S. M. Medvedeva

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.

4,4-dimethyl-4,5-dihydro-1,2-dithiolo-[3,4-c]quinoline-1-thiones in 1,3-dipolar cycloaddition reactions with acetylenic dipolarophiles

The behavior of 4,4-dimethyl-4,5-dihydro-1,2-dithiolo[3,4-c]quinoline-1-thiones in the 1,3-dipolar cycloaddition reaction with acetylenic dipolarophiles has been studied. The rate of cycloaddition is reduced along with the decrease of electron-deficiency of the triple bond. Substituted 4-(1′,3′-dithiol-2′-ylidene)-1,2-dihydroquinoline-3-thiones were shown to be the reaction products. On using a twofold excess of acetylenedicarboxylic acid dimethyl ester, adducts of composition 1∶2 were formed which occured to be substituted 1′, 3′-dithiole-2′-spiro-1-(5,6-dihydrothiino[2,3-c]quinolines).

New multicomponent method for the synthesis of polyhydrogenated pyrazino[1,2-a]quinolines

A new one-pot method for the synthesis of 2,3,4,6,7,8,9,10-octahydro-1H-pyrazino[1,2-a]quinolines was developed based on a three-component reaction between methyl (3-oxopiperazin-2-ylidene)acetate, aromatic aldehydes, and cyclohexane-1,3-diones. It was shown by HPLC-MS analysis that this cascade reaction involved a sequence of steps including condensation between 1,3-diketone and aldehyde, addition of heterocyclic enaminone as a C-nucleophile, and intramolecular heterocyclization.

Novel heterocyclic systems based on 8-R-4,5-dihydro-4,4-dimethyl-[1,2]dithiolo[3,4-c]quinoline-1-thiones

Based on the reaction of 8-R-4,5-dihydro-4,4-dimethyl[1,2]dithiolo[3,4-c]quinoline-1-thiones with oxalyl chloride followed by the reactions of 1,3-dipolar cycloaddition and diene synthesis with participation of acetylenedicarboxylic acid dimethyl ester, we have developed approaches to synthesis of novel polycondensed heterocyclic systems: [1,2]dithiolo[3,4-c]pyrrolo[3,2,1-ij]quinoline-4,5-dione, 6-(1,3-dithiol-2-ylidene)-1,2-dioxo-5-thioxo-7H-pyrrolo[3,2,1-ij]quinoline and 4,5-dioxospiro(pyrrolo)-[3,2,1-ij]thiopyrano[2,3-c]quinoline-11,2′-[1,3]dithiole.

1,3-Dipolar Cycloaddition of Ethyl Propiolate to 4,4-Dimethyl-4,5-dihydro-1,2-dithiolo-[5,4-c]quinoline-1-thiones

The interaction of ethyl propiolate with 4,4-dimethyl-4,5-dihydro-2,3-dithiolo[3,4-c]quinoline-1-thiones leads to 1,3-dithiol-2-ylidenes, 1,6,6a(l4)-trithiapentalene, or thiino[2,3-c]quinolines depending on the conditions.

(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.

Efficient methods for the synthesis of spiroheterocyclic systems based on 4,4,6-trimethyl-4H-pyrrolo[3,2,1-ij]quinoline-1,2-diones

Cyclocondensation of 4H-pyrrolo[3,2,1-ij]quinoline-1,2-diones with some 1,2- and 1,3-dinucleophiles, their three-component cyclocondensations with arylamines and 2-mercapto-acetic acid, as well as with malononitrile and various methylene active carbonyl compounds lead to new heterocyclic systems: spiro[imidazolidine-2,1’-pyrrolo[3,2,1-ij]quinoline], spiro[1,3-dioxolane-2,1’-pyrrolo[3,2,1-ij]quinoline], spiro[1,3-benzothiazole-2,1’-pyrro- lo[3,2,1-ij]quinoline], spiro[β-carboline-1,1’-pyrrolo[3,2,1-ij]quinoline], spiro[3,1-benzoxazine-2,1’-pyrrolo[3,2,1-ij]quinoline], spiro[pyrrolo[3,2,1-ij]quinoline-1,2’-quinazoline], spiro[pyrrolo[3,2,1-ij]quinoline-1,2’-[1,3]thiazolidine], spiro[pyran-4,1’-pyrrolo[3,2,1-ij]- quinoline], spiro[chromene-4,1’-pyrrolo[3,2,1-ij]quinoline], spiro[pyrano[4,3-b]pyran-4,1’- pyrrolo[3,2,1-ij]quinoline], spiro[pyrano[3,2-c]chromene-4,1’-pyrrolo[3,2,1-ij]quinoline], and spiro[pyrano[2,3-c]pyrazole-4,1’-pyrrolo[3,2,1-ij]quinoline].

Synthesis, Docking, and Anticoagulant Activity of New Factor-Xa Inhibitors in a Series of Pyrrolo[3,2,1- ij ]Quinoline-1,2-Diones

New factor-Xa inhibitors in a series of pyrrolo[3,2,1-ij]quinoline-1,2-diones substituted by condensation at the β-carbonyl with rhodanine, arylamines, and H-tryptamines were synthesized, characterized, and studied by molecular docking. Promising factor-Xa inhibitors with inhibitory constants in the micromolar concentration range (IC50 = 0.7 – 40 μM) were discovered.

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.