Some transformations and physicochemical properties of new S-substituted 5-thiophene-(3-ylmethyl)-4R-1,2,4-triazole-3-thiols

Nitrogen-containing heterocyclic compounds are widely represented in modern organic chemistry. A special place among the huge number of substances presented is occupied by derivatives of 1,2,4-triazole due to their uniqueness and prospects. In recent years, these derivatives have remained the object of close attention of both synthetic chemists and researchers engaged in the search for new biologically active substances of a wide spectrum of action, the synthesis of optical materials, dyes, corrosion inhibitors, veterinary drugs, etc. It is known from the literature that the combination of the aromatic heterocycle of thiophene and 1,2,4-triazole is a promising area for research. The result of such combinations is a number of compounds obtained with fairly high yields and a wide range of activities. Thus, further chemical modification of 1,2,4-triazole derivatives by additional administration of a typical thiophene pharmacophore is an urgent task. The aim of the study is to obtain new compounds in a number of S-substituted 5-thiophene-(3-ylmethyl)-4R-1,2,4-triazole-3-thiols and study their physico-chemical properties using complex analysis methods. The study of the physical and chemical properties of the compounds obtained was carried out according to methods that meet the standards of the state pharmacopoeia of Ukraine. The synthesis of new compounds was carried out according to generally accepted methods. The previously obtained 5-thiophene-(3-ylmethyl)-4h-1,2,4-triazole-3-thiol and 5-thiophene-(3-ylmethyl)-4-phenyl-1,2,4-triazole-3-thiol were used as starting compounds. Preparation of thioethanones was performed in an alkaline medium in the presence of methanol. The acids were obtained in an alcohol-alkaline medium with the addition of monochloroacetic acid. To obtain esters, two conventional methods were used. The first method is based on the alkylation in an alkaline-alcohol medium of the starting thiols with isopropyl ester of monochloroacetic acid. The second method is the classical esterification reaction. To confirm the structure and study of the physical and chemical properties, all the resulting compounds were crystallized. As a result, some new compounds that were not previously described were obtained, namely: thioethanones, thioacetamides, thioacetic acids, thioacetates, and a number of other thiopo-derivatives of these initial compounds. The structure and individuality of the obtained molecules were confirmed by elemental analysis (CHNS), IR and 1H NMR spectra. A number of new S-derivatives of 5-thiophene-(3-ylmethyl)-4R-1,2,4-triazole-3-thiols have been obtained. The physical and chemical properties of the obtained compounds are determined and their structure is confirmed using modern analysis methods. Some compounds will be transferred for further research.

Research of the relationship between educational and professional programs of higher pharmaceutical education in Ukraine with the «Ten-star pharmacist» concept

Currently, the training of Masters of Pharmacy (MPh) in Ukraine is based on the competency model as a list of competencies and program learning outcomes according to academic disciplines, which is reflected in the educational and professional programs (EPP) institutions of higher pharmaceutical education (IHPhE). At the same time, MPh, as public trust workers, must have all professional roles (PR) in accordance with of the «ten-star pharmacist» concept. The aim of the study was to analyze the relationship between general (GC) and professional (PC) competencies of MPh and current PR according to the «ten-star pharmacist» concept. The materials of the study were EPP of twenty-two IHPhE that train masters in the specialty 226 «Pharmacy, industrial pharmacy». Methods of critical analysis, generalization, specification and interpretation of results are used. It was found that the lists of GC and PC differ in the analyzed EPP. It is determined that according to the presence of common GC IHPhE can be divided into three groups, while for PC there are six such groups. Significant differences in the formation of individual PR of future MPh due to acquisition them of different numbers of GC and PC are noted. It is established that in the studied EPP of twenty-two IHPhE for the preparation of masters in the specialty 226 «Pharmacy, Industrial Pharmacy» there are 15 GC and 35 PC. At the same time, the majority of GC (12 out of 15) and the minority of PC (16 out of 35) of the studied EPP are similar. Significant differences were found in the formation of the PR MPh, in particular, the analyzed GC do not sufficiently reflect PR a life-long-learner (only GC 4 in all groups and GC 15 in group Z). In PC, this picture is typical for PR a decision-maker (only PC 16 in all groups) and a teacher (PC 1 and 2 in all groups). It is shown that the lack of unified compliance of the studied EPP with PC will not contribute to the formation of MPh, adequate to pharmaceutical practice, and their acquisition of the necessary PR in accordance with the «ten-star pharmacist» concept.

Synthesis and antitumor properties of some new 3-R-6-(5-arylfuran-2-yl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles

One of the promising methods of creating antitumor drugs is the screening of potential antitumor agents among synthesized compounds. Nitrogen-based heterocycle analogues are an extremely important class of organic substances that are widely used in medical chemistry. [1,2,4]Triazolo[3,4-b][1,3,4] thiadiazoles are among the little-studied and hard-to-reach members of this class of compounds. The aim of our work was to synthesize some new 3-R-6-(5-arylfuran-2-yl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles, as well as the study of their antitumor activity. The objects of study were 3-R-6-(5-arylfuran-2-yl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles. The composition and structure of the synthesized compounds were confirmed by the data of elemental analysis and 1H NMR spectroscopy. The antitumor activity of the synthesized compounds was studied in the framework of the international scientific program of the National Cancer Institute (Bethesda, Maryland, USA) DTP NCI (Developmental Therapeutic Program). The synthesis of 11 derivatives of 3-R-6-(5-arylfuran-2-yl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles was carried out. These substances are obtained by the interaction of 5-arylfuran-2-carboxylic acids with 5-substituted 4-amino-4H-1,2,4-triazolo-3-thiols. Primary screening revealed individual 3-R-6-(5-arylfuran-2-yl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles, which showed pronounced selective antitumor activity. The most active among the tested compounds were 3 d, 3 e and 3 j, which were further investigated during secondary screening. The results of these studies confirm the high antitumor activity of these compounds. The proposed approaches and the developed synthesis protocols made it possible to obtain a series of new 3-R-6-(5-arylfuran-2-yl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles. The results of studies of the antitumor activity of the synthesized compounds made it possible to single out 3 highly active compounds with high antitumor activity, which gives reason to consider this condensed system as a promising molecular framework for the design of potential antitumor agents.

Design aspects of the combined medicinal product with multifunctional action based on herbal drugs

Combined herbal medicines for the treatment and prevention of allergic diseases are perspective substitutes for the «classic» drugs of H-1 receptor blockers of the 1st and 2nd generation. Literary-logical methods are quite effectively used for scientifically justified design of these drugs, namely phytopharmacological drug design (PPD) and phytochemical drug design (PCD). The aim of the work – the search for ways of the scientifically justified design of a combined multifunctional medicine based on the bur-marigold, which normalizes the functioning of the body's defence systems, increases the body's nonspecific resistance, normalizes the immune status using literary-logical and statistical methods of analysis. The design of the preparation was carried out using literature data for PPD and experimental and literature data for PCD. Statistical processing method – Spearman's rank correlation coefficient was used. Design aspects of the combined herbal medicine, which includes a bur-marigold herb, calendula flowers, hawthorn leaves and flowers were considered using of a system-comparative analysis of information and its processing by the method of the Spearman's rank correlation coefficient determination. When PCD development of various combinations of herbal drugs, information about the content of such biologically active substances (BAS) as flavonoids, oxycinnamic acids, polyphenols, triterpenes, proteins/amino acids, polysaccharides was used. When PPD development the spectra of pharmacological activity were determined and a quantitative assessment to them in the system of marks for each of the herbal drug of the combined medicine was given. The PCD and PPD data into the matrix for calculating the Spearman rank correlation coefficient of the «action–sum of BAS» was entered. As a result, a strong, direct and statistically significant correlation relation (p from 0.924 to 0.997) between the content of oxycinnamic acids, polyphenols, triterpenes, proteins/amino acids, polysaccharides and such pharmacological actions as capillary-strengthening, anti-inflammatory, immunostimulating; choleretic, hepatoprotective, improving metabolism; diuretic, hypotensive, sedative, tonic, desensitizing, antipruritic, reparative for the studied herbal combinations was found. The obtained results of the PCD and PPD development as well as the study of the correlation «action–sum of BAS» by calculating the Spearman's rank correlation coefficient, this suggests the developed combined herbal medicinal product with multifunctional action is perspective in the complex therapy of allergic diseases accompanied by a decrease in the body's resistance and immunostatus.

Determination of the total content of flavonoids in herbal mixtures with anti-diabetic activity

Diabetes mellitus is an important social and medical problem, as it causes the development of dangerous complications that lead to disability and mortality. This disease is characterized by a multi-vector pathogenesis that requires a comprehensive approach to treatment. Due to the use of mixtures of medicinal plants in the treatment of diabetes, it is possible to cover all aspects of the development of this disease and its complications, because the combination of different medicinal plants contain more biologically active substances that affect all parts of the pathogenetic mechanism of diabetes mellitus and its complications. Plant biocompounds have a wide range of pharmacological action and various mechanisms of influence on the development of diabetes and diabetic angiopathies (inactivation of the antioxidant defense system, activation of lipid peroxidation and the development of oxidative stress). In addition, the niche of the pharmaceutical market of Ukraine with phytomixtures is almost empty. The aim of the work was to study the total flavonoid content in some herbal mixtures, which have established hypoglycemic, hypolipidemic and antioxidant activity in previous studies in vivo The study of the total flavonoid content in herbal samples was carried out by UV-spectrophotometry with the recording of the absorption spectrum of complexation product of flavonoids with aluminum chloride (λmax 415 nm) in terms of rutin. According to the results of UV-spectrophotometric determination, it was found that the total flavonoid content in the herbal mixture No 3 was 1.47 ± 0.04%, in the herbal mixture No 4 – 1.78 ± 0.04%, in the herbal mixture No 7 – 1.29 ± 0.02%, in the herbal mixture No 13 – 1.16 ± 0.02% and in the herbal mixture No 19 – 3.62 ± 0.06% in terms of rutin. It was found that the best flavonoid content (3.62 ± 0.06%) was found in the plant mixture № 19, which contains nettle leaves, dandelion roots, blueberry leaves, rose hips and peppermint herb. Phytochemical studies may indicate a correlation between the content of flavonoids and pharmacological properties of the studied mixtures, because the functional hydroxyl groups of the latter cause strong antioxidant activity by neutralizing free radicals, chelation of heavy metal ions, increasing the activity of antioxidant protection products, which has been confirmed in previous in vivo and in vitro studies.

Study of the effect of dermatological phytogel on the ability of microorganisms to form a biofilm

The development of many chronic infections, including skin diseases, is caused by bacteria growing in the form of biofilms. Bacterial biofilms provide beneficial survival mechanisms that determine virulence, disease pathogenesis, or resistance of the pathogen to antibiotics. As shown by a large number of studies, biofilms play an important role in the pathogenesis of dermatological diseases, including atopic dermatitis. The close relationship between the microbial biofilm that colonizes the skin surface and the negative consequences for human health makes the skin microbiome an object of therapeutic intervention in dermatological pathogenic processes. The work aims to study the effect of dermatological phytogel on the ability of microorganisms to form biofilms. The objects of research were samples of gel containing dry walnut leaf extract with the sum of tannins in terms of gallic acid and dry matter 30 mg/100 g of gel, dry nettle extract with the sum of hydroxycinnamic acids in terms of chlorogenic acid, and dry matter 20 mg/100 g of gel, dry thyme extract with the sum of flavonoids in terms of rutin and dry matter 35 mg/100 g of gel both monocomponent and combined. The study of the ability of individual plant components of phytogel samples N 1, N 2, N 3 and samples of combined phytogel N 4, N 5, and N 6 to influence biofilm formation have shown that the most pronounced decceleration of biofilms formation was registered in the gel sample with phytocomplex N 4 and was 19.7–20.7% to S. aureus, E. coli, P. aerugenosis and C. albicans respectively. The activity of the gel sample with phytocomplex N 4 was 1.3–1.4 times higher than that of monocomponent gel samples N 1, N 2, and N 3. When determining the ability of the test samples to destroy biofilms, it has been found that the gel sample with phytocomplex N 4 showed the greatest activity, which exceeded the specified properties of samples N 5 and N 6 by an average of 1.2 and 1.8 times. The activity of single-component gel samples N 1, N 2, and N 3 was lower in S. aureus, E. coli, P. aerugenosis and C. albicans biofilm destruction. The conducted studies prove the feasibility of further study of the combined gel with the phyto complex № 4 containing dry walnut leaf extract with the sum of tannins in terms of gallic acid and dry matter 30 mg/100 g of gel, dry nettle extract with the sum of hydroxycinnamic acids in terms of chlorogenic acid, and dry matter 20 mg/100 g of gel, dry thyme extract with the sum of flavonoids in terms of rutin and dry matter 35 mg/100 g of gel.

Analysis of information asymmetry in the instructions for medical use on the example of Enterol

There may be variations in the texts of instructions for medical use of medicines (hereinafter – the instructions) containing the same active pharmaceutical ingredient, and registered in the pharmaceutical markets of different countries. First of all this applies to medicines manufactured in one country and distributed to other countries. Therefore, there are questions related to incorrect use of medicines due to the existing asymmetry of information. This problem is especially relevant in connection with tourist activity and labour migration. The aim of the study was to identify discrepancies in the instructions of Enterol, registered in different countries. The materials of the study were the registers of medicines in France, Ukraine, Belarus, Bulgaria, Poland, the Czech Republic and Russia, as well as the texts of instructions of Enterol (Biocodex, France), registered in the above countries. Methods of generalization, systematization, as well as contextual and comparative analysis were used. It was found that the original (French) instruction has two indications for the use of Enterol (treatment of acute diarrhea in children under 12 years old; prevention of antibiotic-associated diarrhea caused by Clostridium difficile or recurrence of diarrhea caused by Clostridium difficile), while Belarusian and Russian instructions have one indication. Polish instruction contains 5 indications, while Bulgarian and Czech – 8. The largest number of indications for the use of Enterol (11) is given in Ukrainian instruction. A contradictory information is in the sections «Therapeutic Indications», «Posology and method of administration», «Contraindications», «Undesirable effects», «Special warnings and precautions for use», including «Pregnancy and lactation». In the text of one instruction there is no information available in the text of another, and none of the instructions is identical to the instructions of Enterol, registered in France (country of manufacture). Actually, these information discrepancies, as well as the patient's perception of information, can lead to improper use of medicines and, as a consequence, drug-related problems. Thus, to minimize the asymmetry of information, the applicant during the registration of the drug must submit a notarized translation of the manufacturer's instructions.

Phytochemical analysis of the main groups of secondary metabolites in the Dracocephalum moldavica L. herb

The genus Dragonhead (Dracocephalum L.) includes 72 species of essential oil-bearing plants belonging to the Lamiaceae family. Many of them have long been used in a folk medicine of different countries. Moldavian dragonhead (D. moldavica L.) has been identified as the most promising species for the complex phytochemical research since it was successfully introduced in the climatic conditions of the Ukrainian forest-steppe zone and due to the presence of its various botanical forms and varieties. The aim of this study was the phytochemical analysis of the main groups of secondary metabolites in the herb of violet-flowered form of Moldavian dragonhead (D. moldavica L.) under its cultivation in Ternopil region (Ukraine). The herb of the plant was harvested in July of 2018‒2019 years during the flowering period. The essential oil was obtained from the plant raw material by the hydrodistillation. Such physical and chemical parameters of the essential oil as a relative density, refractive index, optical rotation, acid number and solubility in ethanol were studied. The method of thin layer chromatography (TLC) was used to determine the specific sequence of bands in the chromatograms of essential oil. The method of high-performance thin-layer chromatography (HPTLC) was used for the identification of phenolic compounds in the herb. The component composition of polyphenols was determined by the high performance liquid chromatography (HPLC). The specific physical and chemical parameters as well as the «chromatographic profile» of essential oil have been established. The main compounds of the polyphenolic nature were revealed by the chromatographic methods. In particular, rosmarinic and caffeic hydroxycinnamic acids were identified in the methanol extract of herb by the HPTLC method. The HPLC analysis of phenolic compounds in the 70% ethanol extract of raw material established that rosmarinic acid was its main polyphenol. It was found the decreasing of polyphenol contents in the D. moldavica herb in such direction: rosmarinic acid (3.01%) > apigenin-7-О-glucoside (0.67%) > apigenin (0.29%) > caffeic acid (0.28%) > luteolin-7-О-glucoside (0.13%)> hyperoside (0.12%) > ferulic acid (0.09%) > chlorogenic acid (0.08%). The obtained data could be used for planning pharmacological studies of the phytosubstances developed from the Moldavian dragonhead herb.

Analysis of the vitamin’s list with pharmacoeconomic rates for the treatment of long covid conditions during the pandemic COVID-19 in Ukraine

To ensure adequate vital activity, especially during the COVID-19 pandemic, the human body needs, in particular vitamins, minerals (macro and micronutrients). The purpose of the study is the range, qualitative and quantitative composition of vitamin complexes (VC) in the pharmaceutical market of Ukraine; to develop a method of pharmacoeconomic analysis to determine the cost of treatment of VC. Materials of research – data DRLZ, «Compendium», prices for VC (www.tabletki.ua). Research methods: webometric, comparative, content, «cost minimization» analysis; systematization, generalization. 20 VCs were analyzed, of which 15 – group A11A (75%) and 5 – A11B (25%). The highest content of vitamins in: Elevit Pronatal, Vitrum Energy, etc. All groups of vitamins contain: Vitrum Centuri, Vitrum Energy. The least vitamins in – Metovitan, Optics. Vitrum Centuri and Vitrum Energy contain most of the trace elements. Metovitan, Optics, Quadevit contain the least amount of trace elements. In addition to trace elements, the composition of VC includes: amino acids (cysteine, methionine), papain, fish oil, etc. It is established that the recommended doses of vitamins A, C, B1, B2, B5, B6, B12 in Ukraine are higher than recommended by the WHO; D, B9, H – the recommended doses in Ukraine are lower than recommended by the WHO; recommended doses of all trace elements in Ukraine are higher than the WHO. 20 VCs are registered in Ukraine, of which 15 are group A11A and 5 are A11B. 90% of VC contain vitamins A, E, C, B1, B2, B9, B12, PP. Vitamin B6 – in 85% of VC; vitamin D3 is in the composition of 62% of VC; vitamin B5 – 58%; vitamins H and K – in the composition of almost 15% of VC. It was found that 54% of VCs contain calcium; 61.5% of VC contain iron and copper; 31% of VC contain phosphorus and manganese; up to 23% of VCs contain molybdenum, boron, nickel, vanadium, tin, etc. It is established that Zinc is a part of 62% of VCs registered in Ukraine. The results of pharmacoeconomic analysis by the method of «minimization of cost» showed that the affordability of domestic multivitamin and vitamin-mineral complexes are 1.5–4.7 times more economically affordable for treatment compared to imported, with a qualitative composition are similar. Quantitative content of vitamins and minerals in domestic VC meets the national requirements of daily intake.

Scientific and practical approaches to optimizing the pharmaceutical supply of pediatric palliative patients with paralytic syndromes

Today, palliative care (PC) as a system has a complex structure with stable orderliness, interrelated elements and subsystems. The problem of providing PD with an appropriate level and quality to the children population is particularly acute; it is due to differences in the duration of provision, the necessity to provide educational services, and the socialization of palliative children. At the same time, an important aspect in achieving an appropriate quality of life for children and their families related to health is the assessment of not only medical and social, but also pharmaceutical provision. The aim of the work is to substantiate the approaches to optimization of pharmaceutical support of pediatric palliative patients with paralytic syndromes. The study objects were data from medical records, theactual consumption of medicines by pediatric patients of the Kharkiv healthcare institution where palliative care was provided, as well as data on the state registration of medicines in Ukraine. During the study, clinical and anamnestic, sociological, and marketing methods were used. Based on the results of the analysis of clinical and anamnestic data and the overall assessment of symptoms in a sample group of palliative children with paralytic syndromes, which was 115 people, pathological conditions that led to frequent or permanent distress were identified. Among them, the spastic syndrome prevailed in 100% of cases, the pain syndrome in 66% of cases, the convulsive syndrome in 59%, respectively, and digestive disorders were observed in 82.6% of patients in the sample. It was found that a large proportions of drugs for pharmacological correction of symptoms in the sample of patients were formed by antiepileptic drugs, laxatives and centrally acting muscle relaxants. The results of the marketing analysis of a definite segment of the pharmaceutical market showed a rather limited range of drugs for pediatric dosage forms and concentrations, and it on average ranged from 3.1% to 25% in the pharmacotherapeutic groups studied. Thus, the results obtained prove the need to develop mechanisms for optimizing the pharmaceutical supply of pediatric palliative patients, in particular, expanding the range of medicines approved for use in pediatric practice.