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A synthetic approach to the modification of the drug Riluzole with pharmacologically active fragments (adamantane, carbazole, tetrahydrocarbazole, γ-carboline, and phenothiazine) was proposed, which is based on the copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition of azide-containing pharmacophores with alkyne-containing derivatives of Riluzole.

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.

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 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.

Copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition reactions of α-azidoalkylphosphonates with propargyl-containing pharmacophores such as phenothiazine, tetrahydro-γ-carboline, tetrahydrocarbazole, carbazole and 3,5-dimethyl-1-aminoadamantanes led to the formation of the corresponding 1, 4-substituted 1,2,3-triazoles and make it possible to introduce a diethoxyphosphorylalkyl fragment into the molecules of potential neuroprotectors using a triazole-containing spacer.

A synthetic approach to the vinylation and allylation of tetrahydro-γ-carbolines with alkane dimethyl sulfonates in the presence of sodium hydride was developed. The effect of the synthesized 5-vinyl- and 5-allyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles on acetylcholinesterase, butyrylcholinesterase, and carboxylesterase activity, mitochondrial functions, and tubulin polymerization was investigated, and their antioxidant activity was evaluated.

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.

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.

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.

Five different synthetic approaches for the conjugation of carbazoles with aminoadamantanes via propylene, 2-hydroxypropylene, 1-oxopropylene, 1-oxoethylene and triazole spacers have been proposed. The corresponding mesylate-, acrylate-, chloroacetate-, propargyl-, azido- and epoxy-containing carbazoles and aminoadamantanes were used as the starting compounds.

Dimethyl and morpholinyl carbamoyl imines of trifluoropyruvate 1a,b were synthesized and studied in cyclocondensation and cycloaddition reactions. Cyclocondensation of carbamoyl imines 1a,b with benzyl urea, benzamidine, 3-aminocrotonitryl, 6-aminouracil, and acetylacetone led to 5-membered trifluoromethylated heterocycles with an ureido substituent. The [2 + 4]-cycloaddition reactions of carbamoyl imines 1a,b were performed with dialkylcyan amines and cyclopentadiene. Formerly unknown carbamoyl imines 1a,b and their derivatives were characterized by NMR spectroscopy ( 1 H, 13 C, 19 F) and elemental analysis.

Reaction of carbazole with dimethyl alkanedisulfonates in the presence of sodium hydride resulted in the formation of three main products: 2-(9H-carbazol-9-yl)alkylmethanesulfonates, 1,2-di-(9H-carbazol-9-yl)alkanes, and 9-alkenyl-9H-carbazoles.

An approach to modify biologically active carbazoles and tetrahydrocarbazoles with 2-trifluoromethyl and 2-methoxycarbonyl(imidazo[1,2-a]pyridin-3-yl)propionylamidic fragments by interaction of N-methyl-N-[2-trifluoromethylimidazo[1,2-a]pyridin-3-yl]prop-2-ene amides and N-methyl-N-[2-methoxycarbonylimidazo[1,2-a]pyridin-3-yl]prop-2-ene amides with carbazoles and tetrahydrocarbazoles in the presence of catalytic amounts of cesium fluoride was proposed. Effect of compounds synthesized on neuronal NMDA receptors using radioligand binding method was studied.

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

Unknown conjugates of carbazoles and tetrahydrocarbazoles were obtained by the alkylation of carbazoles and tetrahydrocarbazoles with 3,6-substituted 9-oxiranylmethylcarbazoles. The influence of synthesized 1-(9Н-carbazol-9-yl)-3-(1,2,3,4-tetrahydro-5Н-pyrido[4,3-b]-indol-5-yl)propan-2-ones on functional characteristics of brain mitochondria has been studied. The potential neuroprotective activity of a several representatives of conjugates has been demonstrated using glutamate toxicity model.

Catalytic alkylation of substituted indoles such as cycloalkaneindoles and tetrahydro-γ-carboline using 9-oxiranylmethylcarbazole leads to the formation of 1-(carbazol-9-yl)-3-{dihydrocycloalkane[b]indol-4(1H)-yl}propan-2-ols and 1-(carbazol-9-yl)-3-{2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl}propan-2-ol, conjugates containing 2-hydroxypropylene spacer.

A series of 5,5-bis(trifluoromethyl)-5,6-dihydropyrimido[4,5-d]pyrimidine-2,4(1 H ,3 H )-diones has been prepared by the cyclocondensation of N -acylimines of hexafluoroacetone and 6-aminouracils. The obtained compounds were screened for their activities against Gram-positive ( Staphylococcus aureus, Staphylococcus epidermidis and Bacillus anthracis ) and Gram-negative ( Escherichia coli ) bacteria, as well as fungus Candida albicans. A few of the title compounds showed promising antimicrobial activity.

Earlier unknown conjugates of carbazoles and γ-carbolines were obtained by the reaction of 3,6-substituted 9-oxiranylmethylcarbazoles and 2,8-substituted 2,3,4,5-tetrahydro-1H-pyrido-[4,3]indoles. The effects of synthesized 1-(9H-carbazol-9-yl)-3-(1,2,3,4-tetrahydro-5H-pyrido-[4,3-b]indol-5-yl)propan-2-ones and their hydrochlorides on neuronal NMDA receptors, polymerization of tubulin to form microtubules, and functional characteristics of rat liver mitochondria were studied.

The first representatives of 3-trifluoromethyl-2-(dialkoxyphosphoryl)imidazo[1,2-a]pyridines have been synthesized by the reaction of N-(pyridin-2-yl)-perfluoropropanimidoyl chlorides with triethyl phosphite.

Synthetic strategy to access new multitarget neuroprotectors by conjugation of pharma-cophoric indole and bis(dimethylamino)phenothiazine moieties via 1-oxopropylene spacer was developed. The transformation was achieved by the cesium fluoride-catalyzed reaction of cycloalkaneindoles with 1-propenone. Effect of the synthesized compounds on neuronal NMDA receptors was evaluated by radioligand binding assay.

Modification of biologically active cycloalkaneindoles by incorporation of a 2-trifluoromethylimidazo[1,2-a]pyridin-6-yl fragment has been proposed and performed via the interaction with 3-fluoro-2-trifluoromethylimidazo[1,2-a]pyridines in the presence of potassium hydroxide. The action of the prepared compounds on neuronal NMDA receptors has been studied by means of radioligand binding.

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.

A new method of the synthesis of heterocyclic derivatives of trifluoroalanine based on the cyclocondensation of methyl trifluoropyruvate tert-butoxycarbonylimine with C,N- and N,N-binucleophiles, like Nsubstituted ureas, 1-benzyl-6-aminouracil, benzamidine, and 3-aminocrotononitrile, followed by hydrolysis of the resulting Boc-derivatives to 5-amino-5-trifluoromethylimidazolidine-2,4-diones, 5-amino-5-trifluoromethyl-1-benzyl-5,7-dihydropyrrolo[2,3-d]-pyrimidine-2,4,6-3H-trione, 4-amino-2-methyl-5-oxo-4-(trifluoromethyl)-4,5-dihydro-1H-pyrrole-3-carbonitrile, or 5-amino-5-trifluoromethyl-2-phenyl-3,5-dihydroimidazol-4-one, respectively, was developed.

New (3-fluoroimidazo[1,2-a]pyridin-2-yl)phosphonates were synthesized by a tandem reaction of imidoyl chlorides with two equivalents of triethyl phosphite.

Cyclocondensation reactions of methyl trifluoropyruvate N-(pyrimidin-2-yl)imines with N-substituted ureas, N-benzylbenzamidine, 2-aminothiazoline, methyl 3-aminocrotonate, and 6-aminouracils leading to imidazolidine-2,4-diones, 3,5-dihydroimidazol-4-ones, 2,3-dihydroimidazo[2,1-d][1,3]thiazol-5(6H)-one, 4,5-dihydro-1H-pyrroles, and 5,7-dihydro-1H-pyrrolo[2,3-d]pyrimidine-2,4,6-triones have been studied.

An approach to the modification of biologically active gamma-carbolines with the N-substituted propionamide fragments by the reaction of N-substituted acrylamides with gamma-carbolines catalyzed by cesium fluoride has been suggested. The compounds synthesized were studied for the influence on the functional characteristics of brain mitochondria, in particular, on the membrane potential, calcium-induced “swelling” and calcium capasity of the rat brain mitochondria.

A series of 5,5-bis(trifluoromethyl)-5,6-dihydropyrimido[4,5-d]pyrimidine-2,4(1 H ,3 H )-diones has been prepared by the cyclocondensation of N -acylimines of hexafluoroacetone and 6-aminouracils. The obtained compounds were screened for their activities against Gram-positive ( Staphylococcus aureus, Staphylococcus epidermidis and Bacillus anthracis ) and Gram-negative ( Escherichia coli ) bacteria, as well as fungus Candida albicans. A few of the title compounds showed promising antimicrobial activity.

Cyclocondensation of ethyl 2-alkoxy-2-isocyanato-3,3,3-trifluoropropianates (novel 1,4-bielectrophiles) with primary amines resulted in 5-trifluoromethylimidazolidine-2,4-diones.

Reactivity of trifluoromethyl carbonyl compounds in a two-step reaction with dialkyl phos-phites (the Abramov reaction and phosphonate—phosphate rearrangement) has been studied and the scope of this reaction for the preparation of O-phosphorylated 1-substituted 2,2,2-trifluoro-ethanols, serine hydrolase inhibitors, has been determined.

Three-component reaction of Piracetam, methyl trifluoropyruvate and 1,3-binucleophiles, such as 6-aminouracils, 6-aminothiouracils, 4-(4-tolylamino)pent-3-en-2-one and N-substituted ureas, has been studied. This reaction resulted in fluorinated heterocyclic derivatives of Piracetam.

An approach to the modification of the known antimicrobial drug, streptocide, with fluorine-containing five-membered heterocycles is proposed. The reaction of the generated in situ methyl 2-[4-(N-acetylamino)phenylsulfonyl]imino-3,3,3-trifluoropropionate with 1,3-C,N- or 1,3-N,N-binucleophiles and subsequent hydrolysis of the resulting products furnished different novel fluorine-containing heterocyclic derivatives of streptocide, including fused heterocycles.

Previously unknown fluorinated α-alkoxy(aryloxy)alkylisocyanates, the esters of α-alkoxy and α-aryloxy-2-isocyanato-3,3,3-trifluoropropionic acids, were obtained. The synthetic potential of these compounds were demonstrated in reactions with anilines leading to 2-substituted 3,3,3-trifluoroalanine derivatives.

Three-component reactions of 6-aminouracils and 6-aminothiouracils with formaldehyde and primary amines gave 6-alkyl-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2,4-diones and 6-alkyl-2-thioxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-ones.

An electrochemical method was developed for production of lead chrome pigment from Cr(VI)-containing spent solutions of electroplating shops and lead battery scrap.

Cyclocondensation of N-substituted imines of methyl trifluoropyruvate with monosubstituted ureas afforded novel 5-amino-5-trifluoromethylhydantoins.

2-Amino-6-(trifluoromethoxy)benzothiazole (riluzol) was modified at the exocyclic N atom with thiazoline and thiazole substituents.

Reactions of acylimines of methyl trifluoropyruvate with C,N-bisnucleophiles gave fluoro-containing heterocycles including the 5-oxo-4,5-dihydro-1H-pyrrole fragment.

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.

The first representative of 3-fluoro-2-(dialkoxyphosphoryl)imidazo[1,2-a]pyrimidi nes has been synthesized by the reaction of N-(pyrimidin-2-yl)-2,2,2-trifluoroacetimidoyl chloride with triethyl phosphite. [Supplemental materials are available for this article. Go to the publisher's online edition ofPhosphorus, Sulfur, and Silicon and the Related Elements to view the following free supplemental file: Figures]

The behavior of methyl 3,3,3-trifluoro-2-(thiazol-2-ylimino)propionate (1) in cycloaddition and cyclocondensation reactions was studied. Cycloaddition of dimethylcyanamide to imine 1 gave a thiazolo[3,2-a][1,3,5]triazine derivative. Cyclocondensations of imine 1 with 2-aminothiazoline, N-cyclohexylbenzamidine, methyl (Z)-3-aminobut-2-enoate, and 6-amino-1-benzyluracil yielded dihydroimidazo[2,1-b]thiazol-5(6H)-one, 4,5-dihydroimidazol-5-one, 4,5-dihydro-1H-pyrrol-5-one, and dihydro-1H-pyrrolo[2,3-d]pyrimidine-2,4,6-trione derivatives, respectively.

The fluorinated 4-ethylidene-2,4-dihydropyrazol-3-ones act as heterodienes and dienophiles in the Diels-Alder reaction with amines and cyclopentadiene to give 1,4-dihydropyrazolo[4,3-e]-1,3-oxazines and spirobicyclo[2.2.1]hept-5-ene-2,4′-pyrazolones, respectively.

The first representative of 3-fluoro-2-(dialkoxyphosphoryl)imidazo[1,2- a ]pyridines has been synthesized by the reaction of N-(pyridin-2-yl)-2,2,2-trifluoroacetimidoyl chloride with triethyl phosphite.

A number of fluorine-containing α-amino phosphonates of the general formula (RO)2P(O)C(CF3)(COOC2H5)NHSO2Ph were obtained and found to irreversibly inhibit four serine hydrolases: acetyl- and butyrylcholinesterases, neuropathy target esterase, and carboxylesterase.