K. A. Frolov

Inhibitors of tick-borne flavivirus reproduction from structure-based virtual screening.

Flaviviruses form a large family of enveloped viruses affecting millions of people over the world. To date, no specific therapy was suggested for the infected people, making the treatment exclusively symptomatic. Several attempts were performed earlier for the design of fusion inhibitors for mosquito-borne flaviviruses, whereas for the tick-borne flaviviruses such design had not been performed. We have constructed homology models of envelope glycoproteins of tick-transmitted flaviviruses with the detergent binding pocket in the open state. Molecular docking of substituted 1,4-dihydropyridines and pyrido[2,1-b][1,3,5]thiadiazines was made against these models, and 89 hits were selected for the in vitro experimental evaluation. Seventeen compounds showed significant inhibition against tick-borne encephalitis virus, Powassan virus, or Omsk hemorrhagic fever virus in the 50% plaque reduction test in PEK cells. These compounds identified through rational design are the first ones possessing reproduction inhibition activity against tick-borne flaviviruses.

Design and synthesis of pyrido[2,1-b][1,3,5]thiadiazine library via uncatalyzed Mannich-type reaction.

This Research Article describes the synthesis of an over 700-member library of (8R/8S)-3-R-8-aryl-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazin-9-carbonitriles by uncatalyzed Mannich-type reaction of N-methylmorpholinium (4R/4S)-4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridin-2-thiolates with a set of primary amines and excessive HCHO. The scope and limitations of the reaction were studied. Starting thiolates were obtained in yields of 53-82% by multicomponent reaction of aromatic aldehydes, cyanothioacetamide, 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrums acid), and N-methylmorpholine, followed by heterocyclization of the resulting Michael adducts.

Synthesis of partially hydrogenated 1,3,5-thiadiazines by Mannich reaction

We offer a systematic and generalized review of literature data over the previous 10 years regarding the synthesis of monocyclic and condensed 1,3,5-thiadiazine derivatives under the conditions of Mannich reaction.

Chemistry of cyanoselenoacetamide (Review)

The recent published data on the chemistry of cyanoselenoacetamide, a prospective reagent for the synthesis of various nitrogen- and selenium-containing heterocycles, are classified and summarized.

Novel [4 + 2] Cycloaddition Reaction of Aryl-Methylidenemalononitriles to Unsaturated Chalcogen Amides. Synthesis, Structure, and Properties of Triethylammonium 3,5,5-Tricyano-1,4,5,6-Tetrahydropyridine-2-Selenolates and -Thiolates

Reaction of arylmethylidenemalononitriles with 3-aryl-2-cyanoprop-2-eneselenoamides in the presence of Et3N gave triethylammonium 4,6-diaryl-3,5,5-tricyano-1,4,5,6-tetrahydropyridine-2-selenolates. A similar reaction with cyclohexylidenecyanothioacetamide yields triethylammonium 4-aryl-1,5,5-tri-cyano-3-azaspiro[5.5]undec-1-ene-2-thiolate. Alkylation of the obtained selenolates and thiolates gives 6-(alkylseleno)-2,4-diaryl-1,4-dihydropyridine-3,3,5(2H)-tricarbonitriles and 4-(alkylthio)-2-aryl-3-aza- spiro[5.5]undec-4-ene-1,1,5-tricarbonitriles, respectivelly. The structure of 2,4-di(2-furyl)-6-{[2-(4-methylphenyl)-2-oxoethyl]seleno}-1,4-dihydropyridine-3,3,5(2H)-tricarbonitrile has been confirmed by the X-ray structural analysis.

Synthesis of pyrido[2,1-b][1,3,5]thiadiazines by the aminomethylation of 4-methyl-6-oxo-2-thioxopiperidine-3-carbonitrile

Pyrido[2,1-b][1,3,5]thiadiazines are a rather rare type of condensed heterocyclic system [1-3], and only isolated studies reporting the preparation of this bicyclic system have been reported [4-6]. We have shown that treatment of the previously synthesized 4-methyl-6-oxo-2-thioxopiperidine-3-carbonitrile 1 [7] with primary amines in the presence of excess HCHO gives the previously unknown pyrido[2,1-b][1,3,5]thiadiazines 2a,b. The structure of compounds 2a,b was confirmed from H NMR and IR spectroscopy and from elemental analysis data. The potential of the method and its optimization will be the subject of further investigations.

Synthesis and properties of triethylammonium 4-aryl(hetaryl)-3,5-dicyano-6-oxo-1,4,5,6-tetrahydro-pyridine-2-selenolates

The reaction of (hetero)aromatic aldehydes, cyanoselenoacetamide, and 1-(cyanoacetyl)-3,5-dimethyl-pyrazole in the presence of triethylamine gives a mixture of the cis and trans diastereomers of triethylammonium 4-aryl(hetaryl)-3,5-dicyano-6-oxo-1,4,5,6-tetrahydropyridine-2-selenolates. The selenolates obtained react with alkyl halides to form the corresponding selenides.

Mannich reaction in the synthesis of N,S-containing heterocycles. 13*. One-pot method for preparing pyrimido[4,3-b]-[1,3,5]thiadiazines by reaction of aldehydes, cyanothioacetamide, formaldehyde, and primary amines

Successive reaction of cyanothioacetamide with aliphatic or aromatic aldehydes, formaldehyde, and primary amines gives the corresponding 3,7-disubstituted 3,4,7,8-tetrahydro-2H,6H-pyrimido-[4,3-b][1,3,5]thiadiazine-9-carbonitriles.

Synthesis and Alkylation of N-Methylmorpholinium 4-Aryl-3-cyano-5-oxo-1,4,5,6,7,8-hexahydroquinoline-2-selenolates

A multicomponent reaction of cyanoselenoacetamide with aromatic aldehydes, cyclohexane-1,3-dione, and N-methylmorpholine gave N-methylmorpholinium 4-aryl-3-cyano-5-oxo-1,4,5,6,7,8-hexahydro-quinoline-2-selenolates. Alkylation of the latter occurs under mild conditions with retention of the 1,4-dihydropyridine fragment to give 2-(2-R-methylseleno)-4-aryl-5-oxo-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitriles.

Synthesis and reactions of 1,2-bis[3-cyano-4-(2-fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl]diselane

The interaction of 2-fluorobenzaldehyde, cyanoselenoacetamide and Meldrum’s acid in the presence of N-methylmorpholine gives 1,2-bis[3-cyano-4-(2-fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl]di-selane, which also is the product of the reaction of cyanoselenoacetamide with 5-(2-fluorobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione. The diselane obtained interacts with alkyl halides in the presence of a base, forming the corresponding 4-(2-fluorophenyl)-2-(2-R-methylselanyl)-6-oxo-1,4,5,6-tetra-hydropyridine-3-carbonitriles.