 and 93% and led to its complete loss. Adding antiseptics used in the production of ophthalmologic preparations (nipagin, sodium metabisulfite, benzyl alcohol, benzalkonium chloride, etc.) caused an activity loss of the ocular medicinal inserts with papain and urea and did not provide microbiological purity and sterility. UV irradiation of ocular medicinal inserts with papain and urea produced microbiologically pure inserts that preserved 63.8% of the proteolytic activity. Manufacturing of ocular medicinal inserts with papain and urea under aseptic conditions using sterilizing filtration (79.7% activity preservation) was recommended for sterilization.
Keywords: ocular medicinal inserts; papain; urea; lysozyme; human serum albumin; sterilization

This paper describes the preparation of molecularly imprinted polymer (MIP) layer-coated silica nanoparticles for separation and determination of p-nitrophenol from active pharmaceutical ingredients. A new MIP was synthesized using p-nitrophenol, methacrylic acid (functional monomer), MPTS (chemically modifier), silica nanoparticles, ethylene glycol dimethacrylate (cross-linker), 2,2′-azobisisobutironitril (intiator) and toluene – acetonitrile (porogenic solvent). The surface of silica nanoparticles (Si–NP) was modified by reaction with 3-)methacryloxy)propyltrimethoxylsilane. Then, MIP coated on silica nanoparticles was synthesized by copolymerization of the vinyl end groups with functional monomer, cross-linking agent, initiator, and template molecule and these particles were used for solid-phase extraction of p-nitrophenol. To compare the performance of this MIP, a control polymer or non-imprinted polymer (NIP) was prepared using the same method and same material without the template molecule. The synthesized polymers were characterized by FT-IR spectroscopy, XRD, and SEM techniques. Parameters such as adsorption time, solution pH, and type of eluent for the elution of impurities from MIP were optimized. Selectivity of the MIP for the absorption of p-nitrophenol was investigated through adsorption experiments and the results were compared with the adsorption of impurities by NIP.
Keywords: molecularly imprinted polymer; genotoxic impurities; pharmaceuticals; solid phase extraction