Modification of phenothiazine and carbazole derivatives with trifluoromethyl-containing 1,3,5-oxadiazines and imidazolidinediones based on the copper(I)-catalyzed alkyne-azide 1,3-cycloaddition was carried out.

Copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition of methyl esters of N-azidoacetyl-2-aminothiophene-3-carboxylic acids to N-propargyl-containing pharmacophores, resulting in the corresponding conjugates combined by 1,2,3-triazole-containing alkylene, was studied. The radioligand-binding experiments show a strong modulating effect of the synthesized compounds on neuronal NMDA receptors.

A synthetic approach was proposed for combining pharmacophore scaffolds, namely, 1-aminoadamantanes and 5-trifluoromethylhydantoins by the copper-catalyzed 1,3-dipolar alkyne-azide cycloaddition reaction.

The transformations of methyl trifluoropyruvate pyrazin-2-ylimine in the cyclocondensation reactions with 2-aminothiazoline, amidines, aminocrotonitrile and aza-DielsAlder reactions with cyanamines, leading to five- and six-membered trifluoromethyl-containing heterocycles, were studied. The possibility of using 4-(pyrazin-2-ylamino)-1-(prop-2-yn-1-yl)-4-(trifluoromethyl)-1H-imidazol-5(4H)-one, the product of methyl trifluoropyruvate pyrazin-2-ylimine cyclocondensation, for modification of phenothiazine by copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition was shown.

The cognitive-stimulating, neuroprotective effects of promising fluorinated tetrahydrocarbazole derivatives (CA-7043x and CA-7050x) on the hippocampus-dependent memory of outbred mice (CD1) and transgenic Tg6799 mice, as well as their effect on anxiety, locomotor activity, and orienting-exploratory behavior of animals, were studied. It was found that both compounds have a pronounced cognitive-stimulating effect on CD1 mice, but do not show neuroprotective effects on memory support in Tg6799 mice. It is noted that, in the open-field test, the CA-7050x compound has a positive effect on the orientating behavior, and the CA-7043x compound has a positive effect on the exploratory response in the nontransgenic control.

Methyl N -(carbazolyl)acetyl-2-aminotetrahydrothiophene-3-carboxylates were synthesized by alkylation of carbazoles with the corresponding chloroacetylamides of 2-aminotiophenes. The radioligand binding method showed the presence of the modulating effect of the synthesized compounds on the neuronal NMDA receptors.

A synthetic approach to combining pharmacophore ligands with an aminoadamantyl-containing spacer based on a copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition of N,N-di(prop-2-yne-1-yl)adamantan-1-amines and azido-containing carbazole, tetrahydrocarbazole, phenothiazine and adamantan-2-amine derivatives was proposed.

A synthetic approach to the modification of the drug “riluzole” with pharmacologically active fragments such as carbazole, tetrahydrocarbazole, phenothiazine, and aminothiophene, based on the copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition of azide-containing pharmacophores with “riluzole” decorated with 5-trifluoromethylhydantoin, has been suggested.

A modification of tetrahydrocarbazoles and tetrahydro-γ-carbolines with pharmacophore ligands was performed based on the copper-catalyzed 1,3-dipolar cycloaddition of their N -propargyl derivatives to azide-containing carbazoles, tetrahydrocarbazoles, 1-aminoadamantanes, and phenothiazine.

The transformations of methyl trifluoropyruvate in cyclocondensation reactions with N-substituted ureas, leading to 3-substituted 5-hydroxy- or 5-methoxy-5-trifluoromethylimidazolidine-2,4-diones, were studied. The possibility of using 5-hydroxy-3-(prop-2-in-1-yl)-5-trifluoromethylimidazolidine-2,4-dione for modifying phenothiazine with a copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition was shown.

The paper considers the influence of the structure of aminoadamantane–carbazole conjugates linked by five different spacers on their ability to inhibit acetylcholinesterase, butyrylcholinesterase (BChE), and carboxylesterase, the radical scavenging and mitoprotective activity, and tubulin polymerization. The nature of the spacer was found to be determinant for the appearance of anti-BChE and radical-scavenging activity. Aminoadamantane–carbazole conjugates linked by flexible spacers proved to be most effective in these assays. The influence of the conjugates on mitochondrial functions and tubulin polymerization largely depends on the structure of the carbazole moiety. A series of lead compounds promising for further study was identified as potential drugs for the treatment of neurodegenerative diseases, in particular, Alzheimer’s disease.

A convenient method for vinylation of tetrahydro-γ-carbolines with ethane-1,2-diyl dimethanesulfonate in the presence of sodium hydride was proposed.

A synthetic approach to the modification of tetrahydrocarbazoles with pharmacophore ligands (carbazole, tetrahydrocarbazole, and phenothiazine) was proposed based on the coppercatalyzed alkyne-azide 1,3-dipolar cycloaddition of azide-containing tetrahydrocarbazoles and propargyl-containing carbazole, tetrahydrocarbazole, and phenothiazine.

Copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition of substituted N-azidoalkylindoles and N-propargylphenothiazine led to the formation of conjugates of substituted indoles and phenothiazine combined with 1,2,3-triazole-containing alkylene spacers.

Some transformations of N-propargyl-α-aminophosphonates synthesized by the Kubachnik–Fields reaction were studied in copper-catalyzed 1,3-dipolar cycloaddition with azide-containing pharmacophores (phenothiazine, tetrahydrocarbazole, carbazole, and 3,5-dimethyl-1-aminoadamantane) leading to the formation of the corresponding 1,4-substituted 1,2,3-triazoles and allowing the introduction of a diethoxyphosphoryl fragment into the molecules of potential neuroprotectors.

Carbamoylimines of methyl trifluoropyruvate react with cyclopentadiene with to formation of trifluoromethyl-containing azabicyclo [2.2.1] heptenes and tetrahydrocyclopenta[e][1,3]oxazines. NMR experiments involving DEPT and 1H{19F} determined the structure of the synthesized heterocycles and assignment of the signals in NMR spectra and established the exo-position of the CF3-group in azabicyclo[2.2.1]heptenes.

Four variants of conjugation of aminoadamantanes with 1,2,3-triazole- and ditriazolecontaining spacers by copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition of azido- and propargyl-containing aminoadamantanes were suggested.