Vol. 14 No. 3(55) (2016)
Published:
2016-09-19
Full Issue
Original Researches
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The synthesis and the biological activity of azolylthioacetic acids
The review systematizes the published data concerning the methods of synthesis of azoles (imidazoles, oxazoles, thiazoles, pyrazoles, triazoles, and tetrazoles) functionalized by the carboxymethyl thiol fragment; the results of studies of the biological activity of this class of compounds have been also analysed. Today the main directions for the synthesis of azolylthioacetic acids and their derivatives are reactions of azoles that contain the thiol group with haloacetic acids and their derivatives, and the nucleophilic substitution of halogen in the haloazoles under the action of thioglycolic acid. Moreover, the addition of thioles to multiple bonds, activated with electron withdrawing groups has found its application together with formation of the azole cycle from heterofunctional systems that already contain the component of thioacetic acid. To obtain polyfunctional derivatives of azolylthioacetic acids the modification of azole functional groups that already contain the fragment of thioacetic acid is sometimes used. The summary of the published data gives strong reasons to assert that the derivatives of azolylthioacetic acids are characterized by diverse biological effects. For instance, they are characterized by the antioxidant, hypoglycemic, antitubercular, analgesic, antiviral, antimicrobial, and antifungal activity. The material analysed indicates that the search for new bioactive compounds among the azolylthioacetic acids is very promising. -
5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolines. Message 4. Spirocompounds with [1,2,4]triazolo[1,5-c]quinazolines moieties. The synthesis and spectral
The present article describes the synthesis of novel spiro-condensed [1,2,4]triazolo[1,5-c]quinazolines. [2-(3-Aryl1H-1,2,4-triazol-5-yl)phenyl]amines were used as effective precursors for the synthesis of the compounds mentioned above. The experimental data have shown that the reaction of the initial anilines with cycloalkanones (cyclopentanone, cyclohexanone) allowed to obtain products of binucleophilic addition, namely spiro-condensed compounds with [1,2,4]triazolo[1,5-c]quinazolines moieties. The initial anilines also readily react with a conformationally rigid bicyclo[2.2.1]heptan-2-one yielding the corresponding spiroderivatives, whereas the reaction with camphor and menthone has failed due to the steric hindrance. It has been found that [5+1]-cyclocondensation of the initial anilines with heterocyclonones (1-R-piperidone-4, dihydrothiophene-3(2H)-one, dihydro-2H-pyran-4(3H)-one, dihydro-2H-thiopyran-3(4H)-one) proceeds without peculiarities and with formation of the corresponding 2’-aryl-6’H-spiro[1,2,4]triazolo[1,5-c]quinazolines. The reaction with 5-R-1H-indole-2,3-dione (isatine) and its N-substituted derivatives also proceeds without any peculiarities with formation of aryl-2’-aryl6’H-spiro[(indol-3,5’-[1,2,4]triazolo[1,5-c]quinazolines] with high yields. The purity of the compounds obtained has been proven by the LC-MS (APCI) method, their structures have been confirmed by the complex of physicochemical methods, including 1H and 13C NMR, IR-, MS-(EI) – spectrometry and the X-ray study. The peculiarities of 1H and 13C NMR-spectra of the compounds synthesized are discussed. It has been shown that signals of NH-protons in the 1H NMR-spectrum and C-5’ in the 13C NMR-spectrum are characteristic for the compounds synthesized. -
The synthesis and the study of antimicrobial properties of 5-r,r’-aminometylene derivatives of thiazolidine-2,4-dione and 4-thioxothiazolidine-2-one
The study is devoted to the rational search of modern potential antimicrobial agents among of 4-thiazolidine(thi)ones. 5-R,R’-Enamin(thi)ones of thiazolidinone series have been tested for design and the initial screening of the antibacterial properties. The use of 5-ethoxymetylene derivatives of thiazolidine-2,4-dione and 4-thioxothiazolidin-2-one as effective “building blocks” for the synthesis of small libraries of bioactive compounds has been proposed. Nucleophilic substitution reactions between 5-ethoxymetylene derivatives and amino alcohols, the primary and secondary functionalized aromatic and heteroaromatic amines, heterocyclic amines (piperidine and substituted pyrazolines) have been studied. The pharmacological screening of the antimicrobial activity for the enamin(thi)ones synthesized on clinical isolates of staphylococci with different resistance mechanisms to protected β-lactams and multiresistance strains of E. coli and Ps. Aeruginosa has been performed. Compounds with a distinct antimicrobial effect have been identified. They can also increase the sensitivity of S. aureus and S. haemolyticus clinical strains to oxacillin, and can be used to create new combined antimicrobial chemotherapeutic agents. The “structure – antimicrobial activity” relationships for design and search for new antimicrobial agents have been analysed. -
The intereaction of 4,5-diformyl-2,3,6,7,8,10-hexahydroacridine-8a(1h)-carbonitrile with n-nucleophiles
Schiff bases are of practical interest as initial materials both for the combinatorial synthesis for libraries of compounds, and for preparation of complexes with metals; thus, currently the intensity of research in this direction is increasing. The possibilities of practical use of complex compounds with organic ligands are quite broad varying from effective catalysts of various chemical processes to molecular sensors. While studying formylation of 5,6,7,8-tetrahydro-1H-spiro[cyclohexane-1,2-quinazolin]-4’(3’H)-one a new domino reaction, which makes it possible to obtain tricyclic acridine systems, has been carried out. In spite of the reduced electrophilicity of the aldehyde groups in 4,5-diformyl-2,3,6,7,8,10-hexahydroacridine-8а(1H)-carbonitrile the latter is shown to react with various amines in benzene with azeotropic removal of water using p-TsOH as a catalyst, and with hydroxylamine hydrochloride in i-PrOH. New Schiff bases and oxime obtained are of potential interest as ligands for formation of chelate complexes. The reaction of dialdehyde with N2H4×H2O instead of the expected hydrazone resulted in obtaining a macrocyclic compound – a derivative of hexaazacyclooctadecine. The structure of the compounds obtained corresponds to the data of 1H NMR-spectroscopy, mass spectrometry and elemental analysis. The preliminary studies have shown that azomethines – 4,5-phenyl(cyclohexcyl)iminomethyl-2,3,6,7,8,10-hexahydroacridine8а(1H)-carbonitrile create complexes with copper and nickel ions. -
4-Aminosubstituted 1,6-dyhidropyrazolo[3,4-e][1,4] diazepines: the synthesis, NMR-spectral and quantum-chemical study
The role of the structural modification of 1,4-benzodiazepine systems with dialkylamino groups previously used successfully for a number of important derivatives possessing a complex of specific biological properties has been noted. This paper significantly expands the variety of hetero-annelated diazepines by developing a preparatively convenient synthetic route of new amino substituted pyrazol[3,4-e][1,4]diazepines. For this purpose, the reaction of 4-chloro-1,6-dihydropyrazolo[3,4-e][1,4]diazepines with the primary alkyl (aryl) amines and the secon- dary cycloalkylamines has been studied in detail. It has been found that this interaction occurs under 8-10 hour reflux in ethanol and for the primary and secondary alkylamines it leads to 4-amino-1,6-dihydropyrazolo[3,4-e] [1,4]diazepine hydrochlorides, and in case of aryl amines – to their corresponding free bases with high yields. The reaction of the secondary amines has been shown to be very sensitive to their steric parameters: dietyl- or diisopropylamines do not interact with 4-chloro derivatives of 1,6-dihydropyrazolo[3,4-e][1,4]diazepines. The structure of the compounds synthesized is consistent with the results of elemental analysis, LS/MS-, IR- and NMR-spectra. The COSY and EXSY methods were used for reliable identification of signals of cycloalkylamino substituents of 1,6 dihydropyrazolo[3,4-e][1,4]diazepines. Changes in NMR-spectra during protonation of 5-cycloalkylaminopyrazolodiazepines correspond to the results of quantum chemical simulations, according to them the preferred structure is the one with the protonated nitrogen atom in position 5 of the pyrazolodiazepine system. -
The synthesis of N-[4-methyl(41-chlorophenyl)-2-R-phenylіmіnothіazol-3-yl]-morpholine derivatives by Hantzsch reaction
Continuing the search for biologically active substances among 2-R-phenylіmіnothіazole derivatives a new series of N-[4-methyl(41-chlorophenyl)-2-R-phenylіmіnothіazol-3-yl]-morpholine derivatives has been synthesized by Hantzsch reaction. Hydrochlorides of N-[4-methyl-2-R-phenylіmіnothіazol-3-yl]-morpholine 3 and hydrobromides of N-[4-(41-chlorophenyl)-2-R-phenylіmіnothіazol-3-yl]-morpholine 5 were obtained by boiling the equimolar amounts of asymmetric thioureas 1 with α-chloroacetone 2 and α-bromo-4-chloroacetophenone 4, respectively, in the ethanol medium. N-[4-(41-Chlorophenyl)-2-R-phenylіmіnothіazol-3-yl]-morpholine 6 were obtained by neutralizing compounds 5 using 10% NH4OH solution. Satisfactory yields of compounds 3, 5, 6 were obtained within 1-3 hours. N-[4-methyl(41-chlorophenyl)-2-R-phenylіmіnothіazol-3-yl]-morpholine derivatives 3, 5, 6 were crystallized from organic solvents and obtained with the yields of 74-87%. The structures and purity of 3, 5, 6 have been confirmed by elemental analysis, 1H NMR-spectra and chromato-mass spectroscopy. As a result of Hantzsch reaction formation of two isomeric structures is possible. Therefore, to determine a true structure of the compounds obtained NMR spectroscopy with its special techniques was used. The studies have been conducted on the example of the reaction product 6i, and it has been proven that this structure is exactly N-[4-(41chlorophenyl)-2-(4’-chlorophenylimino)thiazol-3-yl]-morpholine 6i. Based on the research results of the structure of the compounds synthesized a possible mechanism of the reaction studied has been proposed. -
The synthesis of new pyrrolo[2,3-d]pyrimidine-containing α-hydroxyphosphonic acids
The work is devoted to the synthesis of new pyrrolo[2,3-d]pyrimidine-containing α-hydroxyphosphonic acids as precursors for the synthesis of potential biologically active compounds. The reaction between methyl 7-allyl-1,3dimethyl-2,4-dioxo-2,3,4,7-tetrahydro-1Н-pyrrolo[2,3-d]pyrimidine-6-carboxylate and iodine has resulted in 8-iodomethylpyrimido[5’,4’:4,5]pyrrolo[2,1-c][1,4]oxazine. The composition and structure of the compound has been confirmed by elemental analysis, NMR-spectroscopy and X-ray examination, and it is a convincing evidence of the presence of the oxazine cycle. Elimination of hydrogen halide of the iodomethyl derivative occurred with formation of 1,3,8-trimethyl-2H-pyrimido[5’,4’:4,5]pyrrolo[2,1-c][1,4]oxazine-2,4,6(1H,3H)-trione. The compound obtained upon heating with methanol in the presence of potassium carbonate was subjected to the nucleophilic attack at the carbonyl group. 7-(2-Oxopropyl)-1H-pyrrolo[2,3-d]pyrimidine derivative was formed by cleavage of the lactone ring. The treatment of ketone with diisopropyl phosphite by Abramov reaction resulted in formation of pyrimido[5’,4’:4,5] pyrrolo[2,1-c][1,4]oxazin-8-ylphosphonate, its hydrolysis was carried out by boiling in dilute hydrochloric acid. The reaction proceeded by opening of the oxazine ring, with the concomitant decarboxylation giving pyrrolo[2,3-d] pyrimidine with the 1-hydroxyphosphonoethyl substituent in position 7 of the heterocycle. The structure of the compounds obtained has been proven using NMR spectroscopy, mass-spectra and elemental analysis.
