A comparative study performed in mice investigating the action of DF302, a novel fluoride-containing gamma-carboline derivative, in comparison to the structurally similar neuroprotective drug dimebon. Drug effects on learning and memory, emotionality, hippocampal neurogenesis and mitochondrial functions, as well as AMPA-mediated currents and the 5-HT6 receptor are reported. In the step-down avoidance and fear-conditioning paradigms, bolus administration of drugs at doses of 10 or 40 mg/kg showed that only the higher dose of DF302 improved long-term memory while dimebon was ineffective at either dosage. Short-term memory and fear extinction remained unaltered across treatment groups. During the 5-day predation stress paradigm, oral drug treatment over a period of 2 weeks at the higher dosage regimen decreased anxiety-like behaviour. Both compounds supressed inter-male aggression in CD1 mice, the most eminent being the effects of DF302 in its highest dose. DF302 at the higher dose decreased floating behaviour in a 2-day swim test and after 21-day ultrasound stress. The density of Ki67-positive cells, a marker of adult neurogenesis, was reduced in the dentate gyrus of stressed dimebon-treated and non-treated mice, but not in DF302-treated mice. Non-stressed mice that received DF302 had a higher density of Ki67-positive cells than controls unlike dimebon-treated mice. Similar to dimebon, DF302 effectively potentiated AMPA receptor-mediated currents, bound to the 5-HT6 receptor, inhibited mitochondrial permeability transition and displayed cytoprotective properties in cellular models of neurodegeneration. Thus, DF302 exerts multi-target effects on the key mechanisms of neurodegenerative pathologies and can be considered as an optimized novel analogue of the neuroprotective agent dimebon.

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.

Alzheimer disease is a multifactorial pathology and the development of new multitarget neuroprotective drugs is promising and attractive. We synthesized a group of original compounds, which combine in one molecule γ-carboline fragment of dimebon and phenothiazine core of methylene blue (MB) linked by 1-oxo- and 2-hydroxypropylene spacers. Inhibitory activity of the conjugates toward acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and structurally close to them carboxylesterase (CaE), as well their binding to NMDA-receptors were evaluated in vitro and in silico. These newly synthesized compounds showed significantly higher inhibitory activity toward BChE with IC50 values in submicromolar and micromolar range and exhibited selective inhibitory action against BChE over AChE and CaE. Kinetic studies for the 9 most active compounds indicated that majority of them were mixed-type BChE inhibitors. The main specific protein-ligand interaction is π-π stacking of phenothiazine ring with indole group of Trp82. These compounds emerge as promising safe multitarget ligands for the further development of a therapeutic approach against aging-related neurodegenerative disorders such as Alzheimer and/or other pathological conditions.

The structural analogs of α -aminoacids, α -aminophosphonic acids and their esters, are widely studied as biologically active substances [1]. At the same time, among the numerous publications of the last twenty years there are only a few communications devoted to biological activity of fluorinated α -aminophosphonates, although it is well known that inclusion of fluorine atoms and fluorine-containing substituents into molecules of organic substances results in profound changes of chemical and physicochemical properties and, consequently, the biological activity of these substances. In particular, it was shown that some fluorinated esters and phosphin-oxides inhibited cholinesterases [2, 3] and thrombin [4], in contrast to their nonfluorinated analogues.In this paper, the results of studies of interaction of fluorinated α -aminophosphonates (FAPs, 3a -3h ) with four serine hydrolases are presented. Compounds 3a -3h were synthesized according to the scheme shown below:The serine hydrolases that were studied in this work play an important role in determining the toxic action of organophosphorus compounds (OPs): acetylcholinesterase (AChE) is the target for acute cholinergic toxicity [5]; neuropathy target esterase (NTE) is the target for OP-induced delayed neuropathy (OPIDN) [6-8]; nonspecific esterases, butyrylcholinesterase (BChE) and carboxylesterase (CaE), are sites of loss (scavengers) for OPs that reduce the amount of an active compound reaching the primary targets [9], and in this way influence the character and severity of the toxic effect of OPs. A distinctive feature of FAPs as potential inhibitors of serine hydrolases is their lack of a typical leaving group (F, SR, OAr, etc.), as found in classic antiChE OPs.The molecular properties of FAPs and the mechanism whereby they interact with serine hydrolases were examined using kinetic studies, QSAR analysis, and theoretical molecular modeling, supported by data from X-ray crystallography and chemical reactivity studies.FAPs 3a -3h have been synthesized with yields of 60-90% by mixing ether solutions of equimolar amounts of the corresponding dialkylphosphite 1a -1h and sulfonylimine of hexafluoroacetone 2 with subsequent recrystallization of 3a -3h from petroleum ether. Yields, melting points, and NMR data of the synthesized compounds are presented in the table.Human erythrocyte AChE, horse serum BChE, and pig liver CaE (Sigma, USA) were used. A stable lyophilized hen brain NTE preparation obtained according to our method [10] was used as a source of NTE. AChE and BChE activities were assayed by Ellman's method using acetylthiocholine and butyryltiocholine as substrates. CaE activity was determined spectrophotometrically using p -nitrophenyl acetate as a substrate. NTE activity was determined by differential inhibition according to Johnson [6], using phenyl valerate as a substrate. For kinetic studies of enzyme inhibition, a

No abstract