Vol. 13 No. 1(49) (2015)
Published:
2015-03-12
Full Issue
Original Researches
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Methods of synthesis and properties of thiazolopyridines
The review systematizes the theoretical and experimental data concerning methods of synthesis of condensed thiazolopyridines, which at present have been insufficiently studied, the prospects for their application in the directed synthesis of new physiologically active substances. The recent developments in their pharmacology have been also analyzed. The available methods for the synthesis of condensed thiazolopyridines can be divided into two fundamentally different approaches. The first approach is based on annelation of the thiazolidine or thiazole cycle to the pyridine ring, and the second one use pyridine derivatives as starting materials; their functional groups make it possible to change the pyridine ring. Methods for obtaining thiazolopyridines using solid media carriers, and their synthesis with domino reactions deserve a particular attention. Generalization of the scientific data published confirms that the condensed thiazolopyridines exhibit various biological effects. In particular, they are characterized by analgesic, anti-inflammatory, antimicrobial, antioxidant and antifungal activities. Due to the inhibitory action on integrally linked kinase the specified class of compounds can eliminate the hyperproliferative disorders in the living organisms. It has been found that these derivatives exhibit the antidiabetic, antibacterial and anti-tuberculosis action. It is known that derivatives of thiazolopyridines have shown a positive effect in the treatment of sexual dysfunction. Thiazolopyridine derivatives containing the α-amino phosphonate residue at 2 position of the basic heterocycle exhibit a significant anticancer effect.
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Synthesis and the antimicrobial activity of 1-alkyl-5-methyl-3-phenyl-6-(5-phenyl-1,3,4-oxadiazol-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones
An effective approach for synthesis of 5-methyl-3-phenyl-6-(5-phenyl-1,3,4-oxadiazol-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione by 1,1’-carbonyldiimidazole promoted interaction of 5-methyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylic acid with benzohydrazide has been developed. The procedure also includes cyclization of N’-benzoyl-5-methyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carbohydrazide obtained by boiling in phosphorous oxychloride and further hydrolysis of the chlorine atom at position 2 of the thieno[2,3-d]pyrimidine system. Alkylation of the assembly of two heterocyclic units obtained with benzyl chlorides, chloroacetamides, and 5-(chloromethyl)-3-aryl-1,2,4-oxadiazoles has allowed obtaining of 1-alkyl-5-methyl-3-phenyl-6-(5-phenyl-1,3,4-oxadiazol-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones. The structures of the compounds obtained have been confirmed by the 1H NMR, chromato-mass spectral and elemental microanalysis data. The results of the screening performed by the agar diffusion method (“well method”) have shown the absence of the antimicrobial activity for 1-benzyl-5-methyl-3-phenyl-6-(5-phenyl-1,3,4-oxadiazol-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones and 2-[5-methyl-2,4-dioxo-3-phenyl-6-(5-phenyl-1,3,4-oxadiazol-2-yl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]-N-arylacetamides; but the activity for 1-{[3-aryl-1,2,4-oxadiazol-5-yl]methyl}-5-methyl-3-phenyl-6-(5-phenyl-1,3,4-oxadiazol-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones has been found. The compounds of this range appeared to be active against the strains of Staphylococcus aureus, Escherichia coli and Bacillus subtilis; the diameters of their growth inhibition zones were similar to those for the reference drugs Metronidazole and Streptomycin. -
Peculiarites of interaction between 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)-ones and cyclic anhydrides of non-symmetric dicarboxylic acids
The peculiarities of the reaction between 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)-ones and cyclic anhydrides of non-symmetric (2-methylsuccinic, 2-phenylsuccinic and camphoric) acids have been described in the present article. The influence of electronic and steric effects of substituents in the anhydride molecule on cyclisation processes has been discussed. The results have shown that the interaction of 3-(2-aminophenyl)-6-R-1,2,4-triazin- 5(2H)-ones mentioned above with 2-methylsuccinic and 2-phenylsuccinic acid anhydrides proceeded non-selectively and yielded the mixtures of 2-R1-3-(2-oxo-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-6-yl)propanoic acids and 1-(2-(5-oxo-6-R-2,5-dihydro-1,2,4-triazin-3-yl)phenyl)-3-R1-pyrrolidine-2,5-diones. It has been found that low regioselectivity of the acylation process may be explained by insignificant electronic effects of substituents (of the methyl and phenyl fragment) in position 2 of the anhydride molecule on the electrophilic reaction centre. It has been also determined that the reaction between 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)-ones and camphoric anhydride proceeds regioselectively and yielded 1,2,2-trimethyl-3-(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin- 6-yl)cyclopentan-1-carboxylic acids. Regioselectivity of the interaction mentioned above may be explained by the steric effect of the methyl group. Identity of compounds has been proven by LC-MS, the structure has been determined via a set of characteristic signals in 1H NMR, 13C NMR spectra and position of cross peaks in the correlation HSQC-experiment. Mass spectra of the compounds synthesized have been also studied, the principal directions of the molecule fragmentation have been described. The structure of 1,2,2-trimethyl-3-(3-methyl- 2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)cyclopentane-1-carboxylic acid has been proven by X-ray analysis.
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Synthesis and in silico screening of novel 2-methylquinoline-4-ones bound with the pyrazol-5-ones moiety
The 1,3-dicarbonyl derivatives of 2-methyl-1,4-dihydroquinoline-4-one have been synthesized by alkylation of methylene active compounds with 3-dimethylaminomethyl-2-methyl-1,4-dihydroquinoline-4-one. These compounds are the convenient starting material for creating the new chemical libraries in the series of 3-heteryl substituted 2-methyl-1,4-dihydroquinoline-4-ones. In this work the examples of the synthesis of new quinolone-pyrazolone systems are presented. Their condensation with hydrazine hydrate resulted in the new derivatives of 2-methyl-3-[(5-oxo-4,5-dihydro-1H-pyrazol-4-yl)methyl]-1,4-dihydroquinolin-4-ones. The estimation of novelty of the compounds obtained in such chemical databases as PubChem, ChemBl, Spresi has shown that these substances are not present in these sources, and the chemical scaffold – quinolone bound via the methylene bridge with azoles is new. Determination of 2D similarity of the compounds synthesized by standard molecular descriptors with the biologically active structures in the ChemBl_20 database has shown the uniqueness of a new quinolone scaffold and the potential anti-inflammatory activity for compounds of this series. The molecular similarity has been determined using the ChemAxon software (JKlustor, Instant JChem).
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Synthesis and the hypoglycemic activity of pyrazolidene-3-carboxylic acids and their derivatives exo-functionalized with the hydrazinilidene-1,3-thiazolidine fragment
It has been shown that 4- formylpyrazole-3-carboxylic acids and their ethyl esters interact selectively with thiosemicarbazide and its N4-aryl-derivatives in boiling acetic acid with formation of the corresponding 4-pyrazolylthiosemicarbazones with the yields of 76-91%. It has been found that heating of 4-pyrazolylthiosemicarbazones with diethyl acetylenedicarboxylate in boiling ethanol for 3 hours leads to formation of 1,3-thiazolidine-containing polyfunctional pyrazole derivatives with yields of 73-95%. Formation of compounds of this type indicates that the process occurs according to the scheme of the primary attack of a highly electrophilic triple bond of acetylenedicarboxylate by the nucleophilic atom of sulfur of the thiosemicarbazone fragment with subsequent intramolecular condensation, which leads to formation of the 4-oxo-1,3-thiazolidine-5-ilidene cycle. The structure of the 1,3-thiazolidinilidenehydrazonepyrazoles synthesized has been proven by a complex of spectral methods; the most informative of them are 13C NMR spectra with signals of carbon atoms of the thiazolidine cycle: C4 (159-161 ppm), C2 (162-165 ppm), C5 (163-165 ppm), as well as of the exo-cyclic ethoxycarbonylethylidene fragment: HC= (114-118 ppm); and of C(O) O (165 ppm). It has been determined that the compounds synthesized cause the hypoglycemic dose-dependent effect in mice, which is much more potent than the same effect of the reference medicine – pioglitazone. -
Synthesis and the biological activity of 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazin-3-carboxylic acids trifluoromethyl-substituted anilides
In order to reveal the regularities of the “structure – biological activity” relationship by interaction of esters of 1-R-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazin-3-carboxylic acids and trifluoromethyl substituted anilines in boiling xylene with good yields and purity the corresponding N-aryl-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazin-3-carboxamides have been synthesized. The structure of the compounds obtained has been confirmed by the data of elemental analysis and NMR 1Hspectroscopy. It has been shown that the presence of trifluoromethyl groups having the powerful electron-withdrawing properties affects the position of signals of the aniline moiety protons: comparing to the spectra of the model methyl derivatives they undergo a significant paramagnetic shift. According to the results of the pharmacological studies conducted it has been found that the replacement of methyl groups in the anilide moiety of 1-R-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazin-3-carboxamides to trifluoromethyl has a different effect on their analgesic activity, which can remain at the original level, be completely lost or significantly increase. However, N-aryl-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazin-3-carboxamides definitely lose the ability to influence in any way on the excretory renal function after this chemical modification. -
Creation of innovative drugs (approaches and methodology of drug design) – one of the main issues of the modern pharmaceutical education
The article is devoted to modern approaches to the creation of innovative drugs based on the so-called small molecules combined into the research system – drug design. The most common concepts and phasing of the processes of the innovative drug creation based on the concept “from idea – to a drug” are presented. The importance and role of the computer (in silico) methods in creating drugs reflected in CADD (computer assisted drug design) methods, for instance: QSAR-analysis, docking studies, molecular modeling, assessment of similarity and druglikeness, etc.) are discussed. Currently, being the permanent subject of interest of the scientific community, the approaches described are dominant in creating innovative drugs. Most of the major issues are integrated in training of pharmacy students (PharmD and MS levels in Western countries) within the discipline “Medicinal Chemistry” and are described in authoritative textbooks. At the same time, practically no attention is paid to these issues in Ukraine, and they are beyond the curricula for pharmacy students. There is the necessity of coverage of the current state of drug creation when training pharmacy students taking into account the principle of integrity of the pharmacy branch and based on the “from idea – to a drug” holistic concept mentioned. It allows to fill in the gaps between “western” and post-Soviet education systems (and/or their harmonization), especially in the context of teaching Pharmaceutical/Medicinal Chemistry. One of the possible solutions is our course “Computer Technology in Pharmacy” (for the 4th year students) covering the main milestones of drug design.
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New derivatives of isonicotinic acid hydraside as potential antitubercular agents
The appearance of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) is a stimulus for searching new and efficient antitubercular drugs. Despite the appearance of new antitubercular drugs, isoniazid is still the key and most effective component in all multitherapeutic regimens recommended by the WHO. This paper describes the QSAR design, synthesis and in vitro evaluation of the antitubercular activity of several potent isoniazid derivatives against Mtb strain (H37Rv) and resistant strain (HR). The QSAR method was applied using Artificial Neural Networks. The predictive ability of the regression model was estimated through leave-one-out cross-validation coefficient q2. The inhibition activities of 440 virtual compounds against Mtb were evaluated by the QSAR model developed, and seven isoniazid derivatives were selected and synthesized. In the biological research the multidrug-resistant strain of Mtb with resistance to isoniazid and rifampicin was used. All compounds synthesized with the predicted high activity showed antimycobacterial activity against Mtb strain H37Rv. “The compound-leader” – N1-(3-nitrophenylmethylidene)-pyridine-4-karbohidrazide revealing the activity against multiresistant strain (HR) of Mtb is identified as an original object for further research as an potential antimycobacterial agent. -
Synthesis and the study of physical and chemical properties of 2-((5-(phenoxymethyl)-4-R-1,2,4-triazole-3-yl)thio)ethan-1-ols and their derivatives
The number of new various diseases increases with the development of science and technology. But currently medicine does not have effective ways to overcome this problem. There is a large number of different pharmacological groups of drugs at the pharmaceutical market, but some of them are not available for the Ukrainian consumers. Therefore, the main task of national scientists in the field of pharmaceutical synthesis is the search for new biologically active substances and their further introduction into medical practice as new, low-toxic, original medicines of the Ukrainian production at an affordable price. The aim of our research is the synthesis of a new class of biologically active substances, namely 2-((5-(phenoxymethyl)-4-R-1,2,4-triazol-3-yl)thio)ethan-1- ols and their derivatives. All compounds obtained have been synthesized from 5-(phen-oxymethyl)-4-R-1,2,4- triazol-3-thiones (R = H, C2H5, C6H5) using electrophilic and nucleophilic substitution reactions when heating. The structure of the compounds synthesized has been confirmed by using a modern set of physical and chemical methods such as IR-spectrometry, 1H NMR spectrometry and elemental analysis, and their individuality by high performance liquid chromatography-mass spectrometry. The work in determining the parameters of acute toxicity and biological activity is continued. -
The antimicrobial and antiviral activity of calixarenes
Calixarenes is a promising class of macrocyclic compounds, which are widely used in the design of biologically active substances. Among calixarenes there are anion channel blockers and modulators of cationic pumps, selective enzyme inhibitors and compounds simulating their action, substances with the antithrombotic and antitumour effect. The antimicrobial and antiviral activities of modified calixarenes have been intensively studied in recent years. The results on bactericidal, fungicidal, antituberculosis, as well as antiviral activity of calixarenes have been systematized and analyzed in this review. The data about the mechanisms of action of different types of calixarenes on biological objects are presented. It has been found that the basis of the antimicrobial action of many calixarenes is the interaction with the components of the outer membrane or cell wall. Moreover, functionalization of the calixarene platform with pharmacophoric groups possessing the antimicrobial activity does not always lead to increase in the expected activity. Polycationic calixarenes show the highest antibacterial action, while polyanionic macrocycles inhibit the activity of viruses. Calixarenes modified with cyclopeptide fragments are selective binders and blockers of important bacterial cell glycoproteins. They are mimetics of vancomycin by their mechanism of action and the level of the bactericidal activity. The water soluble calixarene with polyethylene glycol groups has a unique mechanism of the antituberculosis action. It inhibits the growth of M. tuberculosis inside human macrophage cells. The chemotherapeutic indexes of the compounds studied are more than ten units, indicating their low cytotoxicity.
