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Background/Aims Changes in autonomic regulation and psychological distress play an important role in the pathobiology of irritable bowel syndrome (IBS). The aim of the current study is to evaluate the autonomic function and to link it to the levels of somatization in adolescents with IBS.Methods We enrolled 30 adolescents with various types of IBS and 35 healthy controls. Time and frequency domain indexes of heart rate variability (HRV) were measured in supine (baseline) and standing (orthostasis) positions using short-term electrocardiographic recordings. The somatic symptoms index was assessed with the modified Screening for Somatoform Symptoms questionnaire. Results Adolescents with IBS showed no differences of HRV parameters in the supine position compared to healthy control. In orthostasis, a decrease in the standard deviation of normal RR intervals as well as main spectral index total power (TP) were observed. The reduction of TP was attributed to the reduced activities of the high-and low frequency components. Increased somatic symptoms index in IBS patients negatively correlated with TP in orthostasis (r = -0.485, P = 0.007). A subgroup analysis revealed that adolescents with IBS with TP values either < 2500 msec2 or > 5500 msec2 in the supine position demonstrated significantly reduced activity of the low frequency component.Conclusions Adolescents with IBS showed signs of autonomic dysfunction only during the orthostatic test, which were associated with increased somatization scores. Further research is needed to establish the links between emotional wellbeing and autonomic function in this population. (J Neurogastroenterol Motil 2023;29:208-217)

4-Thiazolidinones and related derivatives are regarded as privileged structures in medicinal chemistry and a source of new drug-like compounds. To date it is known that thiazolidinones are able to induce CYP1A1 activity in 3T3-L1 cells. Therefore, to extend the knowledge of the mechanism of thiazolidinones in the cell, four chemically synthesized heterocycles were tested on 3T3-L1 cells. The 3T3-L1 cells were exposed to Les-2194, Les-3640, Les-5935, and Les-6166. Our study showed that 1 μM βNF, Les-2194, and Les-6166 decreased the expression of Ahr mRNA. In turn, βNF, Les-2194, and Les-3640 increased the Cyp1a1 mRNA expression at the same time interval. On the other hand, Les-5935 was found to decrease the Cyp1a1 mRNA expression. Interestingly, the expression of Cyp1a2 mRNA was activated only by βNF and Les-2194. The expression of Cyp1b1 mRNA in the 3T3 cell line increased after the βNF and Les-2194 treatment but declined after the exposure to Les-5935 and Les-6166. Moreover, the Les-2194 and Les-5935 compounds were shown to increase the activity of EROD, MROD, and PROD. Les-3640 increased the activity of EROD and decreased the activity of PROD. In turn, the treatment with Les-6166 resulted in an increase in the activity of EROD and a decrease in the activity of MROD and PROD in the 3T3-L1 cells.

Based on the results of the Licensed Integrated Exam (LIЕ), the level of knowledge of students and interns of higher educational institutions of medical direction is determined, a decision is made on the possibility of their further study and work, and a rating of medical universities is formed. Purpose: to determine, structure, analyze and evaluate factors affecting the process of preparing students and interns in the pharmaceutical field for LIE «Krok 2. Pharmacy» and «Krok 3. Pharmacy» (K2F and K3F); based on the data obtained, study the possibilities of optimizing the implementation of this process. Objects: results (general and by discipline) of the K2F licensed exam of 2016‒2019, the pilot (2017) and licensed (2019) K3F exam at the Danylo Halytskyy Lviv National Medical University. Methods: statistical processing of the results of LIE. Factors that affect the success of student/intern training are structured in three groups: individual (personalized), group (group training) and external. There is no interdependence between the results of LII K2F and the average score for training in the diploma supplement. It is established that there is a connection between the success of preparation for LIE K2F and belonging to the group. This leads to the assumption that the success of training may be partly influenced by the personality and method of teaching, the level of knowledge and demands on pairs of specific teachers, as well as the environment of a particular student (the influence of classmates). The analysis of deviations of the indicator of an estimation of a level of knowledge of students on separate educational disciplines has shown, approximately on 80%, a homogeneous tendency. The largest intervals of deviation of this indicator were observed for pharmaceutical chemistry and pharmacognosy, slightly smaller ‒ drug technology; the smallest ‒ for the organization of the economics of pharmacy, management and marketing in pharmacy, clinical pharmacy. According to the results of the analysis of the indicator of assessment of the level of knowledge it was established that its distribution both in the negative and in the positive direction in the main group was uniform (is at one level), but in others ‒ negative prevails 1.5 times. The value of the deviation of the indicator of assessment of the level of knowledge had a natural relation to the medial indicator.

A series of novel 2-(5-ylidene-4-oxo-2-thioxo-thiazolidin-3-yl)-succinimides and 5-ylidene-3-(1-arylpyrrolidine-2,5-dione)-thiazolidine-2,4-diones were synthesized. An efficient simple protocol for rhodanine-pyrrolidinedione hybrids synthesis which allows avoiding the step of anhydride formation was proposed. Following the previous data on antileukemic properties of related thiazolidinone derivatives, the activity of 19 target compounds was investigated towards four leukemia cell lines: Dami, HL-60, Jurkat, and K562. Among the tested compounds, 3-[5-(4-chloro-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-1-phenyl-pyrrolidine-2,5-dione (Compound 1) possessed good and selective antiproliferative action against Dami and HL-60 cell lines and satisfactory toxicity level (acute toxicity evaluated in vivo in mice).

4-thiazolidinones, which are privileged structures in medicinal chemistry, comprise the well-known class of heterocycles and are a source of new drug-like compounds. Undoubtedly, the 5-bulky-substituted-2,4-thiazolidinediones - a class of antihyperglycemic glitazones, which are peroxisome proliferator-activated receptor gamma (PPARγ) agonists, are the most described group among them. As there are various chemically distinct 4-thiazolidinones, different subtypes have been selected for studies; however, their main pharmacological profiles are similar. The aim of this study was to evaluate the anticancer activity of 5Z-(4-fluorobenzylidene)-2-(4-hydroxyphenylamino)-thiazol-4-one (Les-236) in four human cancer cell lines, A549, SCC-15, SH-SY5Y, and CACO-2, and investigate its impact on the production of reactive oxygen species (ROS) and the apoptotic process as well as cytotoxicity and metabolism in these cell lines. The cell lines were exposed to increasing concentrations (1 nM to 100 µM) of the studied compound for 6, 24, and 48 h, and later, ROS production, cell viability, caspase-3 activity, and cell metabolism were examined. The obtained results showed that the studied compound decreased the production of ROS, increased the release of lactate dehydrogenase, and decreased cell metabolism/proliferation in all the five cell lines at micromolar concentrations. Interestingly, over a wide range of concentrations (from 1 nM to 100 µM), Les-236 was able to increase the activity of caspase-3 in BJ (after 6 h of exposure), A549, CACO-2, and SCC-15 (after 48 h of exposure) cell lines which could be an effect of the activation of PPARγ-dependent pathways.

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Here, we describe the synthesis and anticonvulsant activity of thiazole-bearing hybrids based on 2-imino-4-thiazolidinone and 2,4-dioxothiazolidine-5-carboxylic acid cores. The structure of target compounds was based on the following: (i) A combination of two thiazole cores, (ii) similarity to ralitolin&rsquo, s structure, (iii) the compliance with structural requirements for the new anticonvulsants. Target compounds were synthesized via known approaches based on Knoenavegel reaction, alkylation reaction, and one-pot three-component reaction. Anticonvulsant properties of compounds were evaluated in two different models&mdash, pentylenetetrazole-induced seizures and maximal electroshock seizure tests. Among the tested compounds 5Z-(3-nitrobenzylidene)-2-(thiazol-2-ylimino)-thiazolidin-4-one Ib, 2-[2,4-dioxo-5-(thiazol-2- ylcarbamoylmethyl)-thiazolidin-3-yl]-N-(2-trifluoromethylphenyl)acetamide IId and (2,4-dioxo-5- (thiazol-2-ylcarbamoylmethylene)-thiazolidin-3-yl)acetic acid ethyl ester IIj showed excellent anticonvulsant activity in both models. The directions of compounds modification based on SAR aspects were discussed. The results of the study provide a basis for further study of the anticonvulsant properties of selected thiazole-thiazolidinones.

Розроблений та валідований простий, точний і прецизійний спектрофотометричний метод оцінки кількісного вмісту амлодипіну безилату у таблетках. Метод базується на взаємодії амлодипіну безилату із натрію 1,2-нафтохінон-4- сульфонатом у лужному середовищі, за нагрівання реакційної суміші за 363K протягом 1 хв., з утворенням продукту помаран- чевого кольору. Спектрофотометричний метод включав вимірю- вання оптичної густини продукту при 459 нм. При розробленні методу вивчено та оптимізовано умови реакції. Підпорядкування закону Бера відбувалось у діапазоні концентрацій 10–20 мкг/мл при RSD 0,825 і 0,559%, а молярний коефіцієнт поглинання складав 2,54·104, діапазон застосування методів становить 67–133% від номінального вмісту амлодипіну безилату у лікарськихформах. 1Simple, accurate, and precise spectrophotometric method has been developed and validated for the estimation of amlodipine besylate (AML) in tablets. The method is based on the condensation of AML with sodium 1,2-naphthoquinone-4-sulphonate in an alkaline medium when the reaction mixture was heated at 363K for 1 min to form an orange-colored product. The spectrophotometric method involved the measurement of the colored product at 459 nm. The reaction conditions were studied and optimized. Beer’s law was obeyed in the concentration range of 10–20 μg·ml-1 with RSD of 0.825 and 0.559 % and molar absorption of 2.54·104, the range of methods application is 67–133 % of the nominal content of amlodipine besylate in the dosage forms.

Nowadays, diabetes mellitus type 2 (T2DM) is a serious problem in western European societies and in the United States. Thiazolidinediones (TZDs) are a broad group of compounds used to decrease insulin resistance in TDM2. To date, it has been believed that TZDs act mainly through activation of peroxisome proliferator-activated receptor gamma (PPARγ). The PPARγ receptor is important in differentiation of preadipocytes into mature adipocytes. Therefore, given the potential of structurally related thiopyrano[2,3-d]thiazoles Les-2194 and Les-3377 and 4-thiazolidinone derivative Les-3640 to interact with the PPARγ receptor, the aim of the present study was to evaluate the impact of the 4-thiazolidinone-based derivatives mentioned above on the process of 3T3-L1 cell line differentiation into adipocytes. In the first part of our study, we prove that Les-2194, Les-3377, and Les-3640 are cytotoxic to 3T3-L1 cells. In the next stage, we determine that Les-2194, Les-3377, and Les-3640 stimulate lipid accumulation (using the ORO staining method) and induce specific gene expression (Dlk1, Fabp4, Vegfa, Pai-1, Resistin, Adiponectin, and Pparγ). Our data show that rosiglitazone, pioglitazone, Les-2194, and Les-3640 at a concentration of 2 μM do not affect 3T3-L1 cell viability and do not activate the apoptotic process. Only Les-3377 decreased the number and metabolism of the cells. Although all the studied compounds influenced the expression of Dlk1, Fabp4, Vegfa, Pai-1, Resistin, Adiponectin, and Pparγ genes, none of them caused gene expression similar to that induced by rosiglitazone or pioglitazone. The ORO staining showed that rosiglitazone and pioglitazone induced lipid accumulation in the 3T3-L1 cell line, which is a marker of mature adipocytes. Only rosiglitazone increased Pparγ protein expression after 14 days of differentiation.

PPARγ regulate the expression of genes involved in peripheral insulin sensitivity, adipogenesis, and glucose homeostasis. Moreover, PPARγ agonists, such as pioglitazone and rosiglitazone, are used in the treatment of various diseases, e.g. diabetes (type II), atherosclerosis, inflammatory skin disease, and some types of cancers. PPARγ agonists have also been found to reduce oxidative-stress (OS) and OS-induced apoptosis. Therefore, the aim of the present study was to evaluate the impact of 4-thiazolidinone-based derivatives Les-2194, Les-3377, and Les-3640 on the expression of antioxidant enzymes in human squamous cell carcinoma (SCC-15), lung carcinoma (A549), colon adenocarcinoma (CACO-2), and skin fibroblast (BJ) cell lines. After 24 h of exposure, Les-2194 caused an increase in ROS production in the SCC-15 and CACO-2 cell lines; however, no changes in caspase-3 activity and metabolic activity were observed. Nevertheless, the Ki67 level was significantly decreased. Les-3377 was able to increase ROS production in all tested cell lines, but no impact on metabolic activity and caspase-3 activity were noticed. In turn, Les-3640 was able to induce ROS overproduction in BJ, SCC-15, and CACO-2 and did not affect metabolic activity. However, an increase in caspase-3 activity was observed at the 10 µM concentration in all tested cell lines. All tested compounds were able to influence CAT and SOD1 expression and decreased (Les-2194 in the BJ cells) or increased (Les-3640 in the SCC-15 and CACO-2 cells) PPARγ expression.

The presented review is an attempt to summarize a huge volume of data on 5-ene-4-thiazolidinones being a widely studied class of small molecules used in modern organic and medicinal chemistry. The manuscript covers approaches to the synthesis of 5-ene-4-thiazolidinone derivatives: modification of the C5 position of the basic core; synthesis of the target compounds in the one-pot or multistage reactions or transformation of other related heterocycles. The most prominent pharmacological profiles of 5-ene derivatives of different 4-thiazolidinone subtypes belonging to hit-, lead-compounds, drug-candidates and drugs as well as the most studied targets have been discussed. Currently target compounds (especially 5-en-rhodanines) are assigned as frequent hitters or pan-assay interference compounds (PAINS) within high-throughput screening campaigns. Nevertheless, the crucial impact of the presence/nature of C5 substituent (namely 5-ene) on the pharmacological effects of 5-ene-4-thiazolidinones was confirmed by the numerous listed findings from the original articles. The main directions for active 5-ene-4-thiazolidinones optimization have been shown: i) complication of the fragment in the C5 position; ii) introduction of the substituents in the N3 position (especially fragments with carboxylic group or its derivatives); iii) annealing in complex heterocyclic systems; iv) combination with other pharmacologically attractive fragments within hybrid pharmacophore approach. Moreover, the utilization of 5-ene-4-thiazolidinones in the synthesis of complex compounds with potent pharmacological application is described. The chemical transformations cover mainly the reactions which involve the exocyclic double bond in C5 position of the main core and correspond to the abovementioned direction of the 5-ene-4-thiazolidinone modification., Graphical abstract Image 1, Highlights • Synthesis of 5-ene-4-thiazolidinones. • Pharmacological profiles of 5-ene-4-thiazolidinones. • 5-Ene-thiazolidinones based synthesis.

The concept of oxidative stress (OS) that connects altered redox biology with various diseases was introduced 30 years ago and has generated intensive research over the past two decades. Whereas it is now commonly accepted that macromolecule oxidation in response to ROS is associated with a variety of pathologies, the emergence of NO as a key regulator of redox signalling has led to the discovery of the pathophysiological significance of reactive nitrogen species (RNS). RNS can elicit various modifications of macromolecules and lead to nitrative or nitro-OS. In order to investigate oxidative and nitro-OS in human and in live animal models, circulating biomarker assays have been developed. This article provides an overview of key biomarkers used to assess lipid peroxidation and NO/NO2 signalling, thereby stressing the necessity to analyse several OS biomarkers in relation to the overall (aerobic) metabolism and health condition of patients. In addition, the potential interest of heart rate variability as the non-invasive integrative biomarker of OS is discussed. Linked Articles This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc

Herein, we describe a one-pot, three-component method for the synthesis of 5-arylidene-4-aminothiazol-2(5H)-ones based on the reaction of isorhodanine, aromatic aldehydes, and ethanolamine. The one-pot procedure for chromeno[2,3-d]thiazol-2-one synthesis starting from 4-aminothiazol-2(5H)-one was proposed following the study of 5-(2-hydroxybenzylidene)-thiazolidinones. Structural features of the starting 4-thioxo-2-thiazolidinone, 4-aminothiazol-2(5H)-one, and target compounds are discussed.

Peroxisome proliferator-activated receptors (PPARs) play an important role in numerous chronic diseases such as diabetes, obesity, atherosclerosis and cancer, and PPAR modulators are among the approved drugs and drug-candidates for their treatment. The aim of this study was to elucidate the involvement of PPARs in the mechanism of cytotoxic and pro-apoptotic action of novel anticancer 4-thiazolidinone derivatives (Les-2194, Les-3377, Les-3640) and approved 4-thiazolidinones (Rosiglitazone, Pioglitazone) towards the human squamous carcinoma (SCC-15) cell line. Experiments with 4-thiazaolidinone derivatives and PPAR-specific siRNA were conducted and PPARα, PPARβ and PPARγ mRNA expression was studied. Moreover, after PPARα, PPARβ and PPARγ siRNA gene silencing, cell viability, cell metabolism and caspase-3 activity were measured. The results showed a decrease of mRNA expression of the studied PPARs in SCC-15 cells treated with 10 and 50 μM Les-2194, Les-3377 and Les-3640. PPARγ knockdown protected the cells from the cytotoxic effect of the tested compounds (50 μM). It was established that novel anticancer 4-thiazolidinone derivatives act mainly through the PPARγ pathway in SCC-15 cells. Our results suggest that all studied compounds act as PPARs agonists. Interestingly, silencing of PPARγ gene increases the expression of PPARα, PPARβ mRNA in SCC-15 cells. The anticancer potential of new studied compounds was more expressed as compared to Rosiglitazone and Pioglitazone.

4-Thiazolidinones are a known class of prospective drug-like molecules, especially in the design of new anticancer agents. Two of the most prominent subtypes of these compounds are 5-ene-2-amino(amino)-4-thiazolidinones and thiopyrano[2,3-d]thiazoles. The latter are considered to be cyclic mimetics of biologically active 5-ene-4-thiazolidinones with similar pharmacological profiles. Therefore, the aim of this study was to evaluate the impact of 4-thiazolidinone-based compounds on cytotoxicity, the apoptotic process, and metabolism in the human squamous carcinoma (SCC-15) cell line. The SCC-15 cells were cultured in phenol red-free DMEM/F12 medium supplemented with 10% FBS, hydrocortisone, and exposed to rising concentrations (1 nM–100 μM) of the studied compounds for 6, 24 and 48 h. Afterwards, reactive oxygen species (ROS) formation, cell viability, caspase-3 activity, and cell metabolism were measured. The obtained results showed that all of the studied compounds in a wide range of concentrations (1 nM–100 μM) increased DCF fluorescence which suggests a stimulation of ROS production. Nevertheless, these new compounds showed cytotoxic and proapoptotic properties only at high (10–100 μM) concentrations. Our studies are the first to be carried out on these compounds and require further investigation to clarify the mechanism of action of their anticancer potential.

Different compounds have been investigated as potent drugs for trypanosomiasis treatment, but no new drug has been marketed in the past 3 decades. 4-Thiazolidinone/thiazole as privileged structures and thiosemicarbazides cyclic analogs are well known scaffolds in novel antitrypanosomal agent design. We present here the design and synthesis of new hybrid molecules bearing thiazolidinone/thiazole cores linked by the hydrazone group with various molecular fragments. Structure optimization led to compounds with phenyl-indole or phenyl-imidazo[2,1-b][1,3,4]thiadiazole moieties showing excellent antitrypanosomal activity towards Trypanosoma brucei brucei and Trypanosoma brucei gambiense. Biological study allowed identifying compounds with the submicromolar levels of IC50, good selectivity indexes and relatively low cytotoxicity upon human primary fibroblasts as well as low acute toxicity.

Here we describe the synthesis and the antifibrotic and anticancer activity determination of amino(imino)thiazolidinone derivatives. An efficient one-pot three-component reaction which involved [2 + 3]-cyclocondensation and Knoevenagel condensation was used for the synthesis of 5-ene-2-amino(imino)-4-thiazolidinones. Following amino-imino tautomerism, the compound structures were confirmed by X-ray analysis. Comparison of SRB assays on fibroblasts and cancer cells revealed that compounds which significantly reduced the viability of fibroblasts did not possess an anticancer effect. A series of thiazolidinone derivatives as interesting candidates for further testing has been identified. Among the tested compounds 2-{3-furan-2-ylmethyl-2-[(2-methyl-3-phenylallylidene)hydrazono]-thiazolidin-4-one-5-yl}-N-(3-trifluoromethylphenyl)-acetamide (5), N-(2-methoxyphenyl)-2-[5-(4-oxothiazolidin-2-ylideneamino)-[1,3,4]thiadiazol-2-ylsulfanyl]-acetamide (12), 3-[3-allyl-4-oxo-2-(thiazol-2-ylimino)thiazolidin-5-ylidene]-1,3-dihydroindol-2-one (33), and 5(Z)-(thiophen-2-ylmethylene)-4-(4-chlorophenylamino)thiazol-2-(5H)-one (34) possessed high antifibrotic activity levels, had a similar effect as Pirfenidone, and did not scavenge superoxide radicals. Their antifibrotic potential was confirmed using the xCelligence system.

Pulmonary arterial hypertension (PAH) is a rare multifactorial disease with an unfavorable prognosis. Sildenafil therapy can improve functional capacity and pulmonary hemodynamics in PAH patients. Nowadays, it is increasingly recognized that the effects of sildenafil are pleiotropic and may also involve changes of the pro-/antioxidant balance, lipid peroxidation and autonomic control. In present study we aimed to assess the effects of sildenafil on the fatty acids (FAs) status, level of hydroxynonenal (HNE) and heart rate variability (HRV) in PAH patients. Patients with PAH were characterized by an increase in HNE and changes in the FAs composition with elevation of linoleic, oleic, docosahexanoic acids in phospholipids as well as reduced HRV with sympathetic predominance. Sildenafil therapy improved exercise capacity and pulmonary hemodynamics and reduced NT-proBNP level in PAH. Antioxidant and anti-inflammatory effects of sildenafil were noted from the significant lowering of HNE level and reduction of the phopholipid derived oleic, linoleic, docosahexanoic, docosapentanoic FAs. That was also associated with some improvement of HRV on account of the activation of the neurohumoral regulatory component. Incomplete recovery of the functional metabolic disorders in PAH patients may be assumed from the persistent increase in free FAs, reduced HRV with the sympathetic predominance in the spectral structure after treatment comparing to control group. The possibilities to improve PAH treatment efficacy through mild stimulation of free radical reactions and formation of hormetic reaction in the context of improved NO signaling are discussed., Highlights • Sildenafil showed antioxidant and anti-inflammatory effects in pulmonary hypertension. • Sildenafil reduced hydroxynonenal level and improved fatty acid profile in serum. • Improvement of heart rate variability and functional capacity was noted after therapy. • Mild prooxidant activity is suggested as the mechanism to improve sildenafil efficacy.

Various novel structurally diverse thiazolidinone-derived compounds were synthesized from isorhodanine (4-thioxo-2-thiazolidinone) with ortho-substituted aldehydes, arylidene pyruvic and β-aroylacrylic acids. Michael reaction of isorhodanine with arylidene pyruvic and β-aroylacrylic acids providing 2-oxo-4-(2-oxo-4-thioxothiazolidin-5-yl)-4-phenylbutyric and 4-oxo-2-(2-oxo-2,3-dihydrothiazol-4-ylsulfanyl)-4-phenylbutyric acid is presented. Notably, under the long-term heating, reactions of isorhodanine and APAs underwent as a Michael−cyclization cascade lead to structurally different fused thiopyranoid scaffolds. The structures of newly synthesized compounds were established by spectral data and a single-crystal X-ray diffraction analysis.

Recently, thiazolidinone derivatives have been widely studied as antiparasitic agents. Previous investigations showed that fused 4-thiazolidinone derivatives (especially thiopyranothiazoles) retain pharmacological activity of their synthetic precursors-simple 5-ene-4-thiazolidinones. A series of isothiochromeno[4a,4

This paper presents novel QSAR models for the prediction of antitrypanosomal activity among thiazolidines and related heterocycles. The performance of four machine learning algorithms: Random Forest regression, Stochastic gradient boosting, Multivariate adaptive regression splines and Gaussian processes regression have been studied in order to reach better levels of predictivity. The results for Random Forest and Gaussian processes regression are comparable and outperform other studied methods. The preliminary descriptor selection with Boruta method improved the outcome of machine learning methods. The two novel QSAR-models developed with Random Forest and Gaussian processes regression algorithms have good predictive ability, which was proved by the external evaluation of the test set with corresponding Q2ext =0.812 and Q2ext =0.830. The obtained models can be used further for in silico screening of virtual libraries in the same chemical domain in order to find new antitrypanosomal agents. Thorough analysis of descriptors influence in the QSAR models and interpretation of their chemical meaning allows to highlight a number of structure-activity relationships. The presence of phenyl rings with electron-withdrawing atoms or groups in para-position, increased number of aromatic rings, high branching but short chains, high HOMO energy, and the introduction of 1-substituted 2-indolyl fragment into the molecular structure have been recognized as trypanocidal activity prerequisites.

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed., Graphical abstract fx1, Highlights • RONS are chemical mediators and a communication tool. • RONS and disturbed redox balance play a role in a broad range of diseases and aging. • Bacteria and toxins are important stimulators of cellular RONS formation. • Drugs should preserve beneficial redox signaling and inhibit detrimental RONS sources. • Redox drugs may target the origin, identity, location and time of RONS formation.

Objective To improve the teaching of under-represented medicinal chemistry components (in the field of drug discovery and development) in the PharmD curriculum in Ukraine. Methods The differences between Medicinal Chemistry (according to the “Western standards”) and Pharmaceutical Chemistry (in the post-soviet countries) were evaluated. The gaps in the Ukrainian PharmD curriculum within drug discovery and development were outlined. Results The course “Computer Technologies in Pharmacy” has been introduced to fill in the gaps in training of the pharmacy students in Ukraine. It was designed to help students understand the depth and diversity of the drug design and development processes. The course includes the main principles related to a meaningful literature search, approaches to new drug-candidate design/development, and computerization of pharmaceutical industry. The overall idea is to familiarize students with a more holistic picture of the drug lifecycle: from idea to drug-candidate creation, getting a new drug onto the market, indication extension or withdrawal from the market, or restriction of the label claims. Conclusion “Computer Technologies in Pharmacy” course is a step toward unification the educational systems and reduce the gap between European, USA, and post-Soviet educational systems, in particular elimination the differences in the study of medicinal and pharmaceutical chemistry in the spirit of modern drug design/development education.

The aim of present research was the investigation of antioxidant and antiexudative activities of the series of thiopyrano[2,3-d]thiazoles synthesized based on cinnamic acid amides. Methods. Organic synthesis; spectral methods; free radical scavenging assay (DPPH test); evaluation of antiexudative activity (carrageenan oedema model in rats). Results. The evaluation of the free radicals scavenging activity and antiexudative activity of series of the 2-oxo-5-phenyl-7-aryl(hetaryl)-3,7-dihydro-2H-thiopyrano[2,3-d]thiazole-6-carboxylic acid amides was performed. Among the tested compounds, rel-(5R,6S,7S)-N-(4-methylphenyl)-7-(4-methylphenyl)-2-oxo-5-phenyl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazole-6-carboxamide possessed the highest level of both activities. The experimental data most probably indicate a pronounced effect of methyl groups (phenyl fragments) on the realization of the anti-inflammatory and antioxidant effects and allow a suggestion about the antiradical mechanism of anti-inflammatory activity of the target compounds. Conclusions. The anti-inflammatory and free radicals scavenging activities of some tiopyrano[2,3-d]thiazoles have been established and the most active compounds were identified. Some findings of the structure-activity relationship were set up. Мета даного дослідження полягала у вивченні антиоксидантної та антиексудативної активності похідних тіопі­ра­но [2,3-d]тіазолу одержаних на основі амідів коричної кислоти. Методи. Органічний синтез; спектральні методи; оцін­ка радикал поглинаючої (DPPH тест) та антиексудативної активностей (карагенінової модель набряку лапи щура). Резу­ль­та­ти. Проведено визначення радикал поглинаючої та антиексудативної активності амідів 2-оксо-5-феніл-7-арил(гетерил)-3,7-дигідро-2Н-тіопірано[2,3-d]тіазол-6-карбонових кислот. Серед тестованих сполук rel-(5R,6S, 7S)-N-(4-метилфеніл)-7-(4-метилфеніл)-2-оксо-5-феніл-3,5,6,7-тетрагідро-2H-тіопірано[2,3-d]тіазол-6-карбоксамід характеризувався максимальними значеннями обох видів активності. Отримані дані, очевидно, свідчать про виражений вплив метильних груп (у фенільних фрагментах) на реалізацію протизапального та антиоксидантного ефектів та дозволяють припустити антирадикальний механізм протизапальної активності сполук даного ряду. Висновки. Вста­новлено протизапальну та антирадикальну активності ряду тіопірано[2,3-d]тіазолів, ідентифіковано сполуки з високим рівнем активності та проаналізовані деякі аспекти взає­мо­зв’язку структура-активність. Цель данного исследования заключалась в изучении антиоксидантной и антиэкссудативной активности производных тиопирано[2,3-d]тиазола полученых на основе амидов коричной кислоты. Методы. Органический синтез; спектра­льные методы; оценка радикал поглощающей (DPPH тест) и антиэкссудативной активностей (карагениновая модель отека лапы крысы). Результаты. Проведено исследование радикал поглощающей активности и антиэкссудативного активности амидов 2-оксо-5-фенил-7-арил(гетерил)-3,7-ди­гид­ро-2Н-тиопирано[2,3-d]тиазол-6-карбоновых кислот. Среди испытуемых соединений rel-(5R,6S,7S)-N-(4-метилфенил)-7-(4-метилфенил)-2-оксо-5-фенил-3,5,6,7-тетрагидро-2H-тиопирано[2,3-d]тиазол-6-карбоксамид характеризировался максимальными значениями обоих видов активности. По­лу­ченные данные, по-видимому, свидетельствуют о выраженном влиянии метильных групп (в фенильных фрагментах) на реализацию противовоспалительного и антиоксидан­т­ного эффектов и позволяют предположить антирадикальний механизм противовоспалительной активности соединений данного ряда. Выводы. Установлено противовоспалительную и антирадикальную активности ряда тио­пирано[2,3-d]тиазолов, идентифицировано соединения с высоким уровнем активности, а также проанализированы некоторые аспекты взаимосвязи структура-активность.

Aim. To study anticancer activity of a series of new thiopyrano[2,3-d]thiazoles with a norbornane fragment in the molecules. The search for trypanocidal properties of target compounds. Methods. Organic synthesis, analytical and spectral methods, pharmacological screening, COMPARE and SAR analysis. Results. Fused thiopyrano[2,3-d]thiazoles bearing the norbornane moiety were synthesized and modified at the C9 and N5 positions of the main core in order to obtain the compounds with a satisfactory pharmacological profile. A number of compounds with significant level of cancer cells growth inhibition were identified; they include a hit-compound N1-(4-chlorophenyl)-2-{2-[6-oxo-5,9-dithia-7-azatetracyclo [9.2.1.02,10.04,8]tetradec-4(8)-en-3-yl]phenoxy}acetamide IId that selectively inhibited Leukemia cell lines at submicromolar concentrations. Moreover, a series of thiopyrano[2,3-d]thiazoles showed a moderate antitrypanosomal activity. Conclusions. New thiopyrano[2,3-d]thiazoles with the norbornane fragment as well as their analogues with different substituents at the N5 and C9 position were designed and synthesized. The compounds showed significant levels of anticancer activity towards the selected cancer cell lines and may be used for further optimization. The compounds with a high antitumor activity inhibited the growth of Trypanosoma brucei brucei in in vitro tests. The combined anticancer and antitrypanosomal effect of compounds is the basis for further modification and search for a possible mode of action of the target compounds. Мета. Вивчення протипухлинної та трипаноцидної активності серії нових тіопірано[2,3-d]тіазолів з норборнановим фрагментом у молекулах. Методи. органічний синтез, аналітичні та спектральні методи, фармакологічний скринінг, COMPARE та SAR аналізи. Результати. Для одержання сполук з відповідним фармакологічним профілем синтезовано нові конденсовані похідні тіопірано[2,3-d]тіазолу з норборнановим фрагментом у молекулах, які модифіковані за положеннями С9 та N5 базового гетероциклу. Ідентифіковано ряд сполук з суттєвим рівнем інгібування росту ракових клітин, серед яких сполука-хіт N1-(4-хлорофеніл)-2-{2-[6-оксо-5,9-дитіа-7-азатетрацикло[9.2.1.02,10.04,8]тетрадец-4(8)-ен-3-іл]фенокси}ацетамід IId, що селективно інгібує лінії клітин лейкемії в субмікромолярних концентраціях. Крім того, ряд тіопірано[2,3-d]тіазолів також проявляють перспекти-вну протитрипаносомну активність. Висновки. Синтезовано нові тіопірано[2,3-d]тіазоли з норборнановим фрагментом у молекулах а також їх похідні з різноманітними субституентами в положеннях N5 та C9 базової гетероцик-лічної системи. Сполуки проявили суттєвий рівень протипухлинної активності і можуть бути використані для по-дальшої оптимізації структури як потенційні протиракові агенти. Окрім того, сполуки з високим рівнем протипух-линного ефекту in vitro інгібують ріст Trypanosoma brucei brucei. Поєднання протиракової та протитрипаносомної активності синтезованих сполук є основою для наступної структурної модифікації та пошуку імовірних механізмів реалізації їх біологічної активності. Цель. Изучение антиопухолевой и трипаноцидной активности серии новых тиопирано[2,3-d]тиазолов из нор-борнановым фрагментом в молекулах. Методы. органический синтез, аналитические и спектральные методы, фармакологический скрининг, COMPARE и SAR анализы. Результаты. Для получения соединений с соответствующим фармакологическим профилем синтезированы новые производные тиопирано[2,3-d]тиазола с норборнановым фрагментом в молекулах, которые модифицированы по положениям С9 и N5 базового гетероцикла. Идентифицирован ряд соединений с существенным уровнем ингибирования роста раковых клеток, среди которых соединение-хит N1-(4-хлорфенил)-2-{2-[6-оксо-5,9-дитиа-7-азатетрацикло[9.2.1.02,10.04,8]тетрадец-4(8)-ен-3-ил]фенокси}ацетамид IId, который селективно ингибирует линии клеток лейкемии в субмикромолярных концентрациях. Кроме того, некоторые тіопірано[2,3-d]тіазолы также проявляют перспективную протитрипаносомную активность. Выводы. Синтезированы новые тиопирано[2,3-d]тиазолы с норборнановым фрагментом у молекулах, а также их производные с различными заместителями в положениях N5 и C9 базовой гетероциклической системы. Соединения проявили существенный уровень противоопухолевой активности и могут быть использованы для дальнейшей структурной оптимизации как потенциальные противораковые агенты. Кроме того, соединения с высоким уровнем противоопухолевого эффекта in vitro ингибируют рост Trypanosoma brucei brucei. Сочетание антираковой и противотрипаносомной активности синтезированных соединений может быть основой для дальнейшей оптимизации структуры и поиска возможных механизмов реализации их биологической активности.

Cycloaddition of intermediates formed from the nucleophilic addition of aryl isothiocyanate to acidic cyanomethylenes and α-halocarbonyl compounds gave only 4-thiazolidinones. 5-Thiazolidinones were not observed. Cyano-(4-oxo-3-phenylthiazolidin-2-ylidene)-acetic acid ethyl ester (1) and cyano-[5-(4-methoxybenzylidene)-4-oxo-3-phenylthiazolidin-2-ylidene]-acetic acid ethyl ester (2a) also were shown to exhibit moderate antiviral activity. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]

Here it is described the synthesis, antioxidant and antimicrobial activity determination of novel rel-([Formula: see text])-6-benzoyl-7-phenyl-2-oxo-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazole-5-carboxylic acids. The target compounds were obtained in good yields from 5-arylidene-4-thioxo-2-thiazolidinones and [Formula: see text]-aroylacrylic acids via regio- and diastereoselective hetero-Diels-Alder reaction. The stereochemistry of the cycloaddition was confirmed by NMR spectra. The antioxidant and antimicrobial activity screening identified 7 compounds (3c, 3e, 3f, 3g, 3k, 3l, 3p) with a high level of free radical scavenging (43-77% DPPH assay), and compounds with significant influence on Staphylococcus aureus, Bacillus subtilis and Candida albicans (MIC 3.13-6.25 [Formula: see text]), but slight effect on Escherichia coli.

Excessive production of reactive oxygen species, oxidative stress (OS) and metabolic dysfunction are the major contributors for the development and progression of pulmonary arterial hypertension (PAH). Sildenafil was shown to improve pro-/antioxidant balance but its long–term effects on PAH are not well understood. This work was aimed to study the effect of the prolonged use of sildenafil on the metabolic dysfunction associated with redox imbalance in PAH. In the PAH patients treated at least 12 months with sildenafil, who did not show signs of disease progression, the parameters of lipid peroxidation, endocannabinoid system, redox signaling and apoptosis were measured at the follow up visits scheduled three months apart. Our results showed increase in hydroxynonenal, hydroxyhexanal, and malonic dialdehyde together with decrease in phospholipids derived linoleic, arahidonic and docosahexanoic fatty acids after three month of sildenafil therapy. Also lowering in endocannabinoid anandamide and its receptor 2-arachidonoyl glycerol and increased level of NF-kB were noted. Clinically PAH patients did not show any signs of deterioration by 6 minute walk test, functional class, heart rate variability and pulmonary hemodynamics followed by echocardiography during the study. Obtained results demonstrate that prolonged use of sildenafil does not restore metabolic dysfunction associates with PAH. Concurrent target use of antioxidants would beneficially influence the outcome.

The article presents the synthesis of 5-ene-4-thiazolidinone derivatives with pyrazole core linked by enamine group. The structure and purity of compounds were confirmed by analytical and spectral data including X-ray analysis. Target compounds were screened for their anticancer activity and selective antileukemic action was confirmed. 5-[5-(2-Hydroxyphenyl)-3-phenyl-4,5-dihydropyrazol-1-ylmethylene]-3-(3-acetoxyphenyl)-2-thioxothiazolidin-4-one (compound 1) was selected as most active agent against HL-60 and HL-60/ADR cell lines; IC50 = 118 nM/HL-60 with low toxicity towards pseudonormal cells. The mitochondria-depended apoptosis was identified as the main mode of 1 action. Moreover compound's effect induces G0/G1 arrest of the treated cells and causes inhibition of cell division and is related with activation of ROS production.

The synthesis and evaluation of the anticancer activity of new acylated oximes derivatives of oleanolic acid with 4-thiazolidinone-3(5)-carboxylic acid moieties were described. Newly synthesized compounds were elucidated on the basis of elemental analyses and spectral data (IR, 1H, and 13C NMR). Anticancer activity of the tested compounds has been evaluated in vitro at National Cancer Institute (NCI) in which some structure activity relationships (SARs) were discussed. Among the tested compounds, 3-[(2,4-thiazolidinedione-5-ylidene)-carboxyimino]olean-12-en-28-oic acid methyl ester (IVm) was superior to other related compounds with mean values of pGI50 = 5.51/5.57, pTGI = 5.09/5.13, and pLC50 = 4.62/4.64, low toxicity and moderate activity level in vivo hollow fiber assay.

Utilization of 4-thioxo-2-(thi)oxothiazolidines in the synthesisof new fused thiopyrano[2,3- D][1,3]thiazolederivatives under Knoevenagel and HETERO-Diels-Alderreaction conditions has been studied.

The synthesis and evaluation of the anticancer activity of 3'-aryl-5'-arylidene-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-diones and spiro[3H-indole-3,2'-thi-azolidine]-2,4'(1H)-dione-3'-alkanoic acid esters were described. The structure of the compounds was determined by (1)H and (13)C NMR and their in vitro anticancer activity was tested in the National Cancer Institute. Among the tested compounds, (5'Z)-5'-(benzylidene)-3'-(4-chlorophenyl)spiro[3H-indole-3,2'-thia-zolidine]-2,4'(1H)-dione (IIa) and (5'Z)-3'-(4-chlorophenyl)-5'-[4-(1-methylethyl)-benzylidene]spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-dione (IIb) were superior to other related compounds.

Oxidative stress (OS) and decreased heart rate variability (HRV) are known to be associated with overtraining in athletes. Therefore it is extremely important to estimate profoundness of OS and efficiency of its correction with easy-to-use noninvasive methods. The impact of oil derived from the amaranth (Amaranthus cruentus L.) seeds (AmO) on some parameters of aerobic metabolism and HRV was studied in elite athletes. Possible mechanisms explaining the relationship between HRV and aerobic metabolism were estimated with correlation analysis. The effects of AmO administration (1 ml of concentrated oil per day for 21 days) were studied in 36 competitive male athletes. Short time ECG records were performed in supine and orthostatic position before and after AmO administration, time and frequency domain HRV parameters were calculated. The activities of catalase, superoxide dismutase, levels of thiobarbituric acid reactive species, oxidative modification proteins (OMP), medium mass molecules, hemoglobi...

The use of 3-substituted-2-mercaptoacrylic acids, synthesized via hydrolysis of 5-ylidenerhodanines for the preparation of 2,3,5-trisubstituted-4-thiazolidinones via a new variant of the one-pot, three-component reaction has been studied.

To date treatment of trypanosomiasis urgently requires new effective and non-toxic drugs. The article covers some of the achievements in the search for new antitrypanosomal agents; also the “validated” biological targets used in the antitrypanosomal agents design are outlined. The major part of the manuscript focuses on the synthetic small molecules, such as thiosemicarbazone and thiazole (as their cyclic analogues) derivatives, benzofuran derivatives, heterocycles bearing nitro group etc. Also, the attractiveness of metal complexes and well known drugs as sources for antitrypanosomal agent design is discussed.

The synthesis and antitumor activity screening of 4-aminothiazol-2(5H)-one derivatives were performed. The absence of possible 4-amino-imino tautomerism of thiazolidinones-2 has been confirmed based on the study of the molecule structures. The existence of the alone amino-form was confirmed. An anticancer activity screening was performed within the Developmental Therapeutics Program (National Cancer Institute/NIH, USA). Tested compounds possess low to moderate anticancer activity (average values - 60 cancer cell lines assay) with significant selective action on certain cancer cell lines (CCRF-CEM and RPMI-8226/leukemia, U251/CNS cancer, RFX 393/renal cancer, OVCAR/ovarian cancer etc.). The advantage of 5-ylidene-4-R-amino derivatives in comparison with compounds with free amino group was shown. Some structure-activity findings, the comparison of target compounds with isomeric 5-ylidene-2-imino(amino)thiazol-4(5H)-ones, as well as COMPARE analysis were described. Among the tested compounds (Z)-5-(furan-2-ylmethylidene)-4-(4-chlorophenylamino)thiazol-2(5H)-one (IIIk) and (Z)-5-(4-diethylaminophenylmethylidene)-4-(4-hydroxy-5-isopropyl-2-methylphenylamino)thiazol-2(5H)-one (IIIp) possessed the highest levels of activity.

To date treatment of trypanosomiasis urgently requires new effective and non-toxic drugs. The article covers some of the achievements in the search for new antitrypanosomal agents; also the "validated" biological targets used in the antitrypanosomal agents design are outlined. The major part of the manuscript focuses on the synthetic small molecules, such as thiosemicarbazone and thiazole (as their cyclic analogues) derivatives, benzofuran derivatives, heterocycles bearing nitro group etc. Also, the attractiveness of metal complexes and well known drugs as sources for antitrypanosomal agent design is discussed.

Amaranth oil has several health benefits. It has lipid lowering, anti-diabetic, immune modulatory and cytoprotective properties, activates the function of mitochondria and improves heart rate variability. It has been suggested that the effect of amaranth oil on redox status is involved in this multitude of cellular and clinical influences of the oil. We examined whether amaranth oil can modify free radical production. EPR experiments with amaranth oil dissolved in DMSO showed scavenging of carbon centered radicals but not of oxygen centered radicals. Moreover, a concentration dependent scavenging effect of amaranth oil on ultrasound-induced radicals was observed. However, in adrenaline autoxidation experiments amaranth oil showed a strong prooxidant action through activation of superoxide anion formation. This two-sided effect of amaranth oil, i.e. both anti- and pro-oxidant action, was corroborated in human lung fibroblasts that were exposed to amaranth oil. At low concentrations of amaranth oil, fibroblasts were protected against oxidative stress, whereas in incubations with high amaranth oil concentrations more H2O2-induced intracellular radical damage was found. We suggest that mild pro-oxidant activity could be the underlying mechanism in the health beneficial effect of amaranth oil.

In this paper the oil from seeds of Amaranthus cruentus L. (AmO) was shown to be an efficient modulator of the physical chemical properties of artificial lipid and rat hepatocyte plasma membranes. AmO improved the membrane stability, their stress resistance and the adsorption of neurotensin to plasma membranes with the distinct biphasic interactions being observed even after adrenalin stress exposure. The analysis of pro-/antioxidant balance in rat blood revealed a mild prooxidant activity after AmO intake, which was accompanied by accumulation of oxidative destruction products in plasma membranes. This prooxidant action of AmO was corroborated in vitro in an adrenalin autooxidation model. On the other hand, the observed improved resistance to adrenalin stress in AmO supplemented rats was associated with an antioxidant response in blood and plasma membrane studies. The AmO effects can be attributed to the modulation of the metabolic pathways involved into oxygen and free radical homeostasis.

The aim of present research was to study the effects of Amaranth oil (AmO) supplementation on aerobic metabolism and heart rate variability (HRV) in type 2 diabetes mellitus patients and in athletes. Several parameters of aerobic metabolism and HRV were assessed. Supplementation with AmO caused mild pro-oxidant activity resulting in improved uptake of oxidative destruction products and modulation of catalase and SOD activity with subsequent development of an antioxidant effect. These findings were very distinct in athletes but less pronounced in diabetics. Redistribution of haemoglobin ligands in athletes indicates involvement of haemoproteins in free radical reactions during AmO supplementation. Improvement in HRV by daily consumption of AmO as observed in both study groups suggested increased production of endogenous oxygen and enhancement of the cardio-respiratory function. The advantage of activation of aerobic metabolism in OS-related disorders resulting in improved self-organization of the living system and hormetic reaction mechanisms are discussed.

The aim was analysis of 4-thiazolidinones and related heterocyclic systems anticancer activity data and formation of some rational design directions of potential anticancer agents. Synthetic research carried out in Danylo Halytsky Lviv National Medical University (DH LNMU) allowed us to propose a whole number of new molecular design directions of biological active 4-thiazolidinones and related heterocyclic systems, as well as obtain directed library that numbers over 5000 of novel compounds. At the present time in vitro anticancer activity screening was carried out for more than 1000 compounds (US NCI protocol (Developmental Therapeutic Program), among them 167 compounds showed high antitumor activity level. For the purpose of optimization and rational design of highly active molecules with optimal «drug-like» characteristics and discovering of possible mechanism of action SAR, QSAR analysis and molecular docking were carried out. The ultimate aim of the project is creating of innovative synthetic drug with special mechanism of action and sufficient pharmacological and toxicological features. Some aspects of structure–activity relationships were determined and structure design directions were proposed. The series of active compounds with high anticancer activity and/or selectivity levels were selected. Key words: synthesis, 4-thia(imida)zolidinones, thiopyrano[2,3-d]thiazoles, anticancer activity, (Q)SAR. Метою роботи був аналіз результатів дослідження протипухлинної активності 4-азолідонів і споріднених гетероциклічних сполук та формування деяких напрямків раціонального дизайну потенційних протипухлинних агентів. Синтетичні дослідження, проведені у ЛНМУ імені Данила Галицького, дозволили запропонувати низку нових спрямувань молекулярного дизайну біологічно активних 4-тіазолідинонів та споріднених гетероциклічних систем, а також одержати сфокусовану бібліотеку, яка нараховує понад 5000 нових сполук. На цей час здійснено in vitro скринінг протипухлинної активності понад 1000 сполук (US NCI протокол Developmental Therapeutic Program), з-поміж яких 167 ідентифіковано як такі, що мають високу протиракову активність. Для оптимізації і раціонального дизайну високоактивних молекул з оптимальними «лікоподібними» характеристиками та визначення можливого механізму біологічної дії проведено SAR- і QSAR-аналіз і молекулярний докінг. Кінцевою метою проекту є створення інноваційного синтетичного лікарського препарату з оригінальним механізмом дії та достатнім фармакологічним і токсикологічним профілем. Ключові слова: синтез, 4-тіа(іміда)золідинони, тіопірано[2, 3-d]тіазоли, протипухлинна активність, (Q)SAR. Цель работы состояла в анализе результатов исследования противоопухолевой активности 4-азолидонов и родственных гетероциклических систем и формировании некоторых направлений рационального дизайна потенциалных противоопухолевых агентов. Синтетические исследования, проведенные в ЛНМУ имени Данила Галицкого, позволили предложить ряд новых направлений молекулярного дизайна биологически активных 4-тиазолидинонов и родственных гетероциклических систем, а также получить сфокусированную библиотеку, насчитывающую более 5000 новых соединений. На данный момент осуществлен in vitro скрининг противоопухолевой активности (US NCI протокол Developmental Therapeutic Program) более 1000 соединений, позволивший идентифицировать 167 соединений с высоким противораковым эффектом. Для оптимизации и рационального дизайна высокоактивных молекул с оптимальными «drug-like» характеристиками и установления вероятного механизма биологического действия проведен SAR- и QSAR-анализ и молекулярный докинг. Конечная цель проекта – создание инновацинного синтетического лекарственного сресдтва с оригинальным механизмом действия, достаточным фармакологическим и токсикологическим профилем. Ключевые слова: синтез, 4-тиа(имида)золидиноны, тиопирано[2,3-d]тиазолы, противоопухолевая активность, (Q)SAR.

This study was aimed to demonstrate the efficacy of interval hypoxic training (IHT) in complex treatment of Helicobacter pylori-associated duodenal peptic ulcer disease (DPUD) by parameters of aerobic metabolism and indexes of heart rate variability (HRV). Eighty patients with H. pylori-associated DPUD were included into the study, mean age 32+/-1.8 yrs, duration of the disease up to 10 years (66.3 %). IHT was modulated using Frolov's hypoxicator (TDI-01) for 30 days after standard eradication therapy. Daily hypoxic sessions consisted of three one-minute sessions, one two-minute, and one three-minute sessions separated by one-minute intervals of room-air breathing. Use of IHT resulted in more efficient elimination of clinical symptoms, histological hallmarks of inflammation and signs of oxidative stress in glandulocytes of the gastric mucosa as determined by 4-hydroxynonenal accumulation. Moderate prooxidant activity of IHT was demonstrated by the increased level of TBARS and oxidatively modified products, normalization of hydroperoxides, middle mass molecules and atherogenic beta-lipoproteins with simultaneous increase in catalase activity and mild decline of SOD activity. Therefore, IHT appeared to be accompanied by higher intensity of redox reactions and enhanced regeneratory processes in cells and tissues. Significant increase in HRV was also noted. Such changes were associated with reduction of inflammation signs and modulation of the autonomic homeostasis in DPUD patients. In general, use of IHT in complex treatment of H. pylori in DPUD patients can be recommended to increase resistance to oxidative stress and to modulate autonomic balance and oxidative homeostasis.

This study used monoclonal antibody specific for 4-hydroxynonenal (HNE)-histidine to evaluate immunohistochemical distribution of HNE-protein adducts in gastric mucosa biopsies of 52 peptic ulcer patients (all positive for H. pylori) and of 20 healthy volunteers (eight positive and 12 negative for H. pylori). HNE-modified proteins were present in glandular epithelium in all subjects, both patients with duodenal peptic ulcer and healthy subjects. Hence, the presence of HNE did not appear to be related to the presence of H. pylori. However, in patients with duodenal peptic ulcer accumulation of HNE-protein adducts was frequently observed also in nuclei, while in the control group such subcellular distribution of HNE was not observed at all. This study shows physiological presence of HNE in human gastric mucosa, but also suggests its role in pathology of gastric dysfunction in duodenal peptic ulcer patients manifested by accumulation of HNE-protein adducts in particular in nuclei of gastric glandular epithelium.