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ОСНОВНОЙ РАЗДЕЛ
Panasenko N. V.
Bukovinian State Medical University, Chernivtsy, Ukraine
Панасенко Н. В., к.хим.н.
асистент
кафедра медицинской и фармацевтической химии Буковинский государственный медицинский университет
Украина, г. Черновцы SYNTHESIS AND ANTIMICROBIAL ACTIVITY HYBRID SYSTEMS WITH PYRAZOLE AND IMIDAZOLE RINGS
Annotation By three-component condensation of 1-substituted 3-arylpyrazole-4-carbaldehydes, benzyl, and ammonium acetate in the medium of acetic acid 1-substituted 3-aryl-4-(4,5-diphenylimidazol-2-yl)pyrazoles were synthesized, among which the compounds with moderate antimicrobial activity were found.
Key words: pyrazole-4-carbaldehydes, benzyl, ammonium acetate, 4-(4,5-diphenylimidazol-2-yl)pyrazoles, condensation, antimicrobial activity
I. Introduction
The imidazole cycle is an important structural fragment of a considerable number of naturally occurring substances [1] and pharmaceutical^ active structures [2]. In the variety of imidazole compounds their polysubstituted representatives have a special position because of a wide range of their biological activities: antiinflammatory [3], antiallergenic [4], antimicrobial [5], antineoplastic [6], and analgesic [7]. Besides that, inhibitors of P38 MAP kinase [8] and glucagon receptors [9] were found among these compounds.
II. Formulation of the problem
It is known that acid catalyzed one-pot three-component condensation of aldehydes, a-diketones, and ammonium acetate is one of the effective methods of synthesizing 2-alkyl(aryl)-4,5-diarylimidazoles [10-12]. The usage of reactions of this type for their 2-heteryl analogues' synthesis, 2-pyrazolyl-4,5-diphenylimidazoles in particular, is represented in the literature with only one example [13]. At the same time, taking into account the pharmacological behavior of a row of heterocyclic ensembles that are a combination of imidazole and pyrazole nuclei [14,15], the design of new 4-imidazolylpyrazoles seems to be scientifically reasonable both from chemical and biological points of view. That's why the study of available [16,17] 3-aryl-4-formylpyrazoles (Ia-l) condensation with benzyl and ammonium acetate and testing of bactericidal activity of the synthesized compounds became the subject of our report.
III. Results
It was found that pyrazole-4-carbaldehydes (Ia-l) interact with benzyl and ammonium acetate in the ratio of 1:1:4 in the medium of boiling acetic acid, producing 4-(4,5-diphenylimidazol-2-yl)pyrazoles (IIa-l). The control of the
reaction process using the TLC method has shown that in these conditions the reaction ends in 1 hour and leads to the target products with yields of 64-91 %.
Ar Ar Ph
N ( O O AcOH
CH=O + J-A^ + 2NH4OAc
Ph Ph N-
R R
Ia-1 Ila-l
I, II, R=Ph, Ar=Ph (a), 3-ClC6H4 (b), 4-MeOC6H4 (c), F2HCOC6H4 (e), TieH-2-m (f), pyridin-4-yl (e), benzofuran-2-yl (g) ; R=NCCH2CH2, Ar=3-ClC6H4 (h), 4-BrC6H4 (i); 3,4-Me2C6H3 (j) ; R=HOOCCH2CH2, Ar=- 3-BrC6H4 (k), 3-NO2-4-MeOC6H3 (l).
The composition of the synthesized compounds was reliably proven by elemental analysis and mass-spectra (Table 1), and their structure by IR- and 1H NMR spectroscopy (Table 2). The mass-spectra of all compounds are characterized by the maximum peaks of protonated molecular ions [M+1]+. In the IR-spectra the absorption bands of N-H bond of imidazole cycle in the interval of 3370-3385 cm-1 are present, and for the compounds (Ilj-l) - additional absorption bands of the C^N groups (2255-2260 cm-1) or COOH groups (2490-2905 cm-1). In the 1H NMR spectra, besides the typical signals of aryl and alkyl substitutes of the azole nuclei, the singlets of H5 protons of the pyrazole cycle (8.26-9.07 ppm), and N-H singlets of the imidazole cycle (12.41-12.65 ppm) are present.
We performed the testing of synthesized compounds for their bactericidal activity by the method of two-fold serial dilutions, using the standard strains cultures S.aureus and E.coli as test-microorganisms. The obtained values of minimal inhibiting bacteriostatic (MBsC) and bactericidal (MBcC) concentrations of compounds (Ila-l) are given in the Table 3, and show that they have moderate antimicrobial activity.
Experimental part
IR-spectra of the compounds in the KBr tablets were recorded with the UR-20 device. 1H NMR spectra were measured using the Bruker Avance DRX (500.13 MHz) device, internal standard - TMS. Chromato-mass-spectra were recorded on the PE SCXAPI 150 EX device using UV (250 nm) and ELSOJ detectors.
1-Substituted 4-(4,5-diphenyl-1H-imidazol-2-yl)-3-aryl-1H-pyrazoles
(Ila-l). The mixture of 0.002 mole of aldehyde (Ia-l), 0.42 g (0.002 mole) of benzyl, and 0.62 g (0.008 mole) ammonium acetate in 5 ml of acetic acid were boiled for 1 hour. The reactional mixture was cooled down; the produced sediment was filtered, washed with water, dried, and crystallized from ethanol.
The study of antimicrobial activity
The antimicrobial activity of the synthesized compounds was determined by the micromethod that involved preparation of two-fold serial dilutions using the Takachi microtitrator with two test-cultures of microorganisms (gram-positive and gram-negative) in disposable polystyrene plates.
The polystyrene plates were filled, using the Takachi microtitrator, with 4-hous old broth test-cultures of E.coli and S.aureus in the concentration of 105 microbial bodies per 1 ml. Two-fold serial dilutions (from 500 ^g/ml to 7.8 ^g/ml) were prepared from the studied compounds (in the concentration of 1000 ^g/ml). The inoculations were incubated at 37 °C for 18-24 hours; after that they were visually assessed for presence or absence of microbial growth. The experiment was conducted three times.
The lowest dilution of the studied compound in the presence of which the inhibition of microorganism test-culture occurred was taken as the minimal bacteriostatic concentration (MBsC). It was expressed as numerical value of active substrate dilution.
The minimal bactericidal concentration (MBcC) was determined by inoculation of meat-and-peptone agar in the Petri dishes with the contents of the wells for which the growth was not observed.
The known antimicrobial drug, ethonium, was used as control.
IV. Conclusions
1. 1-Substituted 3-aryl-4-(4,5-diphenylimidazol-2-yl)pyrazoles were synthesized by three-component condensation of 1-substituted 3-arylpyrazole-4-carbaldehydes, benzyl, and ammonium acetate in the boiling acetic acid.
2. The testing of the produced compounds has shown that they demonstrate moderate antimicrobial activity.
Table 1
Characteristics of the compounds Ila-l
Compound Formula [М+1]+ Found, % Calculated Tmelt °C. Yield, %
C H N
II a C30H22N4 439 82.41 82.17 5.17 5.06 12.56 12.78 257-259 76
IIb C30H21C1N4 473 76.38 76.18 4.36 4.48 11.64 11.85 294-296 81
IIc C31H24N40 469 79.18 79.47 5.27 5.16 12.21 11.96 254-256 64
IId C31H22F2N4 О 505 73.54 73.80 4.49 4.40 11.33 11.10 259-262 71
IIe C28H20N4S 445 75.92 75.65 4.64 4.53 12.46 12.60 283-285 83
IIf C29H21N5 404 78.96 79.25 4.93 4.82 15.75 15.93 276-278 87
IIg C32H22N40 479 80.03 80.32 4.55 4.63 11.95 11.71 236-237 91
IIh C27H20C1N5 450 71.81 72.08 4.57 4.48 15.32 15.56 244-245 81
IIi C27H20BrN5 495 65.87 65.60 4.19 4.08 13.94 14.17 275-278 76
IIj C29H25N5 444 78.80 78.53 5.61 5.68 15.65 15.79 216-217 68
IIk C27H21BrN4 О2 514 62.88 63.17 4.23 4.12 10.69 10.91 227-228 73
IIl C28H23N505 510 65.72 66.00 4.64 4.55 13.51 13.74 231-233 87
Table 2
IR and 1H NMR spectra of the compounds IIa-l_
Compo und IR spectrum, v, cm-1 1H NMR spectra, 5. ppm( J, Hz)
IIa 3385 (NH) 7.23-7.59 m (16Harom.), 7.95 d (2Harom., J 7.6 Hz), 8.10 d (2Harom., J 7.6 Hz), 9.04 s (1H, H5pyrazole), 12.52 s (lH, NH)
IIb 3370 (NH) 7.56-7.96 m (15Harom.), 7.96 d (2Harom., J 8.0 Hz), 8.21 d (2Harom., J 8.0 Hz), 9.03 s (1H, H5pyrazole), 12.54 s (lH, NH)
IIc 3380 (NH) 7.02 d (2Harom., J 8.4 Hz), 7.23-7.60 m (13Harom.), 7.93 d (2Harom., J 8.4 Hz), 8.08 d (2Harom., J 8.8 Hz), 8.96 s (1H, H5pyrazole), 12.49 s (1H, NH)
IId 3370 (NH) 7.30-7.62 m (16H, 15Harom.+CH), 7.94 d (2Harom., J 8.0 Hz), 8.23 d (2Harom., J 8.0 Hz), 9.01 s (1H, H5pyrazole), 12.53 s (1H, NH)
IIe 3375 (NH) 7.17-7.63 m (16Harom.), 7.91 d (2Harom., J 8.0 Hz), 8.56 d (2Hthiophene., J 4.0 Hz), 9.03 s (1H, H5pyrazole), 12.59 s (1H, NH)
IIf 3370 (NH) 7.32-7.64 m (13Harom.), 7.97 d (2Harom., J 8.0 Hz), 8.18 d (2Harom., J 6.0 Hz), 8.68 d (2Harom., J 6.0 Hz), 9.08 s (1H, H5pyrazole), 12.45 s (1H, NH)
IIg 3380 (NH) 7.37-7.77 m (17Harom.), 7.98 m (2Harom., J 8.0 Hz), 8.43 s (1H, H3benzofuran), 9.15 s (1H, H5pyrazole),12.65 s (1H, NH)
IIh 3375 (NH) 2255 (C=N) 3.21 t (2H, CH2, J6.0 Hz), 4.55 t (2H, CH2, J6.0 Hz), 7.23-7.97 m (13Harom.), 8.37 s (1Harom.), 8.52 s (1H, H5pyrazole), 12.51 s (1H, NH)
Iii 3380 (NH) 2255 (C=N) 3.19 t (2H, CH2, J6.8 Hz), 4.54 t (2H, CH2, J6.8 Hz), 7.22-7.53 m (10Harom.), 7.62 d (2Harom., J 8.4 Hz), 7.99 d (2Harom., J 8.4 Hz), 8.32 s (1H, H5pyrazole), 12.47 s (1H, NH)
IIj 3385 (NH) 2260 (C=N) 2.24 s (3H, CH3), 2.26 s (3H, CH3), 3.18 t (2H, J 6.4 Hz), 4.51 t (2H, J 6.4 Hz), 7.14-7.65 m (12Harom.), 7.86 s (1Harom.), 8.26 s (1H, H5pyrazole),12.38 s (1H, NH)
IIk 3375 (NH) 2490-2905 (COOH) 2.93 t (2H, CH2, J6.4 Hz), 4.45 t (2H, CH2, J6.4 Hz), 7.22-7.55 m (11Harom.), 8.27-8.35 m (2Harom.), 9.02 s (1H, H5pyrazole), 12.46 m. s (2H, NH+COOH)
IIl 3375 (NH) 2540-2860 (COOH) 2.93 t (2H, CH2, J6.2 Hz), 4.45 t (2H, CH2, J6.2 Hz), 7.22-7.99 m (13Harom.), 8.30 s (1Harom.), 8.67 s (1H, H5pyrazole), 12.44 s (2H, NH+COOH)
Table 3
Bactericidal activity of the compounds IIa-l
Compound Test-cultures of microorganisms
S.aureus E.coli
MBsC MBcC MBsC MBcC
IIa 250 >500 >500 >500
IIb 250 >500 >500 >500
IIc 250 >500 >500 >500
IId 250 >500 500 >500
IIe 250 >500 >500 >500
IIf 250 >500 >500 >500
IIg 250 >500 500 >500
IIh 125 >500 >500 >500
IIi >500 >500 >500 >500
IIj 250 >500 >500 >500
IIk 125 >500 >500 >500
IIl 250 >500 250 >500
Ethonium 7.8 31.2 125 250
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Азаряев Р.Ю. студент Бураков Д.В., к.э.н. научный руководитель, старший преподаватель департамент «Финансовые рынки и банки» Финансовый университет при Правительстве
РФ, г. Москва ТАРГЕТИРОВАНИЕ ИНФЛЯЦИИ В РОССИИ Данная статья посвящена исследованию специфики применения режима таргетирования инфляции в России. Проанализированы основные этапы перехода и особенности применении данного режима в российских условиях.
Ключевые слова: экономический рост, денежная масса, ставка процента, Центральный Банк, таргетирование, инфляция
Azaryaev R. U., student
