L. N. Petrova

Synthesis, Pharmacology, Crystal Properties, and Quantitative Solvation Studies from a Drug Transport Perspective for Three New 1,2,4-thiadiazoles

A novel 1,2,4-thiadiazoles were synthesized. Crystal structures of these compounds were solved by X-ray diffraction experiments and comparative analysis of molecular conformational states, packing architecture, and hydrogen bonds networks were carried out. Thermodynamic aspects of sublimation processes of studied compounds were determined using temperature dependencies of vapor pressure. Thermophysical characteristics of the molecular crystals were obtained and compared with the sublimation and structural parameters. Solubility and solvation processes of 1,2,4-thiadiazoles in buffer, n-hexane and n-octanol were studied within the wide range of temperature intervals and thermodynamic functions were calculated. Specific and nonspecific interactions of molecules resolved in crystals and solvents were estimated and compared. Distribution processes of compounds in buffer/n-octanol and buffer/n-hexane systems (describing different types of membranes) were investigated. Analysis of transfer processes of studied molecules from the buffer to n-octanol/n-hexane phases was carried out by the diagram method with evaluation of the enthalpic and entropic terms. This approach allows us to design drug molecules with optimal passive transport properties. Calcium-blocking properties of the substances were evaluated.

Novel Isothiourea Derivatives as Potent Neuroprotectors and Cognition Enhancers: Synthesis, Biological and Physicochemical Properties

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 degrees C. Chemical stability of tested salts in pH 7.4 phosphate buffer was determined at 25 degrees C.

5-Amino-3-(2-aminopropyl)-1,2,4-thiadiazoles as the basis of hybrid multifunctional compounds

An approach to the synthesis of hybrid multifunctional compounds starting from 1,2,4-thiadiazoles containing an amino group in the side chain was developed.

Novel 1,2,4-thiadiazoles with an NO-producing fragment

311 At present, the design of hybrid multitarget phar maceuticals by introduction of nitric oxide producing fragment in a molecule of known medicinal agent is one of promising directions of medicinal chemistry [1]. Nitric oxide (NO) is an endogenous signaling molecule with a wide spectrum of biological activity and plays an important role in nervous system func tioning. Therefore, NO donors are used for the treat ment of different neurodegenerative disorders, Alzhe imer disease including [2]. The introduction of an NO producing fragment into known pharmaceuti cals, for example, NO donor drugs based on Tacrine, is also applied for this purpose [3]. One of promising approaches to search for phar maceuticals for the treatment of Alzheimer disease and related neurodegenerative disorders is the search for blocking agents for glutamate mediated influx of Ca2+ [4]. In recent time, molecules containing a thiadiazole pharmacophore fragment and showing interesting pharmacological properties, including neuroprotec tive ones, attract much attention as promising phar maceuticals [5].

Physiologically active bis(dialkylamides) of phosphoryl-substituted α,ω-dicarboxylic acids

Bis(dialkylamides) of phosphoryl-substituted α,ω-dicarboxylic acids were synthesized and their biological activity was studied.

Effects of delta sleep-inducing peptide on pre- and postsynaptic glutamate and postsynaptic GABA receptors in neurons of the cortex, hippocampus, and cerebellum in rats.

We studied the effect of delta sleep-inducing peptide on GABA receptors of hippocampal and cerebellar neurons in rats. It was shown that delta sleep-inducing peptide considerably and dose-dependently potentiates GABA-activated currents in these neurons and blocks NMDA-activated potentiation in cortical and hippocampal neurons. The peptide modulates activity of presynaptic NMDA receptors, which is seen from changes in 45Ca2+ uptake into synaptosomes of the brain cortex after uptake stimulation with glutamate and NMDA.

Specificity of glutamate receptors in P2 synaptosomal fraction from rat brain cortex

Specificity of glutamate receptors in the P2 synaptosomal fraction from the cerebral cortex of newborn rats was studied by measuring 45Ca2+ uptake by synaptosomes in the presence of agonists of ionotropic and metabotropic glutamate receptors. It was shown that P2 synaptosomal fraction from rat cortex contains NMDA receptors, kainate receptors, and group 1 metabotropic receptors.

Synthesis and biological activity of dialkylamino-substituted phosphine oxides

A series of dialkylamino-substituted phosphine oxides was synthesized and their physiological activity was studied.

Application of Molecular Topological Descriptors for Clustering a Database of Isothiourea Derivatives in Studying Structure – Activity Relationships

A database of some S,N,N,N′-tetrasubstituted isothiourea derivatives possessing neuroprotective properties was successfully clustered in order to study the quantitative structure – activity relationship. Clustering by k-means was carried out in the factor space of topological descriptors. The identified clusters were combined according to analyses of intra- and intercluster distances. The initial number of clusters in the k-means clustering was determined from the number of iterations for which a solution was obtained. The homogeneity of the database and the identified clusters was estimated by using a coefficient of molecular diversity. A plot of the database compounds as points in factor space led to a conclusion about the successful applicability of the proposed clustering approach.

Securinine Derivatives as Potential Anti-amyloid Therapeutic Approach

BACKGROUND Oxidative stress and amyloid deposition are tightly interconnected pathological features of Alzheimer disease. In this respect, both amyloid production and aggregation may be stimulated by oxidative stress and also the increase of pathogenic β-amyloid and its aggregated form lead to oxidative stress progression. Therefore, the search for potential drugs with both antioxidant and antiaggregation properties are of great interest. METHODS In this study, we described the stereospecific synthesis of alkaloid securinine aminoderivatives. RESULTS We showed that the newly synthesized compounds possess antioxidant and metal-chelating properties. Indeed, we report that one compound has inhibitory effects towards μ-amyloid aggregation. CONCLUSION Based on these results, aminoderivatives of securinine scaffold are promising compounds for development of new drugs for the treatment of neurodegenerative diseases.