Conjugates of Tacrine and Its Cyclic Homologues with p-Toluenesulfonamide as Novel Acetylcholinesterase and Butyrylcholinesterase Inhibitors.

Using the acylation reaction with tosyl chloride of N-aminopropyl analogues of tacrine and its cyclic homologues with different size of the aliphatic cycle (5-8), we synthesized a number of new derivatives of p-toluenesulfonamide. It is shown that the synthesized hybrid compounds of tacrine and p-toluenesulfonamide are effective inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with the preferential inhibition of BChE. They also displace propidium from the peripheral anionic site of the electric eel AChE (Electrophorus electricus). The characteristics of the efficiency and selectivity of cholinesterase inhibition by the test compounds were confirmed by the results of molecular docking.

[Possibilities of cavinton therapy regimen for infusions and cavinton comforte in acute and early recovery periods after ischemic stroke]. / Terapiia preparatami kavinton dlia infuzii i kavinton komforte v ostrom i rannem vosstanovitel'nom periodakh ishemicheskogo insul'ta.

AIM: To study the efficacy of a current regimen of treatment with cavinton for infusions and cavinton comforte in patients with ischemic stroke in acute and early recovery periods and to evaluate an impact of treatment on erythrocyte deformity using atomic power microscopy. MATERIAL AND METHODS: One hundred and sixty-four patients with hemispheric ischemic stroke, aged from 30 to 79 years, were randomized into main (n=100) and control (n=64) groups. Patients of the main group received complex treatment (basic therapy and cavinton R for drop infusions (10 intravenously during 10 days) followed by cavinton R comforte in dose 10 mg, 1 tablet 3 times a day during 90 days). Patients of the control group received basic therapy only. NIHSS, the Rankin scale, the Barthel index, MMSE, MоCA, the Rivermead scale, Beck depression scale, HADS were used to measure the severity of patient's state. To study the erythrocyte membrane by estimating Young's modulus, dry preparations were made with the following scanning of erythrocytes using atomic power microscopy. RESULTS: Positive changes on all scales were observed in both groups. Higher scores on NIHSS, Rankin, Barthel, MоCA, MMSE, Rivermead mobility index were found in the main group compared to the controls. There were no differences in scores on the Beck depression scale and HADS. A decrease in Young's modulus was found in the main group while in the control group this index remained unchanged. CONCLUSION: More rapid and complete regression of neurological deficit, better recovery of self-care function, cognitive function and social activity, an increase in erythrocyte membrane elasticity were found in the main group compared to the control one. These results indicate the efficacy of cavinton R and cavinton R comforte in the regimen used in complex treatment in acute and early recovery periods after ischemic stroke.

Towards the rational design of novel drugs based on solubility, partitioning/distribution, biomimetic permeability and biological activity exemplified by 1,2,4-thiadiazole derivatives.

Novel 1,2,4-thiadiazole derivatives as potent neuroprotectors were synthesized and identified. Their ability to inhibit the glutamate stimulated Ca2+ uptake was investigated. The solubility of thiadiazoles was measured in a buffer solution (pH 7.4) at 298 K. The distribution coefficients in 1-octanol/buffer (pH 7.4) and 1-hexane/buffer (pH 7.4) immiscible phases as model systems imitating the gastrointestinal tract epithelium and the blood-brain barrier were determined. Permeation experiments the new Permeapad™ barrier using Franz diffusion cells were conducted and the apparent permeability coefficients were obtained. The influence of the compound structure on the physicochemical properties determining the bioavailability of drug-like substances was revealed. Solubility-permeability interplay has been assessed to evaluate potential bioavailability of the compounds studied.

Novel conjugates of tacrine with 1,2,4,-thiadiazole as highly effective cholinesterase inhibitors, blockers of NMDA receptors, and antioxidants.

Conjugates of tacrine with 1,2,4-thiadiazole derivatives were synthesized for the first time. Their esterase profile and effects on the key NMDA receptor-binding sites as well as antioxidant activity were investigated. The obtained compounds effectively inhibited cholinesterases (with a predominant effect on butyrylcholinesterase), simultaneously blocked two NMDA receptor-binding sites (allosteric and intrachannel sites, and exhibited a high radical-scavenging activity. Our study shows that the obtained compounds are promising to design drugs for the treatment of Alzheimer's disease and other multifactorial neurodegenerative diseases.

[Cognitive impairment in patients poluchennym ischemic stroke in the acute and early recovery periods in the process of neuroprotection low-dose drug cortexin]. / Dinamika kognitivnykh narushenii u bol'nykh s polusharnym ishemicheskim insul'tom v ostrom i rannem vosstanovitel'nom periodakh na fone nizkodoznoi neiroprotektsii preparatom korteksin.

AIM: To study the effect of repeated low-dose course of neuroprotection by drug cortexin on cognitive impairment in the acute and early recovery periods of hemispheric ischemic stroke. MATERIAL AND METHODS: The study involved 90 patients with poluchennym ischemic stroke. Patients of the first group received cortexin 20 mg (10+10) intramuscularly on the background of basic therapy, patients of the second group (n=30) received cortexin 20 mg (10+10) two courses for 10 days each with a break in between of 10 days, the patients of the third group - only basic therapy. For the objectification of cognitive impairment used a scale MMSE, a test of 5 words, the battery of frontal dysfunction, clock drawing test, MOCA test. RESULTS: It was noted more rapid and complete regression of cognitive disorders in patients of the 1st and 2nd groups, in comparison with patients of the 3rd group. However, the best effect of the therapy was observed still in the group of patients treated with the double rate of the drug cortexin.

[Efficacy of cortexin in acute and recovery periodes of hemispheric ischemic stroke]. / Effektivnost' korteksina v ostrom i vosstanovitel'nom periodakh polusharnogo ishemicheskogo insul'ta.

AIM: To study the effectiveness and sustained effects of early appointment of a repeated course of low-dose drug cortexin neuroprotection in patients in acute and recovery period of hemispheric ischemic stroke. MATERIAL AND METHODS: The study included 90 patients with hemispheric ischemic stroke. Patients of the first group received 20 mg cortexin (10+10) intramuscularly on basic therapy, the patients of the second group (n=30) was obtained cortexin 20 mg (10+10) in the two courses each for 10 days with an interval between them in 10 days, patients of the third group - only basic therapy. For objectification severity used NIH stroke scale, modified Rankin scale, the Barthel index, the Rivermead mobility index, MMSE. RESULTS AND CONCLUSION: Appointment in acute hemispheric ischemic stroke drug cortexin repeated course leads to more complete regression of neurological deficit, compared to the comparison group and the group of patients who received one course of medication cortexin, for all acute and early recovery period of ischemic stroke from 11-13 days of illness.

[EFFECT OF CORTEXIN ON THE QUALITY OF LIFE IN THE EARLY REHABILITATIVE PERIOD AFTER HEMISPHERIC ISCHEMIC STROKE].

AIM: To study the neuroprotective effect of a repeated course of low dose cortexin therapy on the quality of life in the early rehabilitative period after hemispheric ischemic stroke (IS). MATERIALS AND METHODS: 90 patients were divided into group 1 treated with cortexin (10 mg i/m twice daily (morning and afternoon) in addition to basal treatment, group 2 given the repeated course of the same treatment, and control group (basal therapy alone). The standard SF-36 questionnaire was used to assess the quality of life. RESULTS: Treatment of patients following acute hemispheric ischemic stroke with cortexin (10 mg i/m twice daily) and the repeated course of the same treatment after 10 days resulted in the accelerated and more complete normalization of the quality of life in the early rehabilitation petriod (starting from days 21-27 days after the onset of disease) than in the patients given a single course of cortexin therapy or basal treatment alone.

Adamantane derivatives of sulfonamides: sublimation, solubility, solvation and transfer processes in biologically relevant solvents.

Eight adamantane derivatives of sulfonamides were synthesized and characterized. Temperature dependencies of saturation vapor pressure were obtained using the transpiration method and thermodynamic functions of the sublimation processes were calculated. Solubility values of the selected compounds in buffer (pH 7.4), 1-octanol and 1-hexane were determined at different temperatures using the isothermal saturation method. Thermophysical characteristics of fusion processes (melting points and fusion enthalpies) of the substances were studied using the DSC method. Transfer processes from buffer to 1-octanol, from buffer to 1-hexane and 1-hexane to 1-octanol were analyzed. The impact of the molecules' structural modification on sublimation, solubility and solvation/hydration processes in the solvents was studied. Correlation equations connecting the thermodynamic functions with physicochemical descriptors were obtained.

N,N'-Substituted Selenoureas as Polyfunctional Antioxidants.

Analysis of antioxidant activity of synthesized selenourea derivatives showed that N,N'-substituted selenoureas inhibited Fe(III)-induced LPO in rat brain homogenate. On the other hand, oxygen- and sulfur-containing analogs exhibited no antioxidant activity or even slight prooxidant activity. Intramolecular alkylation of selenium atom also led to loss of antioxidant activity. Thus, antioxidant activity of the compounds was due to the presence of a nonalkylated selenium atom in N,N'-substituted selenourea analogs.

The impact of structural modification of 1,2,4-thiadiazole derivatives on thermodynamics of solubility and hydration processes.

The influence of a structural modification on thermodynamic aspects of solubility and hydration processes of 1,2,4-thiadiazole drug-like compounds was investigated. A substitution in the phenyl ring of the 1,2,4-thiadiazole molecule leads to a significant decrease of the solubility of these compounds. In order to rationalize the relationship between the structures of 1,2,4-thiadiazoles and their solubility, the latter was considered in terms of two fundamental processes: sublimation and hydration. It was found that for most of the compounds solubility decline is a result of a differently directed action of the sublimation and hydration contributions, i.e., the introduction of substituents leads to the simultaneous growth of the sublimation Gibbs energy and decrease in the hydration Gibbs energy.

[The effect of vasonit on the structural/functional state of erythrocyte cytoplasmic membrane in patients with ischemic stroke].

OBJECTIVE: To study the effect of vasonit on the structural/functional state of erythrocyte cytoplasmic membrane in patients with ischemic stroke (11) using atomic-power microscopy in vitro. MATERIAL AND METHODS: We examined 45 patients with II. Patients of the main group (n=30) received vasonit and standard treatment, 15 patients of the comparison group received only standard treatment. To assess the severity of patient's condition, we used the NIH stroke scale, modified Rankin scale, the Barthel index and the Rivermead Mobility index. Dried erythrocyte preparations were made to study erythrocyte cytoplasmic membrane. Scanning was performed using an atomic-power microscope manufactured by "SOLVER P47-Pro" (NT-MDT, Russia). RESULTS AND CONCLUSION: A statistically significant positive dynamics of neurological deficit and patient's functional state was found in the 14" day of the study. A significant decrease in Young's modulus value was identified in the main group that suggested the increase in the elasticity of erythrocyte cytoplasmic membrane.

[The influence of docosahexaenoic acid moiety on cytotoxic activity of 1,2,4-thiadiazole derivatives].

Among 3-(2-aminopropyl)-1,2,4-thiadiazole derivatives contatining substitution-ready secondary amino group and exhibiting cytotoxic towards rat C 6 glioma cells three compounds with LD 50 values ranged from 6 to 48 мM were chosen. For these compounds amides with docosahexaenoic acid were synthetised and their cytotoxic activity was studied. It was shown that, although docosahexaenoic acid itself was not toxic for C 6 glioma cells, its addition to the amino derivatives of 1,2,4-thiadiazole increased or decreased resultant cytotoxicity. The effect depended on the structure of 1,2,4-thiadiazole substituents. The obtained data show that the acylation of cytotoxic compounds with docosahexaenoic acid does not necessarily lead to the increase of their activity, but sometimes can inactivate a compound. This fact should be taken into account, especially in the case of anti-cancer drug development.

[Cytoflavin® effect on endothelium function and cerebral hemodynamics in patients with hypertensive enceplalopathy].

One hundred forty patients (the average age of 46.7 ± 7.7 years) with hypertensive encephalopathy (HE) were observed. 74 patients of the main group received Cytoflavin in a dose of 2 tablets twise a day in the standard basic therapy. 66 patients of the reference group received the basic therapy alone. The arterial endothelium function was estimated and ultrasonic examination of the hemodynamics at five structurally functional levels of the cerebral vascular course was used. All the patients with HE had endothelial dysfunction, bloodstream depression in the arterial course of the brain vascular system, decreased reactivity of the intracranial veins, difficulty in venous outflow. In the course of the therapy with Cytoflavin restotation of the arterial endothelial function in the patients with HE I stage, the linear and volume speed of bloodstream in the main and intracranial cerebral arteries in the patients with HE I-II stages, restoration of the intracranial veins reactivity, the linear speed of bloodstream in intracranial veins in the patients with all three stages of HE, the linear speed of bloodstream in the main veins up to the control values in the patients with I-III stages of HE were observed. Interrelation between the values of the cerebral hemodynamics and the state of the endothelium function was shown.

Binary mechanism of action of cognition enhancer NT1505 on glutamate receptors.

Compound NT1505 potentiates AMPA receptors in rat brain neurons and simultaneously noncompetitively blocks NMDA receptors via two different mechanisms. Considering previously obtained data on strong cognition-enhancing properties of this compound we can conclude that NT1505 is a novel cognition stimulator exhibiting properties of a positive modulator of AMPA receptors and a blocker NMDA receptor.

[Simultaneous AMPA receptor potentiation and NMDA receptor blockade as strategy for creating effective stimulants for cognitive functions].

New compounds representing derivatives of acyclic isothioureas have been synthesized, which are capable of simultaneously activating AMPA receptors and blocking NMDA receptors. In order to produce cognitive-stimulating effect, of principal importance is the pathway of NMDA receptor blockade produced by the drug. Positive influence is due to the blockade of NMDA receptors either by mechanism of rapid dissociation of intrachannel site or by inhibition of NR2B subunit of NMDA receptor. Substances that only potentiate AMPA receptor currents or only block NMDA receptors have less pronounced effect on memory than substances with ability to simultaneously potentiate AMPA receptor currents and block NMDA receptor currents. Based on these results, it is concluded that the simultaneous potentiation of AMPA receptors and blockade of NMDA receptors may be a new approach to the stimulation of cognitive functions.

[The influence of some retarding agents NOS of dihydrothiazine-thiazoline rank on postradiational of recovery endogenous CFU-S-8 of mice].

In this work the attempt to estimate a nitric oxide (NO*) role in regulation of the number of pool haemopoietic stem cells at the irradiated mice was made. With this purpose the number of new compounds from dihydrothiazine-thiazoline line was synthesized, their NO-inhibiting activity was investigated in vivo by the method of ESR-spectroscopy of spin trap and their influence on an output endogenous spleen colonies (CFU-S-8) after the total sublethal y-irradiation of mice in a doze of 6 Gy was also investigated. Was shown, that the tested compounds reduced the contents of NO* in a liver tissue of mice which have received an injection of nitric oxide synthesis inductor - lipopolysaccharide, and also increased an output CFU-S-8 forming endogenous colonies in the spleen of the irradiated mice. Received data testify to perceptivity of search radioprotective agents among NO* synthesis inhibitors.

[The importance of molecular parameters of quaternary ammonium salts in their antigibberellin (retardant) activity]. / Rol' molekuliarnykh parametrov solei chetvertichnogo ammoniia v formirovanii ikh antigibberellinovoi (retardantnoi) aktivnosti.

The importance of six theoretically calculated molecular parameters in the antigibberellin (retardant) activity of quaternary ammonium salts is studied using regression analysis. A bioassay system based on cell culture of fungus Gibberella fujikuroi is used to determine the activity. In the case of N,N,N-trimethyl-N-(2-hydroxyethyl)ammonium chloride (choline) and N,N,N-triethyl-N-(2-hydroxyethyl)ammonium chloride (N,N,N-triethylcholine) derivatives with linear structure, the polarizability, proton acceptor activity, and lipophilicity of these compounds exert the largest effect on the antigibberellin activity. The antigibberellin activity of more sterically hindered N,N-dialkylpiperidinium salts was mainly defined by the steric parameter, while the polarizability, proton acceptor activity, and (through them) lipophilicity exert a lesser effect. Other parameters are of minor importance for the three groups of compounds studied. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 6; see also http://www.maik.ru.

[2-Amino-2-thiazoline derivatives--a novel chemotype possessing muscarinomimetic effect]. / Proizvodnye 2-amino-2-tiazolina--novyi khemotip, obladaiushchii muskarinopodobnym deistviem.

Derivatives of 2-amino-2-thiazoline exhibit muscarinomimetic properties in model experiments with isolated rat ileum. The activity of compounds strongly depends on the nature of substituents in 5-position of thiazoline ring. The most active spasmogenic compound is 5-iodomethyl-2-amino-2-thiazoline hydroiodide (EC50 = 13 +/- 2 microM). Its effect is very similar to activity of cholinergic agent pilocarpine (EC50 = 14 +/- 4 microM), but "intrinsic activity" parameter a (alpha = 0.87 +/- 0.12) of 5-iodomethyl-2-amino-2-thiazoline was more significant. Ileum contractions induced by this compounds were inhibited by atropine. Derivatives of 2-amino-2-thiazoline (like pilocarpine) were not demonstrated nicotinomimetic properties. These compounds demonstrate very weak anti-AChE activity. For 5-iodomethyl-2-amino-2-thiazoline hydroiodide the IC50 value is 0.39 +/- 0.09 mM.