A. Yu. Aksinenko

Esterase profile and analysis of structure-inhibitor selectivity relationships for homologous phosphorylated 1-hydroperfluoroisopropanols

352 Organophosphorous compounds (OPCs) are widely used not only in agrochemical practice but are also cited in pharmacopoeias of many countries as drugs for treating schistosomiasis, glaucoma, and Alzheimer’s disease [1]. The physiological effect of such compounds is based on competitive interaction with serine esterases including the primary biological targets, such as acetylcholinesterase (AChE) [2], the target enzyme for the acute toxic effect of antiacetylcholinesterase compounds, and the neuropathy target esterase (NTE) [3], the target enzyme for organophosphate-induced delayed neurotoxicity, as well as the secondary biological targets, such as butyrylcholinesterase (BChE) and carboxylesterase (CaE). BChE and CaE are stoichiometric scavengers, interaction with which reduces the content of active phosphoryl compound at the toxicokinetic stage of development of biological response [4, 5]. The preferential binding of anticholinesterase compounds with one or another target esterase largely determines the resultant therapeutic or toxic effect of a given compound as well as the character and degree of expression of this effect.

Fluorinated α-aminophosphonates—a new type of irreversible inhibitors of serine hydrolases

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:

Modification of biologically active amides and amines with fluoro-containing heterocycles 11. Tetrahydrocarbazoles modified with 2-(5-fluoropyridin-3-yl)ethyl fragment

A method for the modification of tetrahydrocarbazoles with the 2-(5-fluoropyridin-3-yl)ethyl fragment was suggest, which consists in the reaction of 5-fluoro-3-vinylpyridine with tetrahydrocarbazoles under conditions of fluoride ion catalysis and leads to the earlier unknown 9-[2-(5-fluoropyridin-3-yl)ethyl]-2,3,4,9-tetrahydro-1H-carbazoles. Method of radioligand binding was used to study the influence of compounds synthesized on neuronal NMDA-receptors.

Reactions of methyl trifluoropyruvate 2-pyridylimines with trimethyl phosphite

Reactions of methyl trifluoropyruvate 2-pyridylimines with trimethyl phosphite afford methyl 3-fluoroimidazo [1, 2-a]pyridine-2-carboxylates.

Synthesis and biological activity of N-substituted tetrahydro-γ-carbolins bearing bis(dimethylamino)phenothiazine moiety

An approach for modification of biologically active N-substituted tetrahydro-γ-carbolines with bis(dimethylamino)phenothiazine moiety via the CsF-catalyzed reaction of γ-carbolines with 1-[3,7-bis(dimethylamino)phenothiazin-10-yl]propenone was developed. Effects of the synthesized compounds on neuronal NMDA receptors were examined by radioligand binding assay.

Modification of biologically active amides and amines with fluorine-containing heterocycles 8. γ-Carbolines modified with the 2-(2-trifluoromethylimidazo[1,2-a]pyridin-6-yl)ethyl fragment

An approach to modification of biologically active g-carbolines with the 2-(2-trifluoromethylimidazo[1,2-a]pyridin-6-yl)ethyl fragment was proposed. The modification involves a reaction of 2-trifluoromethyl-6-vinylimidazo[1,2-a]pyridine with g-carbolines. The effect of the compounds obtained on neuronal NMDA receptors was studied by the radioligand binding method.

Acylimines of hexafluoroacetone and methyl trifluoropyruvate in cyclocondensation with 2-aminothiazolines

Reactions of acylimines of hexafluoroacetone and methyl trifluoropyruvate with 2-aminothiazolines afforded fluorine-containing heterocycles of two structural types: 6,7-dihydro-2H-thiazolo[3,2-a][1,3,5]triazines and 2,3,5,6-tetrahydroimidazo[2,1-b]thiazoles.

Esterase profile of O-phosphorylated ethyltrifluorolactates in prediction of their therapeutic and toxic effects

81 The use of anticholinesterase compounds in medi cine, veterinary practice and agricultural chemistry is based on their common mechanism of action, which is determined by the inhibition of acetylcholinesterase (EC 3.1.1.7, AChE) [1]. Many cholinesterase inhibi tors, in addition to AChE, interact with other serine esterases, that can lead to both toxic and therapeutic effects [2]. Toxic and therapeutic effects resulting from the inhibition by organophosphorus compounds (OPCs) of four serine esterases—acetylcholinest erase, neuropathy target esterase (EC 3.1.1.5, NTE), butyrylcholinesterase (EC 3.1.1.7, BChE), and car boxylesterase (EC 3.1.1.1, CaE)—are shown in Scheme 1, where the effects that determine the toxic action of OPCs are shown in italic.

Arenesulfonylimines of methyl trifluoropyruvate in the cyclocondensation reactions with 1,3-C,N-and-N,N-binucleophiles

Reaction of arenesulfonylimines of methyl trifluoropyruvate with 1,3-C,N-and-N,N-binucleophiles led to a variety of N-sulfonylated fluorine-containing heterocycles, including the fused ones.

Molecular design of multitarget neuroprotectors 3. Synthesis and bioactivity of tetrahydrocarbazole—aminoadamantane conjugates

A synthetic approach to the design of new multitarget neuroprotectors consisting in combination of the tetrahydrocarbazole and aminoadamantane pharmacophore fragments through a 2-hydroxypropylene spacer upon the reaction of 9-oxiranylmethyl-2,3,4,9-tetrahydro-1H-carbazoles and aminoadamantanes, which affords 1-(adamantan-1-ylamino)-3-(1,2,3,4-tetrahydrocarbazol-9-yl)-propan-2-ols, is proposed. The effect of the synthesized compounds on the neuronal NMDA receptors and the functional characteristics of rat liver mitochondria was studied.