In-vitro antiviral screening of some thiopyranothiazoles.

Thiopyranothiazoles represent a promising class of drug-like molecules with broad pharmacological profiles. Some novel derivatives of isothiochromeno[4a,4-d]thiazole and chromeno[4',3':4,5]thiopyrano[2,3-d]thiazole were synthesized and screened against diverse viruses: coronavirus SARS, Influenza Viruses of type A and type B, Adeno- and Rhinovirus, Dengue Fever Virus, Respiratory Syncytial Virus, Rift Valley Fever Virus, Tacaribe Virus, Venezuelan Equine Encephalitis Virus, as well as Vaccinia and Human Cytomegalovirus. The antiviral activity assays revealed highly active isothiochromeno[4a,4-d]thiazole bearing phenazone fragment towards Influenza Virus type A (H1N1) with the selectivity index (SI) within 150. 5,8-Dihydro-2H-[1,3]thiazolo [5',4':5,6]thiopyrano [2,3-d][1,3]thiazol-2,6(3H)-diones showed moderate antiviral activity against influenza viruses and SARS-CoV. The obtained data indicate thiopyranothiazoles as promising class of fused 4-thiazolidinone derivatives possessing antiviral effects.

Heart Rate Variability and Somatization in Adolescents With Irritable Bowel Syndrome.

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.

Evaluation of Anticancer and Antibacterial Activity of Four 4-Thiazolidinone-Based Derivatives.

Heterocycles are commonly known for their unique features, e.g., antibacterial or anticancer properties. Although many synthetic heterocycles, such as 4-thiazolidinone (4-TZD), have been synthesized, their potential applications have not yet been fully investigated. However, many researchers have reported relevant results that can be a basis for the search for new potential drugs. Therefore, the aim of this study was to evaluate the cytotoxic, cytostatic, and antibacterial effects of certain 4-thiazolidinone-based derivatives, Les-3166, Les-5935, Les-6009, and Les-6166, on human fibroblasts (BJ), neuroblastoma (SH-SY5Y), epithelial lung carcinoma (A549), and colorectal adenocarcinoma (CACO-2) cell lines in vitro. All tested compounds applied in a concentration range from 10 to 100 µM were able to decrease metabolic activity in the BJ, A549, and SH-SY5Y cell lines. However, the action of Les-3166 was mainly based on the ROS-independent pathway, similarly to Les-6009. In turn, Les-5935 and Les-6166 were able to promote ROS production in BJ, A549, and SH-SY5Y cells, compared to the control. Les-3166, Les-6009, and Les-6166 significantly increased the caspase-3 activity, especially at the concentrations of 50 µM and 100 µM. However, Les-5935 did not induce apoptosis. Only Les-5935 showed a minor cytostatic effect on SH-SY5Y cells. Additionally, the antibacterial properties of the tested compounds against P. aeruginosa bacterial biofilm can be ranked as follows: Les-3166 > Les-5935 > Les-6009. Les-6166 did not show any anti-biofilm activity. In summary, the study showed that Les-5935, Les-6009, and Les-6166 were characterized by anticancer properties, especially in the human lung cancer cell. In cases of BJ, SH-SY5Y, and CACO-2 cells the anticancer usage of such compounds is limited due to effect visible only at 50 and 100 µM.

4-thiazolidinone-based derivatives rosiglitazone and pioglitazone affect the expression of antioxidant enzymes in different human cell lines.

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.

4-Thiazolidinone-based derivatives do not affect differentiation of mouse embryo fibroblasts (3T3-L1 cell line) into adipocytes.

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.

Induction of Cyp450 enzymes by 4-thiazolidinone-based derivatives in 3T3-L1 cells in vitro.

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 ßNF, Les-2194, and Les-6166 decreased the expression of Ahr mRNA. In turn, ßNF, 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 ßNF and Les-2194. The expression of Cyp1b1 mRNA in the 3T3 cell line increased after the ßNF 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.

Anticancer properties of 5Z-(4-fluorobenzylidene)-2-(4-hydroxyphenylamino)-thiazol-4-one.

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.

Thiazolidinone/thiazole based hybrids - New class of antitrypanosomal agents.

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.

Isothiochromenothiazoles-A Class of Fused Thiazolidinone Derivatives with Established Anticancer Activity That Inhibits Growth of Trypanosoma brucei brucei.

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-d][1,3] thiazoles was investigated in an in vitro assay towards bloodstream forms of Trypanosoma brucei brucei. All compounds inhibited parasite growth at concentrations in the micromolar range. The established low acute toxicity of this class of compounds along with a good trypanocidal profile indicates that isothiochromenothiazole derivatives may be promising for designing new antitrypanosomal drugs.

Development of Predictive QSAR Models of 4-Thiazolidinones Antitrypanosomal Activity Using Modern Machine Learning Algorithms.

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.

Anticancer properties of 4-thiazolidinone derivatives depend on peroxisome proliferator-activated receptor gamma (PPARγ).

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, PPARß and PPARγ mRNA expression was studied. Moreover, after PPARα, PPARß 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, PPARß mRNA in SCC-15 cells. The anticancer potential of new studied compounds was more expressed as compared to Rosiglitazone and Pioglitazone.

5-Ene-4-thiazolidinones - An efficient tool in medicinal chemistry.

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.

Recent developments with rhodanine as a scaffold for drug discovery.

INTRODUCTION: Rhodanines, as one of the 4-thiazolidinones subtypes, are recognized as privileged heterocycles in medicinal chemistry. The main achievements include the development of drug-like molecules with numerous biological activities as well as approved drugs. Among rhodanines, 5-ene-rhodanines are of special interest, and are often claimed as pan assay interference compounds due to Michael acceptor functionality. Areas covered: Herein, the synthetic protocols for rhodanines and their transformation are reviewed. Biological activity is briefly discussed as well as biotargets, mode of actions and optimization directions. Furthermore, the utilization of 5-ene-rhodanines in Michael additions are discussed while both pro and contra arguments have been outlined within medicinal chemistry application. Expert opinion: Rhodanines remain privileged heterocycles in drug discovery. They are accessible building blocks for optimization and transformation into related heterocycles, simplified analogues and fused heterocycles with a thiazolidine framework. Michael acceptor functionality, as well as the thesis about low selectivity towards biotargets of rhodanines, must be confirmed experimentally and it cannot be based on just the presence of conjugated α,ß-unsaturated carbonyl. Moreover, the positive aspects of Michael acceptors must be considered as well as their multitarget properties. New criteria for target affinity must be found. In conclusion, rhodanines are generally not problematic per se.

Synthesis, antioxidant and antimicrobial activities of novel thiopyrano[2,3-d]thiazoles based on aroylacrylic acids.

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.

Study of novel anticancer 4-thiazolidinone derivatives.

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.

Biomarkers of oxidative and nitro-oxidative stress: conventional and novel approaches.

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.

5-Ene-4-thiazolidinones induce apoptosis in mammalian leukemia cells.

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.

Antifibrotic and anticancer action of 5-ene amino/iminothiazolidinones.

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.

Sildenafil reduces signs of oxidative stress in pulmonary arterial hypertension: Evaluation by fatty acid composition, level of hydroxynonenal and heart rate variability.

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.

Synthesis and evaluation of anticancer activity of 5-ylidene-4- aminothiazol-2(5H)-one derivatives.

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.