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The condensation of 3-formylchromones and 6-amino-5-((3,5-di-tert-butyl-4-oxocyclohexa-2,5-dien-1-ylidene)amino)-1,3-dimethyl-pyrimidine-2,4(1H,3H)-dione allowed us to synthesize chromone based hybrids containing additional pharmacophores - xanthine and sterically hindered phenol fragments. Novel compounds have been characterized by 1H and 13C NMR spectroscopy, mass spectrometry and elemental analysis. The molecular structure of compound 2 was determined by single crystal X-ray diffraction studies. Compounds 2-9, 11, 12 exhibit cytotoxic activity against human colon carcinoma cells HCT116 and breast carcinoma cells MCF7 at submicromolar concentrations. Compound 11 containing 6,8-dimethylchromone core has the highest cytotoxicity against tumor cells and lowest at non-tumor fibroblasts - this is leader compound of the obtained series with acceptable in vitro selectivity. Synthesized compounds exhibit antioxidant activity comparable to the reference drug Trolox. Combination of promising antioxidant activity and a selective antitumor cytotoxicity in vitro determines the prospects of these compounds as chemotherapy agents.

The aim of the study. To evaluate the effect of succinic acid derivatives on changes of mitochondrial function in rats under cerebral ischemia conditions. Materials and methods. In this work, the effect of succinic acid, ethylmethylhydroxypyridine succinate, and acetylaminosuccinic acid at doses of 50 mg/kg, 100 mg/kg, and 200 mg/kg (per os) on the change of the neuronal mitochondria function was studied. Cerebral ischemia was reproduced by the Tamura method. The following parameters were evaluated: changes in aerobic/anaerobic metabolism, mitochondrial membrane potential, the opening rate of the mitochondrial pore of transitional permeability and the activity of apoptotic systems. Results. During the study, it was found that the use of the test-compounds at doses of 100 mg/kg and 200 mg/kg contributed to an increase in ATP-generating activity, as well as the maximum respiration level and respiratory capacity, while accompanied by a decrease in the intensity of anaerobic metabolism reactions. Also, upon administration of the test succinic acid derivatives, an increase in the mitochondrial membrane potential and latent opening time of the mitochondrial pore transitional permeability were observed. Moreover, the activity of caspase-3 and apoptosis-inducing factor on groups treated by test objects at doses of 100 mg/kg and 200 mg/kg was significantly lower than that in untreated animals. Conclusion. The studied succinic acid derivatives contribute to the restoration of mitochondrial function in cerebral ischemia conditions, while the most effective dose can be considered to be 100 mg/kg.

Background: Stress is an integral part of human life and leads to maladaptation of the organism and needs rational pharmacological correction. Objective: The purpose of this experiment was to evaluate the adaptogenic potential of European mistletoe extracts. Methods: The work was performed on Balb/c mice. The test-objects were ethanol and aqueous extracts of European mistletoe (Viscum album L., Santalaceae) collected from pear and black poplar in dose 100 mg/kg (P.O.). Physical overloads were modeled in the forced swimming test. The analyzed parameters were: the duration of animals swimming, changes in the parameters of mitochondrial respiration, the concentration of ATP, activity of caspase-3, and apoptosis-inducing factor in the muscles and lactic acid in the blood serum of animals. The state of the pro / antioxidant system and acute toxicity of the test-extracts was also evaluated. Results: The study found that the LD50 of the test-extracts was more than 5000 mg/kg (P.O.). Ethanol extracts (40 and 70 %) with a single administration had the greatest impact on the physical strain of mice. In the course administration of 40 % ethanol mistletoe extracts the swimming time of mice was increased by 3.4 and 5.05 times (P < 0.05) from black poplar and pear, respectively. Also, the use of 40 % extracts contributed to the normalization of the pro/antioxidant balance, the restoration of the cell energy metabolism, and the decrease of the intensity of the apoptotic reactions. Conclusion: The study showed that the 40 % ethanol extracts from European mistletoe (host plants: pear and black poplar) potentially can be used as adaptogenic agents.

Background: Alzheimer’s disease is the main form of dementia, which affects more than46 million people every year. In the pathogenesis of Alzheimer’s disease, a significant roleplayed mitochondrial dysfunction, which is a promising pharmacotherapeutic target ofneuroprotective therapy. In this regard, this study aimed to evaluate the effect of the 4-hydroxy-3,5-ditretbutyl cinnamic acid on changes of mitochondrial function in experimental Alzheimer’sdisease induced by Aβ injection in rats. Methods: Alzheimer’s disease was modeled on Wistar rats by injecting a fragment of β-amyloid(Aß 1-42) into the CA1 part of the hippocampus. The test-compound (4-hydroxy-3,5-ditretbutylcinnamic acid, 100 mg/kg, per os) and the reference drugs (resveratrol, 20 mg/kg, per os andEGB671, 100 mg/kg, per os) were administered for 60 days after surgery. The restoration of amemorable trace in animals was evaluated in the Morris water maze test. The concentrationof β -amyloid, Tau-protein, and changes in parameters characterizing mitochondrial function(cellular respiration, concentration of mitochondrial ROS, activity of apoptosis reactions(caspase-3 and apoptosis induced factor) were also determined. Results: This study showed that the administration of 4-hydroxy-3,5-ditretbutyl cinnamic acidat a dose of 100 mg/kg (per os) in rats with reproduced Alzheimer’s disease contributed to thenormalization of mitochondrial respiratory function. It was expressed in the normalizationof aerobic metabolism, increased activity of respiratory complexes and stabilization ofmitochondrial membrane potential. Also, when animals were treated with 4-hydroxy-3,5-ditretbutyl cinnamic acid, there was a decrease in the concentration of intracellular calcium(by 39.7% (p

The aim of the study was to assess the effect of certain derivatives of cinnamic acids on changes of the tricarboxylic acid cycle enzymes activity under experimental cerebral ischemia. Materials and methods. Brain ischemia was modeled by irreversible right-sided coagulation of the middle cerebral artery. Test compounds: 4-hydroxy-3,5-ditretbutyl cinnamic acid, coumaric, coffee, synapic, cinnamic, 4-hydroxycinnamic and ferulic acids, as well as a reference drug — succinic acid was administered at a dose of 100 mg / kg per os for 3 days after the reproduction of ischemia. Then, changes in the activity of aconitase, citrate synthase, and α-ketoglutarate dehydrogenase were evaluated in the supernatant of the brain. Results. The use of all the studied compounds and the reference drug helped to restore the activity of enzymes of the tricarboxylic acid cycle. The most pronounced results were obtained when animals were treated by 4-hydroxy-3,5-ditretbutyl cinnamic acid, against the background of which the activity of citrate synthase was higher than in animals treated by succinic, coumaric, coffee, synapic and ferulic acids by 1.53 ( p < 0.05), 1.41 ( p < 0.05), 1.4 ( p < 0.05), 1.46 ( p < 0.05) and 1.41 ( p < 0.05) times, respectively. Also, with the administration of 4-hydroxy-3,5-ditretbutyl cinnamic acid, the activity of aconitase was higher compared to rats that were administered with succinic, coumaric, coffee, synapic and ferulic acids by 2.47 ( p < 0.05), 2.49 ( p < 0.05), 3.44 ( p < 0.05), 2.59 ( p < 0.05) and 1.9 ( p < 0.05) times, respectively. Conclusion. The administration of the studied in this work cinnamic acid derivatives helps to restore the activity of citrate synthase, aconitase, and α-ketoglutarate dehydrogenase in rats under conditions of cerebral ischemia. The most pronounced changes in the activity of enzymes were obtained with the iadministration of 4-hydroxy-3,5-ditretbutyl cinnamic acid.

Objective: to estimate the safety of application of new derivatives of chromon-3-aldehyde and the possibility of its application for correction of muscular dysfunction. Materials and methods: the experiment was performed on 120 mice-males of the Balb/c line. Research objects - halogenated derivatives of chromon-3-aldehyde under codes of X3AF and X3ACl. The safety assessment of its application included the determination ofits single dose toxicity with calculation of LD50 using the Finni method. Further, the influence of derivatives on the development of muscular dysfunction using the myostimmulation test after its preventive introduction was studied. Results: the conducted research showed that new halogenated derivatives of chromon-3-aldehyde under codes of X3AF and X3ACl possessed an optimum profile of safety and wereable to alleviate the manifestations of muscle dysfunction. At the same time the substanceX3AF surpassed the substance X3ACl and comparison drug «Mildronat» in the size of pharmacological action. Conclusions: the low toxicity and high pharmacological efficiency of new halogenated derivatives of chromon-3-aldehyde makes these compounds the perspective ob

Ischemic stroke is a disease with complex pathogenesis that requires timely and rational pharmacological intervention. One possible treatment for this condition may be to improve mitochondrial function as part of neuroprotective therapy.Cerebral ischemic damage was reproduced by middle cerebral artery permanent occlusion in Wistar male rats. 4-hydroxy-3,5-di-tretbutyl cinnamic acid was injected intraperitoneally in dose range of 25 mg/kg, 50 mg/kg, and 100 mg/kg. The time of administration was 3 days from the ischemia modeling. Further, changes in the rats' cognitive functions in the Morris water maze test were evaluated, and the state of mitochondrial function in the hippocampal tissue was studied.The study showed that the use of the studied compound dose-dependently improved mitochondrial function in the rat hippocampus. At doses of 20 mg/kg and 50 mg/kg, administration of the test substance increased citrate synthase activity by 55.1% (Administration of 25 mg/kg and 50 mg/kg 4-hydroxy-3,5-di-tretbutyl cinnamic acid demonstrated neuroprotection action on hippocampal cells under the conditions of irreversible brain ischemia.

The aim of the study was to evaluate experimentally, the myoprotective effect of new chromone-3-aldehyde derivatives in conditions of muscular dysfunction and to establish a potential mechanism of myoprotective activity – the blockade of the function of sirutin 2. Materials and methods. The effect of new chromone-3-aldehyde derivatives on the development of muscular dysfunction under the conditions of an electromiostimulation test, was studied. The degree of muscle fatigue was evaluated in the «grip-strength» and through test biochemical assays (determination of the activity of lactate dehydrogenase, creatine kinase, concentration of lactic and pyruvic acids, creatinine, myoglobin, and total protein) to determine the possible mechanism of action of the test compounds (5 new derivatives of chromone-3-aldehyde) and their effect on the function of sirtuin 2 was evaluated. Results. The study showed that chromone-3-aldehyde derivatives have a pronounced myoprotective effect associated with low toxicity (class 5 toxicity according to the GHS classification), which was confirmed by the results of the «grip-strength» test and biochemical tests data. Test compounds under the X3AC1, X3AOAC and X3AN codes evince sirtuin 2 inhibitory activity, which was reflected in a decrease in its concentration by 63.6% (p Conclusion. The study showed that chromone-3-aldehyde derivatives are promising subjects for further study with the goal of creating a drug with a high myoprotective effect and an optimal safety profile.

Nowdays it is established that ischemic brain damage like ischemic stroke is one of the leading cause of death and disability in the population that assumes relevance development of anti-ischemic drugs. The work studied the anti-hypoxic and anti-ischemic effect of 7 plant extracts. Antihypoxic activity was assessed on models of hypobaric, hypercapnic, histotoxic, hematotoxic hypoxia. Anti-ischemic activity of test-extracts was studied on the focal cerebral ischemia model. Administration of Tagetes patula, Gaillardia pulchella, Sorbaria sorbifolia, Grossularia reclinata, Ribes nigrum, Rubus caesius and Lysimachia punctata extracts contributed to the necrosis zone reduction by 56.6% (p

Background and Purpose: Ischemic stroke remains one of the leading causes of death in the population. In addition, mitochondrial dysfunction is an essential part of the pathogenesis of cerebral ischemia and is a promising pharmacotherapeutic target. Experimental Approach: the work was performed on male Wistar rats, which were simulated cerebral ischemia by irreversible occlusion of the middle cerebral artery. 4-hydroxy-3,5-di-tret-butyl cinnamic acid (25 mg/kg, 50 mg/kg and 100 mg/kg) was injected intraperitoneally for 3 days after ischemia (daily). On the 4th day of the experiment, the changes of rat’s cognitive functions in the Morris water maze test, cellular respiration processes, the activity of the mitochondrial respiratory chain complexes and citrate synthase activity, the intensity of oxidative stress and apoptosis reactions were assessed. Key Results: it was found that the administration of 4-hydroxy-3,5-di-tret-butyl cinnamic acid at doses of 25 mg/kg and 50 mg/kg practically equivalently promotes the restoration of aerobic metabolism reactions and the activity of the mitochondrial respiratory chain complexes, decrease of the intensity of oxidative stress reactions and apoptosis, as well as an increase in the activity of citrate synthase. As a result, the restoration of mitochondrial function in the hippocampal cells contributed to the restoration of the animal’s spatial memory. Conclusion and Implications: a study showed that 4-hydroxy-3,5-di-tret-butyl cinnamic acid at doses of 25 mg/kg and 50 mg/kg has a neuroprotective effect on hippocampal neurons under conditions of permanent occlusion of the middle cerebral artery, realized by restoration of mitochondrial function.

The reaction of 3-formylchromones and 4-((2-aminophenyl)imino)-2,6-di‑tert-butylcyclohexa-2,5-dienone gave a series of N-substituted benzimidazole derivatives, characterized by 1H and 13C NMR spectroscopy, mass spectrometry and elemental analysis. The molecular structures of compounds 1 and 4 were determined by single crystal X-ray diffraction studies. Compounds 1–8 exhibit cytotoxic activity against human colon cancer cells HCT116 and breast cancer cells MCF7 at submicromolar concentrations. Compound 6 is more active against tumor cells than non-malignant fibroblasts. Compounds 1, 3, 5 and 7 exhibit antioxidant activity comparable to the reference drug Trolox.

Synthetic derivatives of flavonoids are a promising class of biologically active compounds. Here we report a family of (chromon-3-yl)-bis(3,5-dimethylpyrazol-1-yl)methanes bearing various substituents in chromone fragment. They have been studied for the antioxidant activity and spectra of their biological activity have been predicted. New Ni(II), Co(II) and Pd(II) complexes, supported by 3-[bis(3,5-dimethylpyrazol-1-yl)methyl]-6-fluoro-chromen-4-one, have been synthesized and characterized using 1H NMR, high-resolution MALDI-TOF spectrometry and elemental analyses. The molecular structures of 3-[bis(3,5-dimethylpyrazol-1-yl)methyl]-chromen-4-one 1, 3-[bis(3,5-dimethylpyrazol-1-yl)methyl]-6‑chloro-chromen-4-one 7 and Co dichloride complex with 3-[bis(3,5-dimethylpyrazol-1-yl)methyl]-6-fluoro-chromen-4-one 15 have been determined using single crystal X-ray diffraction studies. The cytotoxic activity of metal complexes and the ligand 1 has been studied on 4 cell lines of different histological origin. It has been observed that Ni complex exhibits higher cytotoxicity against breast cancer cells MCF7 and Co complex has almost the same effect on the growth of all studied tumor cells.

Background and objectives: To evaluate the effect of a new pyrimidine derivative on the change of mitochondrial function in experimental chronic traumatic encephalopathy. Materials and methods: The study was performed on male mice of the BALB/c line (acute toxicity was assessed) and male rats of the Wistar line, which were modeled chronic traumatic encephalopathy by the method of free fall of the load (weight 150 g from a 50 cm height). The injury to rats was reproduced once a day for 7 days. Further, cognitive functions, changes in sensorimotor deficiency, cerebral blood flow, neuron-specific enolase(NSE), S100&beta, glial fibrillary acidic protein (GFAP) (in blood serum) and &beta, amyloid, adenosine triphosphate (ATP) (in brain tissue supernatant) were evaluated. Mitochondrial respiration was also measured. Choline alfoscerate (100 mg/kg) was used as a reference drug. Results: The study found that the use of a new pyrimidine derivative contributed to the preservation of the mitochondrial respirometric function and cognitive functions in rats. In addition, against the administration of test-object marked increase in the concentration of ATP, the velocity of cerebral blood flow was 4.2 times (p &lt, 0.05) and 35.6% (p &lt, 0.05), respectively, as well as reduced concentration and GFAP, NSE, S100&beta, &beta, amyloid and sensorimotor deficit at 2.7 (p &lt, 0.05) times, 2 times (p &lt, 0.05), 2.4 times (p &lt, of 30.4% (p &lt, 0.05 and 46.5% (p &lt, 0.05), respectively. The LD50 (per os) for the test-object was 4973.56 &plusmn, 573.72 mg/kg. Conclusion: Based on the obtained data, high therapeutic efficacy and low systemic toxicity of the application are assumed 4-{2-[2-(3,4-dimethoxyphenyl)-vinyl]-6-ethyl-4-oxo-5-phenyl-4H-pyrimidine-1-Il}benzsulfamide in chronic traumatic encephalopathy.

To date, stress is a common medical and socially significant disease that requires rational pharmacotherapeutic correction. The anti-stress properties of ethnolic and aqueous extracts obtained from leaves of Ribes nigrum L., inflorescences of Gaillardia pulchella Foug., stems of Lysimachia punctata L were studied in this work. Acute stress was modeled by immobilization of rats for 2 hours. The test-extracts were administered per os prophylactically in a dose of 1/20 of LD 50 (2000 mg/kg). The following parameters were evaluated: organs mass coefficient (adrenal glands, thymus, spleen), the number of stomach erosion; the biochemical changes in the blood serum (adrenaline, cortisol, total protein and glucose concentration); the mitochondrial function parameters in brain and myocardium (evaluation of mitochondrial pore transitional permeability opening and mitochondrial membrane potential). 70% ethanol extract from Gaillardia pulchella Foug. inflorescences has the highest anti-stress activity, the course application of which contributed to the normalization of the weight index of organs, a decrease in glucose concentration by 64.5% (p

Conducted research devoted to the study of potential mechanisms of action implementation endotelioproteсtion 4-hydroxy- 3,5-di-tretbutyl cinnamic acid in experimental conditions simulated cerebral ischemia in rats. The research found that the cerebral ischemia in rats is accompanied by the development of endothelial dysfunction, expressed in increasing the concentration of asymmetric dimethylarginine, nNOS, iNOS and PKC, as well as reducing the concentration of eNOS. Introduction of sulodexide (to a greater extent compared with thioctic acid and mexidol restores endothelial function in conditions of brain ischemia in rats. The use of 4-hydroxy-3,5-di-tretbutyl cinnamic acid helped reduce the concentration of ADMA, nNOS, iNOS and PKC on 83.9% (p >0.05), 60.6% (p >0.05), 61. 9% (p >0.05), 108.6% (p >0.05), respectively, as well as improve the content of eNOS at 114.2% (p >0.05), thereby contributing to the correction that has developed in conditions cerebral ischemia, endothelium dysfunction