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Full research publication. Technical section. The study of biological activity. Registration code of publication: Subdivision: Biochemistry. Publication is available for discussion in the framework of permanent operating internet conference "Butlerov readings". http: // butlerov.com/readings/ УДК 615.012.01. Received RADICAL BINDING ACTIVITY PRODUCT OF THE INTERACTION OF THE METHYL ESTER OF 3,4-DIHYDROXY-6-OXO-2,4-HEXADIENE ACID WITH 1,2DIAMINOBENZENE Karmanova Olga Gennadevna1*, Zykov Svetlana Sergeevna2+, Lyuboseev Vladislav 2, Peter Mukovoz3, Vladislav Kozminyh4 1 Department of General Chemistry. VPO "Moscow Institute of Physics and Technology (State University)." st. Kerch, 1-A, building 1. Moscow, 117303, Russia 2 Department of animal science. FKOU VPO Perm Institute FSIN Russia. St. Karpinski, 125. Perm, 614012. Russia. Tel .: (342) 228-60-77 (253). E-mail: [email protected] 3 Institute of Cellular and Intracellular Symbiosis, RAS. St. Pioneer, 11. Orenburg, 460000, Russia. 4 Department of Chemistry. VPO «Perm State University of Humanities and Education." St. Siberian,24 Perm, 614000, Russia. * Leading direction; + Corresponding author Tags: 1,3,4,6-tetracarbonyl compounds, methyl 3,4-dihydroxy-6-oxo-2,4-hexadiene acid, methyl (2Z) - [3- (2-oxopentyl) quinoxalin-2- (1H) -ylidene] etanoat radical binding activity. Annotation Reaction of methyl 3,4-dihydroxy-6-oxo-2,4-hexadiene and 1,2-acid diaminobenzene obtained methyl (2Z) - [3- (2-oxopentyl) quinoxalin-2 (1H) -ylidene] etanoat. On the basis of IR and 1H NMR spectroscopy and mass spectroscopy the structure of the synthesized compounds was found out. Its radical binding activity in the reaction with DPPH (DPPH) was studied, which was at the level of the standard anti-radical activity - water-soluble form of vitamin E (Trolox). Introduction It is known that 1,3,4,6-tetracarbonyl compound (TCS) react with 1,2-diaminobenzene to form bis-2,3-dioxo-1,3,4,6 oksoilidenproizvodnyh [1-6]. The aim of this work is to study the interaction of 1,2-diaminobenzene with methyl 3,4-dihydroxy-6-oxo-2,4-hexadiene acid [7], which is an intermediate class of tetracarbonyl compounds directly from 1,3,4,6 tetraoksogeksanov with traditional end-keto esters of hexadiene acid [7-9]. Experimental part Method of synthesis of methyl (2Z) - [3- (2-oxopentyl) quinoxalin-2 (1H) -ylidene] etanoate (2). Yield 3.44 g (48%), m.p. 94-95 ° C. To 6.01 g (25 mmol) of the compound (1) in 50 ml of ethanol was added 2.7 g (25 mmol) of 1,2diaminobenzene after brief refluxing. The solvent was evaporated, the residue triturated with diethyl ether and dried, then the yielding compound was found (2). Recrystallization from ethyl acetate. Found,%: C 67.12%; H 6.34%; N 9.67%; S16N18N2O3. Calculated,%: C 67.33%; H 6.53%; N 9.78%. M 286.33. IR spectrum, ν, cm-1 (vases. Oil): 1732 (O = C (CH2) 2CH3), 1604 (O = COCH3), 1569 (C = C, chelate, C6H4), 1462 δas (CH3), 1435 (N = C), 1374 δs (CH3), 1179 (C-OCH3), 1154, 1114, 1067, 998 νskeletnye (CC), the pendulum 854 δ (CH3). Mass spectrum (m / z, Iotn.%): 287 M + 1˥ + (3,08), 286 M˥ + (15.60), 255 M + SN3O˥ O Pr H N N H (8.94), 243 M + S3N7˥ (6.46) 216 O Pr H N 216 ˥+ (100), 215 М-С3Н7СО˥+ (3.27), N H ˥ (100) 199 + N ÑÍ N CH COCH 2 2 3 ˥+ (3.47), 184 М-С3Н7СО-СН3О˥+ N N (70.13), 158 ˥+ (22.16), 103 С6Н5СN˥+ (8.50), 77 С6Н5˥+ (10.46), 71 С3Н7СО˥+ (42.46), 43 С3Н7˥+ (85.79). 1H NMR (DMSO-d6, δC, ppm): 0.97 t (3H, CH2CH2CH3, J 7.0 Hz, 2B), 1.63 m (2H, CH2CH2CH3, 2B), 2.38 m (2H, CH2CH2CH3, J 7.0 Hz , 2B), 3.67 c (3H, OCH3, 2B), 4.00 a (2H, CH2COOCH3, 2B), 5.67 c (1H, CH, 2B, 94%), m 7.41-7.75 (4H, S6H4, 2B), 14.70 with (1H, NH, 2B). 1H NMR (CDCl3, δC, ppm): 0.96 t (3H, CH2CH2CH3, J 7.0 Hz, 2B, 2C), 0.97 t (3H, CH2CH2CH3, J 7.0 Hz, 2D), 1.71 m (2H, CH2CH2CH3 , 2B, 2C), 1.73 m (2H, CH2CH2CH3, 2D), 2.44 m (2H, CH2CH2CH3, J 7.0 Hz, 2B, 2C), 2.61 m (2H, CH2CH2CH3, J 7.0 Hz, 2D), 3.75 c (3H , OCH3, 2B), 3.73 c (3H, OCH3, 2C), to 3.90 (3H, OCH3, 2D), 4.09 a (2H, CH2COOCH3, 2B), 4.24 a (2H, CH2COOCH3, 2D), 5.27 a (1H , CH, 2D, 28%), from 5.49 (1H, CH, 2B, 42%), from 5.65 (1H, CH, 2C, 30%), m 6.93-8.05 (4H, S6H4, 2B, 2C, 2D), 11.69 c (1H, NH, 2D), 14.12 c (1H, NH, 2C), with 15.03 (1H, NH, 2B). Results and discussion The interaction of the compound (1) with 1,2-diaminobenzene was first studied, whereby methyl(2Z)-[(3Z)-3-(2-oxopentiliden)-3,4-dihydrohinoxalin-2(1H)-ilidene]etanoat (2) [7] (Scheme 1) were found out. Previously synthesized compound was not known. Compound (2) is a yellow crystalline substance soluble in common organic solvents and insoluble in water. . In contrast to 2,3-bis (aroylmethylene) quinoxalines, existing in the form of bis-chelated NH system [3-6], the compound (2) are in the form of endo-2,3-C = N- isomer 2A, as indicates the absence of the corresponding absorption bands in the region of amino 3100-3500 cm-1 in the IR spectra. Presence of RF signal of absorption nonconjugated carbonyl group of the acyl chain at 1732 cm-1 and the absorption signal of the ester carbonyl group at 1604 cm-1 also confirms the structure 2A. Scheme 1. Synthesis of methyl (2Z) - [(3Z) -3- (2-oksopentiliden) -3,4dihydrohinoksalin-2 (1H) -ylidene] etanoat (2) 1 O MeO Me O + MeO 2 OMe + Me H O O + H 2:1:2 Alk O O MeONa Pr - CH 3OH Pr H2N + H2N - 2 H2O N H 2 O OMe O OMe O N H H O 1 In polar solvents (DMSO) in the compound (2) predominant is the form of monohelat 2B (94%), a stable chelate ring NH, indicating that considerable stability of this solution of DMSO is in the form (Scheme 2) Scheme 2. The tautomeric form dihydrohinoxalin-2(1H)-ilidene]etanoat (2) O Pr H O Pr of methyl(2Z)-[(3Z)-3-(2-oxopentidilen)-3,4- H O Pr N N N N N N H H OMe 2Â O OMe 2C O Pr O OMe N N 2À O O OMe 2D Apparently, DMSO molecules polarize the carbonyl group of the acyl-level, creating conditions for the delocalization of double bonds in the chelate stabilized by intramolecular hydrogen bonds in the steady-chelating heterocyclic NH. At the same time, the ester moiety of the molecule does not form a chelate-NH depolarizing influence due to the unshared electron pairs of oxygen alkoxy, weakening the charge on the carbonyl carbon of the ester group unit and polarizing molecules DMSO strength giving the result of insufficiency This confirms 1H NMR spectrum of the compound (2) recorded in DMSO-d6, wherein signals other than n-propyl level such as, methoxy, ester moiety, and groups of heterocyclic proton signals mono methine proton at δ 5,67 ppm, mono amino proton NH-chelate at δ 14,70 ppm mono and two methylene protons of the methyl acetate moiety at δ 3,67 ppm integral with comparable intensities are present. Furthermore predominant form of monohelatnoy 2B is present in the spectrum signals of the two minor forms 2C and 2D each containing with not more than 3%. Slight their content probably is connected with the lower stability of the structure having the chelating moiety with the ester units. This also may be caused by specific solvation of polar molecules DMSO oxygen of the carbonyl group of the ester moiety, reducing it effective negative charge and preventing the formation of NH ... O = C-chelate IMHB stabilizing NH-chelating heterocyclic. Change the non-polar solvent to chloroform leads to significant changes in the ratios of the tautomeric forms. Thus, the content of forms 2C and 2D increases to 30% and 28%, respectively. The reason for this apparently is the absence of the polarizing effect of the solvent molecules, which do not create conditions for delocalization of double bonds in the chelate anymore. 2B form stability decreases, resulting in the formation of alternate tautomers 2C and 2D. Thus, 2C correspond form two magnetically equivalent mono methine protons at δ 5,65 ppm mono and two magnetically equivalent protons of two amino groups NH-chelates at δ 14.12 ppm Thus, form 2C correspond two magnetically equivalent mono methine protons at δ 5,65 ppm mono and two magnetically equivalent protons of two amino groups NH-chelates at δ 14.12 ppm. 2B form of content in deuterochloroform is 42%. This form correspond to mono methine proton with the value of the chemical shift δ 5.49 ppm mono amino proton NH-chelate with the value of the chemical shift δ 15.03 ppm and mono two methylene protons of the methyl acetate with a fragment value of the chemical shift δ 4.09 ppm integral with comparable intensities. A shift signal of the methine proton bis-chelated form of into the weak field 2C (at δ 0.16 ppm) as compared with the shape monohelatnoy 2B explains coupling and chain extension, respectively, decrease in the intensity of the external magnetic field in the area of the two anisotropic kvazigeterotsiklam conjugate in which are located methine protons. The presence of such a pairing is evidenced by the fact that the two methine proton and two protons of two amino groups of two different chelates are magnetic equivalent and give appropriate, unsplit mono signals in the 1H NMR spectrum. At the same time, the shift of the signal of two magnetically equivalent protons of two amino bis-chelated form of 2C in strong fields (at δ 0.91 ppm) compared with the signal monohelat form of 2B also well explained by chain extension interface, in which the electron density on the atoms nitrogen increases, resulting in the screening of the NH protons. The signal value of the two methylene protons monohelatnoy form of 2B shifted to a strong field compared to the same signal form of 2D (at δ 0,15 ppm), which is probably due to the shielding effect of lone pairs of oxygen metoksizvena these protons. In the form of 2D methoxy link adjacent to the methylene group of the acetyl moiety is absent, so the corresponding signal of the group shifted to weak fields. Signals corresponding to the endocyclic form 2A 1H NMR spectra of the compound (2), were not detected. The nature of the mass fragmentation quinoxaline (2) is consistent with the previously established general laws of the collapse of the well-known quinoxaline derivatives [7, 10-12]. The mass spectrum of quinoxaline (2) there is an intense molecular ion signal 287 M˥ +. Further fragmentation of molecules by electron impact in the gas phase takes place in four main areas (Figure 3). The first direction is the fragmentation of the molecule quinoxaline (2) is associated with the separation of the methyl acetate fragments M - SN2SOOSN3˥ + and the formation of O Pr H N N H The second and third directions correspond to the separation of the acyl ions S3N7SO˥ + ions and SN3O˥ + to fragment ions with maximum intensity H N CH2 N form an intense signal ketene ion The fourth line corresponds to the rule of maximum emission radical and characterized by the formation of very intense ion signals S3N7˥ +. Subsequent fragmentation associated decay process azine ring O N and further destruction to the ions N and PhCN˥+. Scheme 3. Mass fragmentation quinoxaline (2) IV II O Pr H N III N H 2 I O OMe To determine the antiradical activity reaction was used with a stable free radical DPPH (DPPH) (production Sigma-Aldrich) [13]. The concentration of DPPH in 95% ethanol was 6.5h10-5M. As a reference standard of antiradical activity of Trolox was used (production Sigma-Aldrich) (Table 1). Table 1 Antiradical activity of methyl (2Z) - [(3Z) -3- (2- oksopentiliden) -3,4-digidrohinoksalin2 (1H) - ylidene] etanoat (2) Compound 2 Trolox Decrease of radicals Q,% 86.51 ± 6.42* 87.40 ± 5.18* * p <0,05 compared to control The reaction mixture, which consists of 3 ml of 0.3 mM DPPH solution, 1 ml Tris-HCl, pH = 7.4 and 1x10-5M Trolox or substances dissolved in DMSO, incubated under standard conditions of temperature (T = 293K) for 30 minutes. Then, at a wavelength of 517 nm in it cuvettes with a 0.5 cm thick layer of the optical density of the reaction mixture at photoelectrocolorimeter CPK-3-01. Control measurements were made of the synthesized compounds without DPPH at 517 nm. The inhibitory effect is a decrease of DPPH radicals (Q), which is calculated by the formula: Q= 100(D0 – Dx)/D0 where D0 - optical density of a control solution of DPPH, Dx - DPPH absorbance of the solution in the presence of the test substance or reference standard solution. The resulting measurements were treated by standard methods using Student's t test (confidence level was 0.95). The result represents the mean ± standard error of the mean. Methyl (2Z) - [(3Z) -3- (2-oksopentiliden) -3,4-dihydro quinoxalin-2 (1H) -ylidene] etanoat (2) showed binding activity expressed radical standard level - soluble form of vitamin E trolox. Findings 1. studied, as a result of reaction of methyl 3,4-dihydroxy-6-oxo-2,4-hexadiene acid with 1,2-diaminobenzene methyl (2Z) - [(3Z) -3- (2- oksopentiliden) digidrohinoksalin -3,4-2 (1H) -ylidene] etanoat (2) was gained. 2. Found that the compound (2) in solid state exists in the form 2A, solution of polar solvents (DMSO) at a mono-NH-chelated 2B, and non-polar solvents (chloroform) in three forms chelate 2B, 2C, 2D with advantage first shape. 3. Revealed that the synthesized compound (2) exhibits pronounced radical binding activity at the level of the standard - a water-soluble form of vitamin E (Trolox). Literature [1] M. Poje, K. Balenović J. Heterocycl. Chem. 1979. Vol. 16. N 3. P. 417-420. [2] VO Kozminykh, NM Igidov, YS Andreychikov, ZN Semenov. Chem-Pharm. Zh. 1992. T. 26. № 9-10. S. 59-63. [3] OG Karmanova, PP Mukovoz, VO Kozminykh, EN Kozminykh. Proceedings of the higher educational institutions. Chemistry and chemical technology. ISUCT. 56. T. 2013. Vol. 3. S. 3-7. [4] OG Karmanova, PP Mukovoz, EN Kozminykh, VO Kozminykh Innovation processes in the field of chemical and teaching and science education. Proceedings of the Second All-Russian scientific-practical conference. Orenburg. OGPU. 2012. pp 115-119. [5] OG Karmanova, PP Mukovoz, VO Kozminykh Proceedings of the International correspondence scientific-practical conference: biology, chemistry, physics: issues and trends of development. Novosibirsk. 2012. pp 117-122. [6] O.G. Karmanova, V.O. Kozminykh, P.P. Mukovoz, E.N. Kozminykh. Bulletin of the South Ural State University. A series of "Chemistry". 2012. Vol. 9. № 24. C. 39-45. [7] OG Karmanova Synthesis, structure and reaction with N-nucleophiles aliphatic derivatives of 3,4-dihydroxy-1,6-dioxo-2,4-hexadiene systems: Author. Dis ... Cand. chem. Sciences: 02.00.03. Moscow. 16, 2013. p. [8] PP Mukovoz, VA Tarasova, VO Kozminykh. Zh. body. chemistry. 2014. T. 59. №5. S. 1698-1700. [9] VA Tarasova, PP Mukovoz, VO Kozminykh Journal of South Ural State. University. Series: Chemistry. 2014 V.6. № 3. S. 11-16. [10] J. Janev, B. Soptrajanov, L. Jovevska, J. Janculev. Glas. Hem. Techol. 1976. Vol. 3. N 1-4. P. 25-31. [11] Takeshi Inagaki, Iwanami Yasuo. Mass Spectroscopy. 1978. Vol. 26. N 4. P. 353-358. [12] SS Zykovа, TF Odegova, OG Karmanova, RR Makhmudov. Chem-Pharm. Zh. 2014. T. 48. № 10. S. 8-13. [13] K. Bezmaternykh, TI Shirshov, IV Besliu, NV Matistov., GV Smirnov, ON The October, VV Volodin Evaluation of the antioxidant activity of extracts of Allium schoenoprasum L. and Rubus chamaemorus L., growing in the Komi Republic // Chem Pharm. magazine. № 2. 2014. S.36-40.