N. V. Kovaleva

Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment

A new group of compounds, promising for the design of original multitarget therapeutic agents for treating neurodegenerative diseases, based on conjugates of aminoadamantane and carbazole derivatives was synthesized and investigated. Compounds of these series were found to interact with a group of targets that play an important role in the development of this type of diseases. First of all, these compounds selectively inhibit butyrylcholinesterase, block NMDA receptors containing NR2B subunits while maintaining the properties of MK-801 binding site blockers, exert microtubules stabilizing properties, and possess the ability to protect nerve cells from death at the calcium overload conditions. The leading compound C-2h has been shown the most promising effects on all analyzed parameters. Thus, these compounds can be regarded as promising candidates for the design of multi-target disease-modifying drugs for treatment of AD and/or similar neuropathologies.

Further studies toward a mouse model for biochemical assessment of neuropathic potential of organophosphorus compounds

Inhibition and aging of neuropathy target esterase (NTE) by neuropathic organophosphorus (OP) compounds triggers OP compound‐induced delayed neuropathy (OPIDN), whereas inhibition of acetylcholinesterase (AChE) produces cholinergic toxicity. The neuropathic potential of an OP compound is defined by its relative inhibitory potency toward NTE vs. AChE assessed by enzyme assays following dosing in vivo or after incubations of direct‐acting compounds or active metabolites with enzymes in vitro. The standard animal model of OPIDN is the adult hen, but its large size and high husbandry costs make this species a burdensome model for assessing neuropathic potential. Although the mouse does not readily exhibit clinical signs of OPIDN, it displays axonal lesions and expresses brain AChE and NTE. Therefore, the present research was performed as a further test of the hypothesis that inhibition of mouse brain AChE and NTE could be used to assess neuropathic potential using mouse brain preparations in vitro or employing mouse brain assays following dosing of OP compounds in vivo. Excellent correlations were obtained for inhibition kinetics in vitro of mouse brain enzymes vs. hen brain and human recombinant enzymes. Furthermore, inhibition of mouse brain AChE and NTE after dosing with OP compounds afforded ED50 ratios that agreed with relative inhibitory potencies assessed in vitro. Taken together, results with mouse brain enzymes demonstrated consistent correspondence between in vitro and in vivo predictors of neuropathic potential, thus adding to previous studies supporting the validity of a mouse model for biochemical assessment of the ability of OP compounds to produce OPIDN. Copyright

Alkyl 2-arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates as new effective and selective inhibitors of carboxylesterase.

A series of alkyl 2-Arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates was synthesized and their inhibitory activity with respect to porcine liver carboxylesterase (CaE, EC 3.1.1.1), human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7), and horse serum butyrylcholinesterase (BChE, EC 3.1.1.8) was studied. The molecular docking method was used to study the binding mode of the compounds in the active site of CaE. It was found that compounds containing the trifluoromethyl group in the third position of carbonyl chain are highly effective and selective inhibitors of CaE with nanomolar IC50 values, which agrees well with the results of molecular docking.

Focused design of polypharmacophoric neuroprotective compounds: Conjugates of γ-carbolines with carbazole derivatives and tetrahydrocarbazole

Abstract Alzheimer’s disease has a complex multifactorial nature; therefore, a promising approach for the development of efficient therapeutic agents is the concept of multitarget drugs, which affect several biological targets involved in the pathogenesis of the disease. We developed a synthetic algorithm for conjugating several pharmacophoric ligands acting on the key stages of pathogenesis of several neurodegenerative diseases and synthesized hybrid structures combining the γ-carboline fragment of Dimebon with carbazole and tetrahydrocarbazole moieties. Using the complex primary screening system the structures have been revealed that combine the high inhibitory activity and selectivity towards butyrylcholinesterase with the radical-scavenging activity and the ability to potentiate tubulin polymerization to microtubules with a normal structure and/or prevent mitochondrial permeability transition. The lead compound was identified for future optimization and development of new multi-target drugs against neurodegenerative diseases combining the cognitive-stimulating and neuroprotective potentials.

Synthesis, structure, and properties of polynuclear molybdenum(v,vi) oxomethoxides with magnesium

General conditions for the formation of heterometallic clusters by the simultaneous methanolysis of MoCl5 and MgCl2 were determined. The resultant alkalinity of the reaction solution, the Mg/Mo molar ratio, and the presence of traces of water are key factors responsible for the composition and structure of the mixed magnesium molybdenum methoxides that formed. The new decanuclear mixed-valence MoV,VI Mg oxomethoxide [MoV4O4(μ3-O)2(μ2-O)2MoVI2-O4(OMe)2Mg4(MeOH)6(μ3-OMe)6(μ2-OMe)8] (1) was synthesized by the reaction of lowernuclearity magnesium molybdenum oxoalkoxide complexes: NaMoV of the complex Na(MeOH)MoV2O2(μ2-OMe)3(OMe)4 (2) and MgMoVI of the complex [MoVIO2Mg(MeOH)2-(OMe)4]2 (3). The molecular structure of 1 was determined by X-ray diffraction.

1,2,4-Thiadiazoles as promising multifunctional agents for treatment of neurodegenerative diseases

Detailed studies of properties of new 3-substituted 5-anilino-1,2,4-thiadiazoles containing different substituents at position 3 of the thiadiazole ring were carried out, in particular, their esterase profile and antioxidant properties. It was found that the presence in the molecule of 2-aminopropyl fragment determines an efficient and selective inhibition of butyrylcholinesterase as compared to acetylcholinesterase and carboxylesterase, with radical-scavenging activity being weak. The compounds containing a 2-aminopropenyl fragment possess a high radicalscavenging activity, weakly inhibit cholinesterases, and exhibit anticarboxylesterase activity. A wide spectrum of activity of 3-substituted 5-anilino-1,2,4-thiadiazoles as inhibitors of cholinesterases and highly efficient scavengers of free radicals gives a basis for the optimization of structure and development in this series of original agents for therapy of neurodegenerative diseases.

Synthesis of γ-carbolines containing NO-donor fragment and assessment of their anticholinesterase activity

Hybrid γ-carboline-based compounds containing a nitrooxy group as an NO-donor were prepared. It was shown that the introduction of this group did not affect the inhibitory activity of γ-carboline pharmacophore against acetyl- and butyrylcholinesterase.

1,2,4-Thiadiazole derivatives as effective NMDA receptor blockers with anticholinesterase activity and antioxidant properties

New 5-anilino-1,2,4-thiadiazole derivatives with different substituents at position 3 were synthesized and their influence on the key binding sites of NMDA receptors, inhibitory activity against acetylcholinesterase, butyrylcholinesterase, and carboxylesterase, as well as antioxidant properties were studied. The compounds with a 2-aminopropyl fragment were found to be efficient blockers of allosteric modulator [3H]ifenprodil binding site of the NR2B-containing NMDA receptors and moderate butyrylcholinesterase inhibitors. Some compounds were found to be able to simultaneously block the [3H]ifenprodil and intrachannel [3H]MК-801 binding sites of NMDA receptors. Compounds containing a 2-aminopropenyl fragment did not exhibit activity against NMDA receptors and butyrylcholinesterase, but showed high radical-scavenging activity.

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.

Synthesis and investigation of biological activity of phosphorylated amines and amides

A series of phosphoryl-substituted amines and amides was synthesized and their inhibition activity towards acetylcholinesterase, butyrylcholinesterase, and carboxylesterase was investigated.