Vol. 12 No. 1(45) (2014)
The literature sources concerning application of 1-(pyrrolidin-2 ylmethyl)pyrrolidine as an effective organocatalyst of asymmetric reactions have been reviewed and systematized. The role of the tertiary amine fragment in the structure of the catalyst has been emphasized; it makes an asymmetric arrangement in the transition state of the key step during the new C-C bond formation. The importance of Bronsted acid as a promoter (additive), which protonates the basic nitrogen atom transforming it to the N-H-donor system, has been noted. Aldol condensation catalyzed by 1-(pyrrolidinyl-2-ylmethyl)pyrrolidine that can be undoubtedly considered as one the most valuable tools in asymmetric synthesis and construction of various optically active organic frameworks has been reviewed in details. A powerful catalytic activity of 1-(pyrrolidinyl-2-ylmethyl)pyrrolidine in the Mannich reaction leading to a new C-C bond and chiral centre creation has been demonstrated. A significant attention in the review is devoted to application of 1-(pyrrolidin-2-ylmethyl)pyrrolidine in the asymmetric version of the Mannich reaction as a convenient approach for the synthesis of chiral β-aminoketones and β-aminoesters being well known as useful building blocks and precursors for important nitrogen-containing natural products and heterocycles.
Synthesis and antiviral activity of [(9-R1-10-R2-3-R-2-oxo-2H-[1,2,4]-triazino[2,3-c]quinazolin-6-yl)thio]acetamides derivatives with the fragments of carcass amines
Alkylation of potassium 9-R1-10-R2-3-R-2-oxo-2Н-[1,2,4]triazino[2,3 с]quinazolin-6-thiolates by N-cycloalkyl-(cycloalkylaryl-)-2-chloracetamides and interaction of [(9-R1-10-R2-3-R-2-оxo-2H-[1,2,4]triazino[2,3-с]quinazolin-6-yl) thio]acetiс acids imidazolides and chloranhydrides with carcass amines yielded the corresponding amides. The structures of the compounds synthesized have been confirmed by 1H, 13C NMR, LC–MS and EI-MS analysis.
The features of 1H, 13C NMR, LC–MS and EI-MS spectra have been described, and characteristic signals have been identified. The compounds synthesized have been studied for their antiviral activity. The results of the antiviral assay have shown that some compounds exhibit a moderate and high activity against the strains studied.
The correlation between the structure and the antiviral action has been also discussed. According to the data obtained the conclusion can be made that the combination of carcass amine moieties with the fragment of little known [(9-R1-10-R2-3-R-2-оxo-2H-[1,2,4]-triazino[2,3-с]quinazolin-6-yl)thio]асetic acid results in compounds with a high antiviral activity. High indicators of the antiviral activity of compounds 3.2 and 3.14 against Influenza Type A H3N2 allow to suppose the expediency of further chemical modification of [1,2,4]triazino[2,3-с]quinazoline directed to obtaining new antiviral agents.
The investigation of the “chemical structure – antihypoxic action” dependence in a series of indole and 2-oxindole derivatives containing the ethylamine fragment
The article describes the study of the antihypoxic action of the compounds previously synthesized, namely indole and 2-oxindole derivatives, containing an ethylamine fragment being characteristic of melatonin, and the “chemical structure – antihypoxic action” dependence based on in vivo and in silico data. The screening has been conducted on the models of acute normobaric and hemic hypoxia in white male mice. The substances under research were administered in the dose of 0.50 mg/kg that was similar to the reference drug melatonin.
The second antihypoxic reference drug mexidol was administered in the dose of 42 mg / kg. The compound R-77 (4,3’-spiro[(2-amino-3-cyano-4,5-dihydro-pyrano[3,2-c]chromen-5-on)-5-methyl-2’-oxindole]) caused a maximum effect (of about 101% on the hemic hypoxia model, and 176% on the normobaric hypoxia model). By its effect size the new compound is significantly superior to the reference drug melatonin (the antihypoxic activity is 67.6% and 109%) and somewhat dominates mexidol (the antihypoxic activity is 94.3 % and 161%). A set of essential molecular descriptors (miLogP, TPSA, MV) has been calculated for each of the 30 compounds. The compounds having lipophilicity (miLogP) estimated approximately from 1.2 to 2.5, the calculated topological descriptor of the polar surface molecules area (TPSA) from 85 to 125 and the optimal molecular volume (MV) 250 to 320 have shown the highest antihypoxic activity. The results obtained demonstrate the expediency of a further detailed pharmacological study of spirocyclic oxindole derivatives for the purpose of searching for highly efficient substances with the antihypoxic action.
Calixarene α-hydroxymethylphosphonic acids as potential inhibitors of protein tyrosine phosphatases
Calixarene are known to be a promising scaffold for designing inhibitors of protein tyrosine phosphatases.
In this work calixarene mono- and bis-α-hydroxymethylphosphonic acids have been tested in vitro for the inhibitory activity against some therapeutically important protein tyrosine phosphatases. The results obtained have shown that these macrocyclic compounds can inhibit CD45, PTP1B, and SHP2 with IC50 values in the micromolar range. At the same time the inhibitors have demonstrated lower activity toward other protein tyrosine phosphatases such as TC-PTP and PTPβ. It has been found that mono-substituted calixarene is more potent inhibitor of CD45 than the bis-substituted one and shows about 2-15 fold selectivity over TC-PTP, PTPβ, SHP2 and PTP1B. Model 4-hydroxyphenyl-α-hydroxymethylphosphonate displays at least one order lower activity than the phosphonate derivatives of calixarene. Thus, the combination of a macrocyclic platform and α-hydroxymethylphosphonate group is essential for the inhibition activities of these compounds. Computer-simulated docking studies have been performed using AutoDock 4.2 programme by the example of PTP1B. The data obtained indicate that the inhibitors can bind in the active site of the enzyme. To clarify the inhibition mechanism the possible enzyme-inhibitor complexes have been considered using several crystal structures of PTP1B and all stereoisomeric forms of the inhibitors.
Directed synthesis of potential antitumor substances among derivatives of 3-mercapto-4-(1H-pyrrol-1-yl)-5-cyclohexyl-1,2,4-triazole(4H)
Synthesis of the series of new 4-(1H-pyrrol-1-yl)-5-cyclohexyl-1,2,4-triazole(4H)-3-yl thioacetanilides from 4-amino-5-cyclohexyl-1,2,4-triazole(4H)-3-yl thioacetanilides previously synthesized is described. The target products 3a-z have been obtained by Paal-Knorre pyrrole condensation of the initial aminocompounds 1 with 2,5-dimethoxytetrahydrofuran (2) in the acetic acid medium. The structure of the substances synthesized has been proven by elemental analysis and NMR spectra data. All compounds synthesized contain signals of the cyclohexane system protons as two multiplets in their NMR spectra at 2.39-2.33 ppm (methyne proton) and 1.76-1.13 ppm (cyclohexyl methylene groups protons). Unlike the starting compounds (1) the end products (3a-z) have no signal of 4-aminogroup proton as a singlet in the spectra at 5.87-5.92 ppm. Instead of it, signals of the pyrrole ring are present as two triplets at 7-20-7.17 and 6.32-6.29 ppm. Among activities being more probable for the substances synthesized due to preliminary PASS-prognosis were inhibition of MAO and some enzymes (Pa = 0.554-0.729). Compound (3w) was selected by the National Cancer Institute (NCI) for in vitro screening on different tumour cell lines. As result of this investigation we have noted that, unfortunately, substance 3w is not an effective inhibitor of tumour cells in the dose studied, in particular the growth percent for leukemia cells for more sensitive lines is 68.48 (RPMI-8226); 69.30 (HL-60(TB)); for non-small cell lung cancer – 63.06 (HOP-92); for melanoma – 47.82 (SK-MEL-5); 67.37 (UACC-62); for renal cancer – 56.66 (UO-31). Sensitivity of all cancer cell lines for the colon, CNS, ovarian, prostate and breast cancer was approximately at the control level.
Arylmethyliden derivatives of 2,2-dimethyl-1,3-dioxane-4,6-dione; Meldrum`s acid; 6,7-dihydro-7-aryltetrazolo [1,5-a]pyrimidin-5(4H)-ones; synthesis; pharmacological activity
Cyclocondensations of 1H-tetrazol-5-amine with methylcinnamates, arylmethyliden malonic acids and arylmethyliden derivatives of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum`s acid) proceed regioselectively and lead to formation of 7-aryl-6,7-dyhidrotetrazolo[1,5-a]pyrimidin-5(4H)-ones. The direction of cyclization corresponds to the interaction of the carbon atom in β-position of the unsaturated carbonyl compounds with the endocyclic nitrogen atom and the carbonyl group with amino group in the aminoazole molecule. Compounds of the isomeric structure in any of the experiments have been not identified. The structures and composition of the newly synthesized tetrazolo[1,5-a]pyrimidin-5(4H)-ones have been confirmed by elemental analysis, infrared spectroscopy (IR), nuclear magnetic resonance on protones (1H NMR) and mass spectra data. Virtual screening of 7-aryl-6,7-dihydrotetrazolo[1,5-a]pyrimidin-5(4H)-ones carried out using the PASS programme for 780 types of the pharmacological action has demonstrated that it is expedient to test these compounds by their analgesic and anti-inflammatory activity, as well as as potential agents for the treatment of heart failure.
N-Benzyl-1-(2-cyanoethyl)-4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxamides as promising analgesics
Based on the regularities of the “structure – analgesic activity” relationship revealed earlier in the complex study of the biological properties of numerous N-substituted amides of 1-R-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids the target chemical modification of the structurally related N-alkyl-1-(2-cyanoethyl)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides has been conducted. These changes concerned only the amide fragment of the given compounds, and they are actually the replacement of one of the hydrogen atoms of the methyl group in N-methyl-1-(2-cyanoethyl)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide by the aromatic ring. It has been shown that in the synthesis of the target compounds various variants of amidation of 4-hydroxy-2-oxo-1-(2-cyanoethyl)-1,2-dihydroquinoline-3-carboxylic acid ethyl ester with the benzyl amines can be successfully used: by thermolysis of the ester and amine without a solvent at 140°C or by interaction of the ester with the excess of amine in boiling alcohol. The peripheral component in the mechanism of analgesic properties of N-benzyl-1-(2-cyanoethyl)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides has been studied on the standard model of “acetic acid-induced writhing” in white mice concomitantly and in comparison with diclofenac. It has been found that some of the substances synthesized exceed notably the reference drug as for the analgesic effect when administered orally in the dose of 5 mg/kg, and they can be recommended for more profound research as potential analgesics.
Interaction of 5-chloro-1-phenyl-1H-pyrazole-4-carboxamide and 5-chloro-N-formyl-1-phenyl-1H-pyrazole-4-carboxamide with hydrazine hydrate
This article represents the research of the interaction of 1-phenyl-5-chloro-1H-pyrazole-4-carboxamide and 1-phenyl-N-formyl-5-chloro-1H-pyrazole-4-carboxamide with hydrazine hydrate in order to get pyrazole derivatives as potential bioactive substances. It has been found that during the short (~40 min) boiling of 1-phenyl-5-chloro-1H-pyrazole-4-carboxamide with hydrazine hydrate a previously unknown 5-hydrazino-1-phenyl-1Hpyrazole-4-carbohydrazide with the yield of 50% is formed. The further boiling (~15 h) of the product obtained with hydrazine hydrate leads unexpectedly to 1-phenyl-1H-pyrazole-4-carbohydrazide. The probable mechanism of its obtaining, which includes dimerization of the prototropic isomer formed while cleaving the hydrazine molecule and the further elimination of the nitrogen molecule, has been considered. When boiling with hydrazine hydrate for 3 hours 1-Phenyl-N-formyl-5-chloro-1H-pyrazole-4-carboxamide gives 5-amino-1-phenyl-1H-pyrazole-4-carbohydrazide. At first, obviously, N-[(5-hydrazino-1-phenyl-1H-pyrazol-4-yl) carbonyl]formamide is formed with further cyclization into pyrazole[3,4-d][1,2,3]triazin-4-one. The latter eliminates the nitrogen molecule when heating with the formation of the reactive 4-carbonyl-1-phenyl-4,5-dihydro-1H-pyrazole-5-imine. Addition of hydrazine to it leads to 5-amino-1-phenyl-1H-pyrazole-4-carbohydrazide. The composition of all compounds synthesized has been proven by elemental analysis and the structure has been confirmed by spectroscopic methods.
3D Pharmacophore modeling in the molecules of 5,7-dimethyl-6-phenylazo-3H-thiazolo[4,5-b]pyridine-2-one derivatives
Flexible molecular docking studies for 5,7-dimethyl-6-phenylazo-3H-thiazolo[4,5-b]pyridin-2-ones have been performed with the purpose to reveal their potency as enzymes involved in the arachidonic acid (AA) cascade inhibitors: both cyclooxygenase isoforms (COX-1 and COX-2), and microsomal prostaglandin E synthase-1 (mPGES-1). The protein-ligand interaction fingerprint (PLIF) tool implemented in MOE software has been used for summarizing the interactions between ligands and the abovementioned enzymes. Receptor interaction fingerprints have been generated from the docked poses of the virtual screening hits with COX-1,2 and mPGES-1 active sites coordinates. 3D pharmacophore models containing two and three points queries as the combination of their structures steric and electronic parameters have been generated and it provides the affinity and inhibitory activity of the novel compounds towards multiply receptors. The analysis of the pharmacophore models obtained indicates the functionality of fused bicyclic thiazolopyridine scaffold which provides the steric placement of at least one of these heterocycles atoms in the respective pharmacophore centres. The fused thiazolo[4,5-b]pyridine-2-one system may be considered as a promosing scaffold for creating diverse combinatorial libraries of potential biologically active substances. The final conclusion has been confirmed by the results of the virtual screening procedures and pharmacophore centres modeling in molecules of novel thiazolo [4,5-b]pyridine-2-one.
The reactivity of N-phenylanthranilic acids derivatives. XXV. Kinetic parameters of activation and isoparametricity of the reaction of the alkaline hydrolysis of methyl esters of substituted 4,5-dimethoxy-N-phenylanthranilic acids in the binary dioxane-water solvent
Kinetics of the alkaline hydrolysis reaction of methyl esters of substituted 4,5-dimethoxy-N-phenylanthranilic acids has been studied in the binary solvent of dioxane-water at 55, 75, 85°C. It has been found that at each experimental temperatures lgkT dependence on the nature and position of substitutes in a non-anthranilic fragment of the molecule is described by the Hammett equation. It has been demonstrated that introduction of electrodonor substituents in the molecule of ester assists increasing of the activation energy and free activation energy. The activation entropy for all substances is significant and high according to the absolute value, which indicates the BAC2 mechanism of the reaction with formation of high-symmetrical intermediates. The analysis of the numerous kinetic and activation parameters has shown isokinetics of the reaction with the enthalpy type of control. It has been experimentally found that the compounds synthesized show the anti-inflammatory, analgesic, diuretic, bacteriostatic activities.
Investigation of the structure changes of tannides acylated derivatives in the process of synthesis using differentiating electronic absorption spectroscopy
A number of acylated derivatives of industrial gallotannin and ellagitannin from alder cones with different substitution degrees of phenolic hydroxyls has been synthesized. The synthesis involved the preparation of a mixture of derivatives with different substitution places of phenolic hydroxyls and different number of substitutions. The synthesis of acylated derivatives was carried out under reflux with the mixture of the modifier with tannides in glacial acetic acid, and recrystallization of the derivatives obtained was performed from the water-ethanol mixture. Succinic and maleic anhydrides were used as modifiers. The primary electronic absorption spectrum and its first and second derivatives – differential electronic absorption spectra were studied. As the result of the study of the electronic absorption spectra of tannides with varying degrees of modification it has been found that significant changes in the spectrum shift of the absorption band of aromatic groups (250-270 nm) is observed only for the acylated gallotannins. Thus, it has been shown that the degree of modification correlates with the degree of the shift of the absorption band, and it allows to use this reaction for identification of the combinatorial derivative of gallotannin. The electronic absorption spectra of various acylated ellagitannins derivatives did not actually differ. It indicates a more stable and rigid electronic and spatial structure of digallic acid, which prevents the use of spectroscopy in the UV region to identify individual combinatorial derivatives of ellagitannins. In HPLC the spectrunm of acylated tannins contains additional bands, including the low molecular weight region of the spectrum. It indicates the appearance of new acylated derivatives in the combinatorial mixture of tannides.
Erythrocytes and neutrophilic leukocytes of human blood have been used as biosensors for in vitro screening of new biologically active functionally substituted oxazoles and nitrogen-containing bisphosphonates with the known fungistatic activity. It has been found that none of the compounds under research do not reveal the hemolytic action in the reaction of osmotic hemolysis of human red blood cells. For all compounds tested the erythrocyte sedimentation rate is changed. The functionally substituted oxazoles decreased the reaction rate approximately by 70%, and nitrogen-containing bisphosphonates increased it approximately by 30%. The reactivity found can indicate high affinity of the compounds studied to erythrocyte membranes adrenoreceptors. It can be used for characteristics and prediction of a number of other potential effects of the antimycotical compounds tested.
According to the NBT-test the functionally substituted oxazoles are activators of the antimicrobial potential of neutrophilic leukocytes and can be considered as potential stimulators of nonspecific human immunity reactivity. The experimental data obtained significantly expand the range of biological effects of the fungistatic compounds synthesized and confirm perspectiveness of their further study as antimycotic agents. In vitro screening with the use of human blood cells as biosensors is an important part of potential drugs research and can be recommended for testing new biologically active compounds with the known biological activity.