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S O Bachurin - One of the best experts on this subject based on the ideXlab platform.
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Molecular construction of multitarget Neuroprotectors 4.* Synthesis and biological activity of conjugates of carbazoles and tetrahydrocarbazoles
Russian Chemical Bulletin, 2016Co-Authors: V B Sokolov, T A Epishina, T V Goreva, A. Yu. Aksinenko, E F Shevtsova, L G Dubova, P N Shevtsov, E. S. Dubrovskaya, S. G. Klochkov, S O BachurinAbstract:Unknown conjugates of carbazoles and tetrahydrocarbazoles were obtained by the alkylation of carbazoles and tetrahydrocarbazoles with 3,6-substituted 9-oxiranylmethylcarbazoles. The influence of synthesized 1-(9 Н -carbazol-9-yl)-3-(1,2,3,4-tetrahydro-5 Н -pyrido[4,3- b ]-indol-5-yl)propan-2-ones on functional characteristics of brain mitochondria has been studied. The potential neuroprotective activity of a several representatives of conjugates has been demonstrated using glutamate toxicity model.
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molecular construction of multitarget Neuroprotectors 4 synthesis and biological activity of conjugates of carbazoles and tetrahydrocarbazoles
Russian Chemical Bulletin, 2016Co-Authors: V B Sokolov, Yu A Aksinenko, T A Epishina, T V Goreva, Sergey G Klochkov, E F Shevtsova, L G Dubova, P N Shevtsov, E. S. Dubrovskaya, S O BachurinAbstract:Unknown conjugates of carbazoles and tetrahydrocarbazoles were obtained by the alkylation of carbazoles and tetrahydrocarbazoles with 3,6-substituted 9-oxiranylmethylcarbazoles. The influence of synthesized 1-(9Н-carbazol-9-yl)-3-(1,2,3,4-tetrahydro-5Н-pyrido[4,3-b]-indol-5-yl)propan-2-ones on functional characteristics of brain mitochondria has been studied. The potential neuroprotective activity of a several representatives of conjugates has been demonstrated using glutamate toxicity model.
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molecular design of multitarget Neuroprotectors 2 synthesis and bioactivity of carbazole γ carboline conjugates
Russian Chemical Bulletin, 2016Co-Authors: V B Sokolov, Yu A Aksinenko, T A Epishina, T V Goreva, V Grigor V Ev, D V Vinogradova, E F Shevtsova, L G Dubova, P N Shevtsov, S O BachurinAbstract:Earlier unknown conjugates of carbazoles and γ-carbolines were obtained by the reaction of 3,6-substituted 9-oxiranylmethylcarbazoles and 2,8-substituted 2,3,4,5-tetrahydro-1H-pyrido-[4,3]indoles. The effects of synthesized 1-(9H-carbazol-9-yl)-3-(1,2,3,4-tetrahydro-5H-pyrido-[4,3-b]indol-5-yl)propan-2-ones and their hydrochlorides on neuronal NMDA receptors, polymerization of tubulin to form microtubules, and functional characteristics of rat liver mitochondria were studied.
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synthesis biological activity distribution and membrane permeability of novel spiro thiazines as potent Neuroprotectors
European Journal of Medicinal Chemistry, 2014Co-Authors: Svetlana V Blokhina, A N Proshin, Tatyana V Volkova, S O Bachurin, Angelica V Sharapova, Marina V Olkhovich, German L PerlovichAbstract:Abstract New spiro-derivatives of 1,3-thiazine – potential Neuroprotectors have been synthesized. It has been determined that the obtained compounds are biologically active and capable of blocking the glutamate-induced calcium ion uptake into synaptosomes of rat brain cortex. The inhibitory activity of the test substances was shown to depend on the chemical nature and structure of the substituents bound with an exocyclic nitrogen atom. Non-polar alkyl and polar radicals with halogen, oxygen and nitrogen atoms were used as substituents. It is typical of the active spiro-thiazines to have alkyl substituents in ortho- and para-position of the benzene ring. Among the investigated spiro-thiazines it is the derivatives with ethyl- and isopropyl-groups in the aril part of the molecules that are the lead-compounds with a high inhibitory ability. We measured the distribution coefficients of the substances in octanol/buffer and hexane/buffer systems and made conclusions about the ability of the investigated drug-like compounds to penetrate the biological membranes. By using the parabolic model we derived a quadratic equation that allowed us to evaluate quantitatively the inhibitory activity of spiro-thiazines with hydrophobic substituents based on lipophilicity data. We also studied the permeability through the phospholipidic membrane and introduced a correlation equation describing the dependence of the investigated spiro-thiazines activity on the descriptors characterizing the donor–acceptor properties.
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novel 1 2 4 thiadiazole derivatives as potent Neuroprotectors approach to creation of bioavailable drugs
Molecular Pharmaceutics, 2012Co-Authors: German L Perlovich, A N Proshin, Tatyana V Volkova, L N Petrova, S O BachurinAbstract:Novel 1,2,4-thiadiazole derivatives as potent Neuroprotectors were synthesized and identified. Their ability to inhibit the glutamate stimulated Ca uptake was measured. Permeation experiments on the phospholipid membranes were conducted, and the apparent permeability coefficients were obtained. The partition coefficients in n-octanol/buffer (pH 7.4) and n-hexane/buffer (pH 7.4) immiscible phases (as model systems for characterizing gastrointestinal tract membranes and BBB) were determined. A classification of the studied compounds from the standpoint of “permeability–activity” properties was proposed.
Tatyana V Volkova - One of the best experts on this subject based on the ideXlab platform.
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impact of biorelevant media on pharmacologically important properties of potential Neuroprotectors based on 1 2 4 thiadiazole
Journal of Molecular Liquids, 2017Co-Authors: Tatyana V Volkova, A N Proshin, Ekaterina Chibunova, Oleg Silyukov, Irina V TerekhovaAbstract:Abstract Pharmacologically important properties of two structurally related biologically active 1,2,4-thiadiazole derivatives were investigated in phosphate buffer and biorelevant media FaSSIF simulating the intestinal fluid. Solubility and distribution coefficients of thiadiazoles were found to be substantially higher in FaSSIF than in blank buffer. On the contrary, permeability coefficients decreased and dissolution rate was not changed in FaSSIF. Mechanism of FaSSIF components action on thiadiazoles behavior was revealed using 1H NMR and UV-spectroscopy.
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synthesis biological activity distribution and membrane permeability of novel spiro thiazines as potent Neuroprotectors
European Journal of Medicinal Chemistry, 2014Co-Authors: Svetlana V Blokhina, A N Proshin, Tatyana V Volkova, S O Bachurin, Angelica V Sharapova, Marina V Olkhovich, German L PerlovichAbstract:Abstract New spiro-derivatives of 1,3-thiazine – potential Neuroprotectors have been synthesized. It has been determined that the obtained compounds are biologically active and capable of blocking the glutamate-induced calcium ion uptake into synaptosomes of rat brain cortex. The inhibitory activity of the test substances was shown to depend on the chemical nature and structure of the substituents bound with an exocyclic nitrogen atom. Non-polar alkyl and polar radicals with halogen, oxygen and nitrogen atoms were used as substituents. It is typical of the active spiro-thiazines to have alkyl substituents in ortho- and para-position of the benzene ring. Among the investigated spiro-thiazines it is the derivatives with ethyl- and isopropyl-groups in the aril part of the molecules that are the lead-compounds with a high inhibitory ability. We measured the distribution coefficients of the substances in octanol/buffer and hexane/buffer systems and made conclusions about the ability of the investigated drug-like compounds to penetrate the biological membranes. By using the parabolic model we derived a quadratic equation that allowed us to evaluate quantitatively the inhibitory activity of spiro-thiazines with hydrophobic substituents based on lipophilicity data. We also studied the permeability through the phospholipidic membrane and introduced a correlation equation describing the dependence of the investigated spiro-thiazines activity on the descriptors characterizing the donor–acceptor properties.
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novel 1 2 4 thiadiazole derivatives as potent Neuroprotectors approach to creation of bioavailable drugs
Molecular Pharmaceutics, 2012Co-Authors: German L Perlovich, A N Proshin, Tatyana V Volkova, L N Petrova, S O BachurinAbstract:Novel 1,2,4-thiadiazole derivatives as potent Neuroprotectors were synthesized and identified. Their ability to inhibit the glutamate stimulated Ca uptake was measured. Permeation experiments on the phospholipid membranes were conducted, and the apparent permeability coefficients were obtained. The partition coefficients in n-octanol/buffer (pH 7.4) and n-hexane/buffer (pH 7.4) immiscible phases (as model systems for characterizing gastrointestinal tract membranes and BBB) were determined. A classification of the studied compounds from the standpoint of “permeability–activity” properties was proposed.
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novel isothiourea derivatives as potent Neuroprotectors and cognition enhancers synthesis biological and physicochemical properties
Journal of Medicinal Chemistry, 2009Co-Authors: German L Perlovich, A N Proshin, Tatyana V Volkova, L N Petrova, Sergey V Kurkov, Vlaimir V Grigoriev, S O BachurinAbstract:Various salts of 3-allyl-1,1-dibenzyl-2-ethyl-isothiourea, 1 (hydrochloride), 2 (hydrobromide), and 3 (hydroiodide), were synthesized. Ca-blocking properties of these salts were studied. Comparative analysis of the potentiating effects of 3 and cyclothiazide (CT) on transmembrane currents caused by kainic acid (KA) and glutamate in Purkinje neurons was performed. Analysis of the effects of 1 on N-methyl-d-aspartate (NMDA) receptors was performed on primary culture of heterogeneous neurons of rat cerebral cortex. Single crystals were grown and X-ray diffraction experiments solving the crystal structures of 1−3 were carried out. Analysis of conformations of the molecules in the crystal lattices was performed. The temperature dependencies of the solubility of 1−3 in water and n-octanol were obtained, and the thermodynamic parameters of solubility process were calculated. The effect of halogen atoms on the solubility was analyzed. The partitioning processes in the water−octanol system were studied at 25 °C. C...
A N Proshin - One of the best experts on this subject based on the ideXlab platform.
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impact of biorelevant media on pharmacologically important properties of potential Neuroprotectors based on 1 2 4 thiadiazole
Journal of Molecular Liquids, 2017Co-Authors: Tatyana V Volkova, A N Proshin, Ekaterina Chibunova, Oleg Silyukov, Irina V TerekhovaAbstract:Abstract Pharmacologically important properties of two structurally related biologically active 1,2,4-thiadiazole derivatives were investigated in phosphate buffer and biorelevant media FaSSIF simulating the intestinal fluid. Solubility and distribution coefficients of thiadiazoles were found to be substantially higher in FaSSIF than in blank buffer. On the contrary, permeability coefficients decreased and dissolution rate was not changed in FaSSIF. Mechanism of FaSSIF components action on thiadiazoles behavior was revealed using 1H NMR and UV-spectroscopy.
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synthesis biological activity distribution and membrane permeability of novel spiro thiazines as potent Neuroprotectors
European Journal of Medicinal Chemistry, 2014Co-Authors: Svetlana V Blokhina, A N Proshin, Tatyana V Volkova, S O Bachurin, Angelica V Sharapova, Marina V Olkhovich, German L PerlovichAbstract:Abstract New spiro-derivatives of 1,3-thiazine – potential Neuroprotectors have been synthesized. It has been determined that the obtained compounds are biologically active and capable of blocking the glutamate-induced calcium ion uptake into synaptosomes of rat brain cortex. The inhibitory activity of the test substances was shown to depend on the chemical nature and structure of the substituents bound with an exocyclic nitrogen atom. Non-polar alkyl and polar radicals with halogen, oxygen and nitrogen atoms were used as substituents. It is typical of the active spiro-thiazines to have alkyl substituents in ortho- and para-position of the benzene ring. Among the investigated spiro-thiazines it is the derivatives with ethyl- and isopropyl-groups in the aril part of the molecules that are the lead-compounds with a high inhibitory ability. We measured the distribution coefficients of the substances in octanol/buffer and hexane/buffer systems and made conclusions about the ability of the investigated drug-like compounds to penetrate the biological membranes. By using the parabolic model we derived a quadratic equation that allowed us to evaluate quantitatively the inhibitory activity of spiro-thiazines with hydrophobic substituents based on lipophilicity data. We also studied the permeability through the phospholipidic membrane and introduced a correlation equation describing the dependence of the investigated spiro-thiazines activity on the descriptors characterizing the donor–acceptor properties.
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novel 1 2 4 thiadiazole derivatives as potent Neuroprotectors approach to creation of bioavailable drugs
Molecular Pharmaceutics, 2012Co-Authors: German L Perlovich, A N Proshin, Tatyana V Volkova, L N Petrova, S O BachurinAbstract:Novel 1,2,4-thiadiazole derivatives as potent Neuroprotectors were synthesized and identified. Their ability to inhibit the glutamate stimulated Ca uptake was measured. Permeation experiments on the phospholipid membranes were conducted, and the apparent permeability coefficients were obtained. The partition coefficients in n-octanol/buffer (pH 7.4) and n-hexane/buffer (pH 7.4) immiscible phases (as model systems for characterizing gastrointestinal tract membranes and BBB) were determined. A classification of the studied compounds from the standpoint of “permeability–activity” properties was proposed.
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novel isothiourea derivatives as potent Neuroprotectors and cognition enhancers synthesis biological and physicochemical properties
Journal of Medicinal Chemistry, 2009Co-Authors: German L Perlovich, A N Proshin, Tatyana V Volkova, L N Petrova, Sergey V Kurkov, Vlaimir V Grigoriev, S O BachurinAbstract:Various salts of 3-allyl-1,1-dibenzyl-2-ethyl-isothiourea, 1 (hydrochloride), 2 (hydrobromide), and 3 (hydroiodide), were synthesized. Ca-blocking properties of these salts were studied. Comparative analysis of the potentiating effects of 3 and cyclothiazide (CT) on transmembrane currents caused by kainic acid (KA) and glutamate in Purkinje neurons was performed. Analysis of the effects of 1 on N-methyl-d-aspartate (NMDA) receptors was performed on primary culture of heterogeneous neurons of rat cerebral cortex. Single crystals were grown and X-ray diffraction experiments solving the crystal structures of 1−3 were carried out. Analysis of conformations of the molecules in the crystal lattices was performed. The temperature dependencies of the solubility of 1−3 in water and n-octanol were obtained, and the thermodynamic parameters of solubility process were calculated. The effect of halogen atoms on the solubility was analyzed. The partitioning processes in the water−octanol system were studied at 25 °C. C...
German L Perlovich - One of the best experts on this subject based on the ideXlab platform.
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new derivatives of hydrogenated pyrido 4 3 b indoles as potential Neuroprotectors synthesis biological testing and solubility in pharmaceutically relevant solvents
Journal of The Saudi Pharmaceutical Society, 2018Co-Authors: Svetlana V Blokhina, Angelica V Sharapova, Marina V Olkhovich, Anatoly Ustinov, German L PerlovichAbstract:Abstract The derivatives of hydrogenated pyrido[4,3-b]indoles as potential Neuroprotectors have been synthesized. The different substituents were introduced into position 8 of the carboline fragment of the molecule: methyl-, methoxy-, fluorine- and chlorine-. Biological tests have shown that all the studied compounds can modulate glutamate-dependent uptake of calcium ions in rats’ cerebral cortex synaptosomes. The shake-flask method was used to measure the solubility of the compounds in the buffer solution (pH 7.4), hexane and 1-octanol within the temperature interval of 293.15–313.15 К. All the derivatives have been found to have low solubility (not exceeding 8 ∙ 10−4 mole fractions) in the mentioned solvents. The effect of thermophysical and protolytic properties of the compounds on the solubility have been studied and the thermodynamic functions of compounds dissolution in the solvents used have been calculated.
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synthesis biological activity distribution and membrane permeability of novel spiro thiazines as potent Neuroprotectors
European Journal of Medicinal Chemistry, 2014Co-Authors: Svetlana V Blokhina, A N Proshin, Tatyana V Volkova, S O Bachurin, Angelica V Sharapova, Marina V Olkhovich, German L PerlovichAbstract:Abstract New spiro-derivatives of 1,3-thiazine – potential Neuroprotectors have been synthesized. It has been determined that the obtained compounds are biologically active and capable of blocking the glutamate-induced calcium ion uptake into synaptosomes of rat brain cortex. The inhibitory activity of the test substances was shown to depend on the chemical nature and structure of the substituents bound with an exocyclic nitrogen atom. Non-polar alkyl and polar radicals with halogen, oxygen and nitrogen atoms were used as substituents. It is typical of the active spiro-thiazines to have alkyl substituents in ortho- and para-position of the benzene ring. Among the investigated spiro-thiazines it is the derivatives with ethyl- and isopropyl-groups in the aril part of the molecules that are the lead-compounds with a high inhibitory ability. We measured the distribution coefficients of the substances in octanol/buffer and hexane/buffer systems and made conclusions about the ability of the investigated drug-like compounds to penetrate the biological membranes. By using the parabolic model we derived a quadratic equation that allowed us to evaluate quantitatively the inhibitory activity of spiro-thiazines with hydrophobic substituents based on lipophilicity data. We also studied the permeability through the phospholipidic membrane and introduced a correlation equation describing the dependence of the investigated spiro-thiazines activity on the descriptors characterizing the donor–acceptor properties.
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Crystal structure analysis and sublimation thermodynamics of bicyclo derivatives of a neuroprotector family
Acta Crystallographica Section B Structural Crystallography and Crystal Chemistry, 2013Co-Authors: Artem O. Surov, Alexey N. Proshin, German L PerlovichAbstract:The crystal structures of three new structurally related drug-like bicyclo derivatives are correlated with measured thermodynamic quantities for their sublimation and melting processes. The sublimation thermodynamics are determined using the temperature dependencies of the vapour pressure, and the melting processes are examined using differential scanning calorimetry. The three compounds contain a common N-(3-thia-1-azabicyclo[3.3.1]non-2-ylidene)aniline core, with either a CH3, F or CF3 substituent at the 4-position of the aniline ring. Lattice energy calculations are made using both the PIXEL and Coulomb–London–Pauli (CLP) models, and the conformational flexibility of the molecules is examined using gas-phase density functional theory (DFT) calculations. The experimentally measured crystal lattice energies (ΔH0sub) decrease in the order: CH3 > F > CF3. The calculated lattice energies using the PIXEL approach are in good agreement with the experimental values, and the partitioned intermolecular interaction energies suggest that dispersion contributions dominate the crystal structures of all three compounds. The sublimation energies and melting points are inversely correlated for the three molecules, with the melting points increasing in the order CF3 < F < CH3.
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novel 1 2 4 thiadiazole derivatives as potent Neuroprotectors approach to creation of bioavailable drugs
Molecular Pharmaceutics, 2012Co-Authors: German L Perlovich, A N Proshin, Tatyana V Volkova, L N Petrova, S O BachurinAbstract:Novel 1,2,4-thiadiazole derivatives as potent Neuroprotectors were synthesized and identified. Their ability to inhibit the glutamate stimulated Ca uptake was measured. Permeation experiments on the phospholipid membranes were conducted, and the apparent permeability coefficients were obtained. The partition coefficients in n-octanol/buffer (pH 7.4) and n-hexane/buffer (pH 7.4) immiscible phases (as model systems for characterizing gastrointestinal tract membranes and BBB) were determined. A classification of the studied compounds from the standpoint of “permeability–activity” properties was proposed.
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novel isothiourea derivatives as potent Neuroprotectors and cognition enhancers synthesis biological and physicochemical properties
Journal of Medicinal Chemistry, 2009Co-Authors: German L Perlovich, A N Proshin, Tatyana V Volkova, L N Petrova, Sergey V Kurkov, Vlaimir V Grigoriev, S O BachurinAbstract:Various salts of 3-allyl-1,1-dibenzyl-2-ethyl-isothiourea, 1 (hydrochloride), 2 (hydrobromide), and 3 (hydroiodide), were synthesized. Ca-blocking properties of these salts were studied. Comparative analysis of the potentiating effects of 3 and cyclothiazide (CT) on transmembrane currents caused by kainic acid (KA) and glutamate in Purkinje neurons was performed. Analysis of the effects of 1 on N-methyl-d-aspartate (NMDA) receptors was performed on primary culture of heterogeneous neurons of rat cerebral cortex. Single crystals were grown and X-ray diffraction experiments solving the crystal structures of 1−3 were carried out. Analysis of conformations of the molecules in the crystal lattices was performed. The temperature dependencies of the solubility of 1−3 in water and n-octanol were obtained, and the thermodynamic parameters of solubility process were calculated. The effect of halogen atoms on the solubility was analyzed. The partitioning processes in the water−octanol system were studied at 25 °C. C...
O A Krishtal - One of the best experts on this subject based on the ideXlab platform.
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electrical responses in hippocampal slices after prolonged global ischemia effects of Neuroprotectors
Brain Research, 2000Co-Authors: D P Artemenko, V D Gerasimov, O A KrishtalAbstract:Abstract A simple and reproducible animal model of global ischemia, induced by decapitation in 30-day-old Wistar rats, has been developed. It allows to perform electrophysiological analysis of the postischemic reperfusion period in the brain slices. Periods of ischemia up to 40 min increase population spikes measured in the CA1 area of the hippocampus during 2–5 h of reperfusion. Thus after 30-min decapitation-induced ischemia (at tischem=25°C), the mean amplitude of the recorded maximum orthodromic population spikes was 159% of the control obtained in the non-ischemic animals. Longer ischemic episodes result in the depression of the population spikes. After 2 h of ischemia, the amplitude of population spikes was about 89% of control. After 3 h of decapitation ischemia, the neurons could not be reactivated. The duration of ischemic episode needed for the irreversible depression of the electrical activity of the brain neurons drastically depends on the temperature at which the ischemic brain is maintained. Thus, only 2 h were needed at 30°C as compared to nearly 3 h at 25°C. We have found that intraperitoneal injection of Neuroprotectors which precedes decapitation enables reactivation of the post-ischemic neurons even after very long periods of global ischemia. Thus, MK-801, a non-competitive NMDA receptors antagonist, or NBQX, a blocker of AMPA receptors, administrated 15 min before the long-term (90 min) decapitation ischemia (30°C), induced dose-dependent recovery of population spike with ED50 values 0.2 mg/kg and 3 mg/kg respectively. Our results demonstrate that, in spite of the high vulnerability of hippocampal neurons to hypoxia and ischemia, their electrical activity can be restored after prolonged (more then 1 h) decapitation ischemia. Administration of NMDA or AMPA antagonists enhances recovery.
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Electrical responses in hippocampal slices after prolonged global ischemia: effects of Neuroprotectors.
Brain research, 2000Co-Authors: D P Artemenko, V D Gerasimov, O A KrishtalAbstract:A simple and reproducible animal model of global ischemia, induced by decapitation in 30-day-old Wistar rats, has been developed. It allows to perform electrophysiological analysis of the postischemic reperfusion period in the brain slices. Periods of ischemia up to 40 min increase population spikes measured in the CA1 area of the hippocampus during 2-5 h of reperfusion. Thus after 30-min decapitation-induced ischemia (at t(ischem)=25 degrees C), the mean amplitude of the recorded maximum orthodromic population spikes was 159% of the control obtained in the non-ischemic animals. Longer ischemic episodes result in the depression of the population spikes. After 2 h of ischemia, the amplitude of population spikes was about 89% of control. After 3 h of decapitation ischemia, the neurons could not be reactivated. The duration of ischemic episode needed for the irreversible depression of the electrical activity of the brain neurons drastically depends on the temperature at which the ischemic brain is maintained. Thus, only 2 h were needed at 30 degrees C as compared to nearly 3 h at 25 degrees C. We have found that intraperitoneal injection of Neuroprotectors which precedes decapitation enables reactivation of the post-ischemic neurons even after very long periods of global ischemia. Thus, MK-801, a non-competitive NMDA receptors antagonist, or NBQX, a blocker of AMPA receptors, administrated 15 min before the long-term (90 min) decapitation ischemia (30 degrees C), induced dose-dependent recovery of population spike with ED(50) values 0.2 mg/kg and 3 mg/kg respectively. Our results demonstrate that, in spite of the high vulnerability of hippocampal neurons to hypoxia and ischemia, their electrical activity can be restored after prolonged (more then 1 h) decapitation ischemia. Administration of NMDA or AMPA antagonists enhances recovery.