Khidmet S. Shikhaliev

Application of Molecular Modeling to Development of New Factor Xa Inhibitors

In consequence of the key role of factor Xa in the clotting cascade and absence of its activity in the processes that do not affect coagulation, this protein is an attractive target for development of new blood coagulation inhibitors. Factor Xa is more effective and convenient target for creation of anticoagulants than thrombin, inhibition of which may cause some side effects. This study is aimed at finding new inhibitors of factor Xa by molecular computer modeling including docking SOL and postdocking optimization DISCORE programs. After validation of molecular modeling methods on well-known factor Xa inhibitors the virtual screening of NCI Diversity and Voronezh State University databases of ready-made low molecular weight species has been carried out. Seventeen compounds selected on the basis of modeling results have been tested experimentally in vitro. It has been found that 12 of them showed activity against factor Xa (IC50 = 1.8–40 μM). Based on analysis of the results, the new original compound was synthesized and experimentally verified. It shows activity against factor Xa with IC50 value of 0.7 μM.

Alkylation of 1,3-benzothiazin-4-one 2-oxo-, 2-arylimino-, and 2-thioxo derivatives

Sodium salt of 3Н-benzo[e][1,3]thiazine-2,4-dione is easily alkylated at position 3. In the case of 2-(arylimino)-2,3-dihydrobenzo[e][1,3]-thiazin-4-ones, the alkylation reaction at this position occurs regioselectively. Alkylation of 2-thioxo-2,3-dihydrobenzo[e][1,3]thiazin-4-one under the same conditions produced regioisomers, but S-alkylation at the exocyclic sulfur atom occurred in the presence of triethylamine. The reaction of 1-(4-oxo-3,4-dihydrobenzo[e][1,3]thiazin-2-ylidene)guanidine with methyl anthranilate led to the formation of tetracyclic quinazolinо[2,1-b]quinazolinedione.

Reactions of pyrazole-3(5)-diazonium salts with 4-hydroxy-2Н-chromen-2-one and isochroman-1,3-dione

Derivatives of a previously unknown heterocyclic system 6Н-chromeno[4,3-e]pyrazolo[5,1-c][1,2,4]triazin-6-one were obtained via reaction of pyrazole-3(5)-diazonium salts with 4-hydroxy-2Н-chromen-2-one. Analogous reactions with isochroman-1,3-dione are followed by recyclization leading to the formation of 2-(4-hydroxypyrazolo[5,1-c][1,2,4]triazin-3-yl)benzoic acids.

A novel synthetic approach to hydroimidazo[1,5-b]pyridazines by the recyclization of itaconimides and HPLC–HRMS monitoring of the reaction pathway

The novel cascade two-stage reaction between itaconimides and 1,2-diamino-4-phenylimidazole proceeds regio- and chemoselectively to form tetrahydroimidazo[1,5-b]pyridazines and includes nucleophilic C-addition by the activated C=C double bond and subsequent intramolecular recyclization of the intermediate with the amino group involved.

A novel method for the synthesis of pyrimido[1,2- a ]benzimidazoles

Condensation of 1,2-diaminobenzimidazole with N-arylitaconimides was studied. It was found that 2-(10-amino-N-aryl-2-oxo-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazol-3-yl)acetamides were formed in the course of this reaction upon brief heating to reflux of the reagent mixture in 2-propanol in the presence of catalytic amounts of acetic acid.

Condensation of 1,2-diamino-4-phenylimidazole and N-arylmaleimides with the formation of new tetrahydroimidazo[1,5-b]pyridazines

We studied the condensation of 1,2-diamino-4-phenylimidazole with N-arylmaleimides and established that this reaction occurred upon brief refluxing of reactants in isopropanol in the presence of a catalytic amount of acetic acid and produced substituted 7-amino-N-aryl-2-oxo-5-phenyl-1,2,3,4-tetrahydroimidazo[1,5-b]pyridazine-4-carboxamides. Performing this reaction at room temperature led to the acyclic intermediates N-aryl-3-(1,2-diamino-4-phenylimidazol-5-yl)pyrrolidine-2,5-diones.

Cyclization of 5-amino-1-aryl-1H-pyrazole-4-carbonitriles with β-dicarbonyl compounds

A method has been developed for the preparation of new pyrazolo[3,4-b]pyridines and tetrahydropyrazolo[3,4-b]quinolinones by the reactions of 5-amino-1-aryl-1H-pyrazole-4-carbonitriles with aliphatic and cyclic 1,3-dicarbonyl compounds in the presence of anhydrous tin(IV) chloride.

(3+2) Cycloaddition reactions in the synthesis of C(4)–N(5)-condensed tetrahydropyrrolo[3,4-c]pyrrole-1,3-diones (microreview)

This microreview summarizes the approaches to constructing tricyclic tetrahydropyrrolo[3,4-c]pyrrole-1,3-diones condensed at the C(4)–N(5)bond with five-, six-, or seven-membered heterocycles based on the (3+2) cycloaddition reaction of a variety of azomethine ylides with maleimides described in the literature over the past 10 years.

Synthesis of N -vinylformamide and 1-vinyl-(1-methacryloyl)-3,5-dimethylpyrazole copolymers and their extraction ability in relation to histidine in water-salt media

Copolymers of N-vinylformamide (VF) with 1-vinyl-3,5-dimethylpyrazole (VDMP) and 1-methacryloyl-3,5-dimethylpyrazole (MDMP) are synthesized by free radical copolymerization in dioxane. The compositions of copolymers are determined by means of UV-spectroscopy and FTIR, and copolymerization constants r1 and r2 are calculated. N-vinylformamide demonstrates higher reactivity than pyrazole-containing monomers in both cases. Solubility of the synthesized copolymers in water was studied. VF–VDMP copolymers are water soluble at VF content higher than 0.65 molar fractions, and VF–MDMP copolymers—at VF content over 0.8 molar fractions. The formation of complexes between water-soluble copolymers and essential α-amino acid histidine in aqueous solutions is confirmed by UV-spectroscopy, FTIR, dynamic light scattering (DLS), and transition electron microscopy. It is found via DLS that the interactions between the amino acid with copolymer macromolecules lead to conformation changes in macromolecular coils. It is shown that VF–VDMP and VF–MDMP copolymers are effective extragents for histidine. Extraction is carried out at different pH values. The highest extraction degree (98%) is achieved in an acidic medium.

Efficient synthesis of substituted 8-(pyrazolo[3,4-d]pyrimidin-6-yl)-1,2-dihydroquinolines

An effective method for the synthesis of 8-(1-aryl-4-methoxy-1Н-pyrazolo[3,4-d]pyrimidin-6-yl)-2,2,4-trimethyl-1,2-dihydroquinolines was developed on the basis of a three-component reaction between substituted 4,4,6-trimethyl-4H-pyrrolo[3,2,1-ij]quinoline-1,2-diones and 5-amino-1-aryl-1H-pyrazole-4-carbonitriles in refluxing methanol in the presence of an excess of sodium methoxide. HPLC-MS analysis showed that the cascade process started by addition of methanol molecule to the nitrile group of aminopyrazolecarbonitrile.