Synthesis of New 1,4-Diarylimidazoles and 1-Aryl-4-(5-Nitrofuran-2-il)imidazoles and Study of Their Anti-Infective Activity

Article abstract of DOI:10.1134/S1068162018050096

Using 1-R-benzimidazoles and ω-bromoacetophenones or 2-bromoacetyl-5-nitrofuran, the corresponding quaternary 1-R-3-acylmethylbenzimidazolium salts have been obtained which transformed under the action of ammonium acetate into the previously undescribed 1

Full text of DOI:10.1134/S1068162018050096

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2018, Vol. 44, No. 6, pp. 795–800. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © T.A. Kuzmenko, L.N. Divaeva, A.S. Morkovnik, Yu.V. Koshchienko, A.A. Zubenko, Yu.D. Drobin, L.N. Fetisov, A.N. Bodryakov, 2018, published in
Bioorganicheskaya Khimiya, 2018, Vol. 44, No. 6, pp. 686–691.
Synthesis of New 1,4-Diarylimidazoles
and 1-Aryl-4-(5-Nitrofuran-2-il)imidazoles
and Study of Their Anti-Infective Activity
T. A. Kuzmenkoa, L. N. Divaevaa, 1, A. S. Morkovnika, Yu. V. Koshchienkoa, A. A. Zubenkob,
Yu. D. Drobinb, L. N. Fetisovb, and A. N. Bodryakovb
aResearch Institute of Physical and Organic Chemistry, South Federal University, Rostov-on-Don, 344090 Russia
bNorth Caucasus Zonal Veterinary Research Institute, Branch of the Federal Rostov Agricultural Research Center,
Novocherkassk, 346421 Russia
Received February 14, 2018; in final form, March 7, 2018
Abstract⎯Using 1-R-benzimidazoles and ω-bromoacetophenones or 2-bromoacetyl-5-nitrofuran, the cor-
responding quaternary 1-R-3-acylmethylbenzimidazolium salts have been obtained which transformed
under the action of ammonium acetate into the previously undescribed 1,4-diarylimidazoles and 1-aryl-4-
(5-nitrofuran-2-il)imidazoles. The antiprotozoal, fungistatic, and antimicrobial activities of these com-
pounds have been tested.
Keywords: 1-R-benzimidazoles, ω-bromoacetophenones, 2-bromoacetyl-5-nitrofuran, recyclization, 1,4-
diarylimidazoles, 1-aryl-4-(5-nitrofuran-2-il)imidazoles, anti-infective activity
DOI: 10.1134/S1068162018050096
INTRODUCTION
The imidazole ring, which is regarded as a privi-
leged structure, is present in many modern drug
tions [9, 10], and other techniques [11]. All these tech-
niques have certain limitations caused by isomer for-
mation, use of expensive reagents and catalysts, and
preparations with different therapeutic actions, low yield of the target product.
including those used to cure diseases caused by patho-
genic protists and fungi. It will suffice to mention metro-
RESULTS AND DISCUSSION
nidazole, a 5-nitroimidazole derivative with broad prac-
tical application, which has a destructive impact on
Trichomonas, amoebae, lamblia, and anaerobic bacteria
[1]. A series of highly active antifungal drugs containing
imidazole (nizoral, econazole, miconazole, clotrima-
zole, etc.) [1], has been developed which give ground
for hope that further searches for new anti-infective
agents in this group will yield promising results.
In the present work, we have synthesized the previ-
ously undescribed representatives of 1,4-diarylimidaz-
oles and 1-aryl-4-(5-nitrofuran-2-il)imidazoles and
tested the antiprotozoal, fungistatic, and antimicrobial
activity of the obtained compounds.
To obtain 1,4-diarylimidazoles and 1-aryl-4-(5-
nitrofuran-2-il)imidazoles we relied upon the previ-
ously suggested, but illustrated by just a few examples,
rather uncommon reaction between quaternary salts
of 1-R-3-acylmethylbenzimidazolium with ammo-
nium acetate in acetic acid, in the course of which a
specific imidazole–imidazole recyclization occurs
with the breakage of the original imidazole ring and
formation of the new one [12]. The authors of the
abovementioned work have demonstrated that the
introduction of a nitro group into benzimidazole or
acylmethyl moiety of the original cations makes it pos-
sible to considerably increase the yield of the corre-
sponding imidazoles. In this view, in our study we
intentionally produced quaternary salts of 1-R-3-
acylmethylbenzimidazolium containing electron-
withdrawing substituting groups (Scheme 1).
There exist several approaches to the synthesis of
1,4-diarylimidazoles, including as examples N-aryla-
tion of 4-arylimidazoles [2–7], N-phenylacylation of
arylamines [8], cyclization and cycloaddition reac-
1
Corresponding author: phone: +7 (928) 175-66-54; e-mail:
divaevaln@mail.ru.
795

796
KUZMENKO et al.
R2
N
CH2COR2
R1
R1
R1
Br−
N
N
N
N
BrCH2COR2
CH3COONH4
CH3COOH
+
N
CH2R
NHCH2R
CH2R
(Iа)−(If)
(IIа)−(IIl)
(IIIa)−(IIIl)
(I) R = C2H5 (a), H (b), C6H5 (c), 4-ClC6H4 (d), 2-ClC6H4OCH2 (e), 2,4-Cl2C6H3OCH2 (f);
R1 = ΝΟ2 (a, b), H (c−f).
(II), (III) R = C2H5 (a−c), H (d), C6H5 (e, f, j), 4-ClC6H4 (g, k), 2-ClC6H4OCH2 (h),
2,4-Cl2C6H3OCH2 (i, l); R1 = ΝΟ2 (a−d), H (e−l);
R2 = 4-NO2C6H4 (a, e, g−i), 3,4-Cl2C6H3 (b), 4-(1,1′-biphenyl)(c), 4-CF3C6H4 (d),
4-CNC6H4 (f), 5-nitrofuran-2-il (j−l).
Scheme 1. Synthesis of 1,4-diarylimidazoles and 1-aryl-4-(5-nitrofurane-2-il)imidazoles (III).
The compounds (IIa)–(IIi) can be easily obtained azole (IIIh) containing chlorophenoxyethyl group
by boiling benzimidazole (I) and ω-bromoacetophe- showed comparable efficiency, while other tested
none solutions in acetonitrile. Previously unknown compounds were demonstrated to be less active (see
1-chlorophenoxyethylbenzimidazoles (Ie) and (If) Table 1).
were obtained by alkylation of benzimidazole with
The majority of the tested imidazoles demon-
the corresponding 2-phenoxyethyl bromides in the
strated antibacterial activity against E. coli although
presence of KOH. Heating the salts of the
even 5-nitrofuran derivatives (IIIj)–(IIIl), the most
compounds (IIa)–(IIi) with ammonium acetate in
active compounds among them, underperform by
acetic acid leads to the formation of 1,4-diarylimid-
30−40% compared to the reference product. A sub-
azoles (IIIa)–(IIIi) with the 72−90% yield.
stantial inhibitory effect on S. aureus was also demon-
For the antimicrobial activity studies it seemed
practical to synthesize 4-(5-nitrofuran-2-il)-substi-
tuted analogs of 4-arylimidazoles. It was demon-
strated that in the case of 2-bromoacetyl-5-nitrofural,
the quaternary salts (IIj)–(IIl) can be produced with
the yield not higher than 70% which is apparently due
to the well-known instability of 2-acetyl-5-nitrofuran
in the presence of bases. It seems likely that the reac-
tion between the salts (IIj)–(IIl) with ammonium ace-
tate is followed by intensive asphaltization with the
yields of 4-nitrofuril-substituted imidazoles (IIIj)–
(IIIl) not exceeding 28%.
The anti-infective activity of imidazoles (I) was
studied in vitro, antiprotozoal activity was studied
using the specially prepared field Colpoda steinii infu-
soria isolates, and antibacterial activity was analyzed
using the strains of such typical representatives of
Gram-positive and Gram-negative bacteria as Staph-
ylococcus aureus (strain P-209) and Escherichia coli
(field strain 078) by agar diffusion technique using
furazolidone as a reference product. Fungistatic activ-
ity of imidazoles (III) was studied using Penicillium
italicum via an agar diffusion technique.
strated by the derivatives (IIIj)–(IIIl) containing
nitrofuran substituting group and by just a single 4-
nitrophenylimidazole (IIIg).
None of imidazoles (III) revealed fungistatic prop-
erties.
Thus, the data indicates that it is necessary to carry
out a more detailed study of the antiprotozoal activity
of compounds of this type.
EXPERIMENTAL
1H NMR spectra (δ, ppm, J, Hz) were recorded
using the Bruker Avance-600 (600 MHz) spectrome-
ter (United States) for the compounds (IIh), (IIk),
(IIIe), (IIIh), and (IIIi) and using the Varian Unity-
300 (300 MHz) device (Germany) for the other com-
1
pounds analyzed in the study. H NMR chemical
shifts are given relative to residual CDCl3 and DMSO-
d6 signals (7.25 ppm and 2.50 ppm respectively). Melt-
ing temperatures were determined using Fisher-Jones
Melting Point Apparatus (Fisher Scientific) (United
States). Elemental analysis was performed using the
classical microanalysis technique [13]. The reaction
course and the purity of the compounds obtained were
monitored by means of TLC (plates containing Al2O3,
degree of activity III, CHCl3 as eluent, detection by
It has been demonstrated that the compounds
(IIIa)–(IIIc) containing a nitro group in the 1-aryl
substituting group possess high protistocidic activity,
which significantly exceeds the activity of toltrazuril,
one of the most efficient modern coccidiostats; imid- iodine vapor in a humid chamber).
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
Vol. 44
No. 6
2018

SYNTHESIS OF NEW 1,4-DIARYLIMIDAZOLES
797
Table 1. Antiprotozoal and antibacterial activity of 1,4-dia-
rylimidazoles and 1-aryl-4-(5-nitrofuran-2-il)imidazoles (III)
5-Nitro-1-methylbenzimidazole (Ia) and 5-nitro-
1-propylbenzimidazole (Ib) were obtained according
to the technique described in [14], 1-benzylbenzimid-
azole (Ic), according to [15], and 1-(4-chloroben-
zyl)benzimidazole (Id), according to [16].
Growth inhibition zone, mm
Compound
C. steinii
S. aureus
E. coli
Synthesis of 1-(2-phenoxyethyl)-1H-benzimidaz-
oles (Ie) and (If). General approach. The correspond-
ing 2-phenoxyethylbromide (0.15 mol) was added to
the solution obtained with 11.8 g (0.1 mol) of benzim-
idazole, 10.1 g (0.15 mol) KOH (calculated consider-
ing KOH percentage content equal to 85%), 20 mL of
water, and 30 mL of acetone for 30 min with constant
stirring. The mixture was incubated for 1 h at 25°C and
for 15 min at 60°C. After cooling the mixture, the
upper organic layer was isolated and evaporated to
dryness. The pellet was dissolved in chloroform and
run on a chromatographic column containing Al2O3
using chloroform as eluent. The first fraction was col-
lected.
1-(2-(2-Chlorophenoxy)ethyl)-1H-benzimidazole (Ie).
Yield 77%, colorless crystals, Tm 131–133°С (toluene).
Found, %: C 65.83; H 4.68; Cl 13.24; N 10.35.
C15H13ClN2O. Calculated, %: C 66.06; H 4.80; Cl
13.00; N 10.27.
1-(2-(2,4-Dichlorophenoxy)ethyl)-1H-benzimid-
azole (If). Yield 79%, colorless crystals, Tm 129–130°С
(propanol-2). Found, %: C 58.90; H 4.17; Cl 22.92;
N 8.86. C15H12Cl2N2O. Calculated, %: C 58.65; H 3.94;
Cl 23.08; N 9.12.
Synthesis of quaternary salts (IIa)–(IIl). General
approach. The corresponding benzimidazole (I)
(0.01 mol) and bromoketone (0.01 mol) solution in
30−40 mL of acetonitrile was boiled for 2−2.5 h. The
precipitate formed after cooling the solution was sepa-
rated by filtration and washed with acetone. The com-
pounds are obtained in a chromatographically pure
form and therefore are used in subsequent chemical
transformations without performing any additional
purification procedures. The physicochemical char-
acteristics of some of them are provided below.
(IIIa)
7.8
7.8
0
0
5
0
(IIIb)
(IIIc)
7.8
0
5
(IIId)
>500
500
0
0
(IIIe)
0
8
(IIIf)
>500
>500
62.5
>500
125
0
0
(IIIg)
12
0
8
(IIIh)
0
(IIIi)
0
5
(IIIj)
12
9
14
12
12
20
–
(IIIk)
250
(IIIl)
>500
8
Furazolidone
Toltrazuril
19
–
62.5
3-[2-(4-Nitrophenyl)-2-oxoethyl]-1-[2-(2-chloro-
phenoxy)ethyl]-1H-benzimidazole-3-ium bromide (IIh).
Yield 84%, pale-yellow crystals, Tm 254–255°C
1
(n-butanol). H NMR spectrum (DMSO-d6): 4.57
(2 Н, t, J 4.8, СН2O), 5.16 (2 Н, t, J 4.7, СН2N), 6.55
(2 Н, s, СН2СO), 6.96 (1 Н, t, J 7.5, Н4''), 7.17 (1 Н,
d, J 7.5, H6''), 7.29 (1 H, t, J 8.1, H5''), 7.37 (1 Н, d, J
7.9, Н3''), 7.69 (1 Н, t, J 7.7, Н5 or Н6), 7.73 (1 Н, t, J
7.7, Н6 or Н5), 8.10 (1 Н, d, J 8.3, Н4 or Н7), 8.26 (1
Н, d, J 8.3, Н7 or Н4), 8.36 (2 Н, d, J 8.8, Н2', H6' or
Н3', Н5'), 8.47 (2 Н, d, J 8.8, Н3, H5' or Н2', Н6'),
9.80 (1 Н, s, Н2). Found, %: C 53.67; H 3.48; Br and
Cl 22.03; N 8.29. C23H19BrClN3O4. Calculated, %: C
53.46; H 3.71; Br 15.46; Cl 6.86; N 8.13.
5-Nitro-3-[2-(4-nitrophenyl)-2-oxoethyl]-1-propyl-
1H-benzimidazole-3-ium bromide (IIa). Yield 88%,
pale-yellow crystals, Tm 244–245°C (n-butanol).
1-Benzyl-3-[2-(5-nitrofuran-2-il)-2-oxoethyl]-1H-
benzimidazole-3-ium bromide (IIj). Yield 70%, pale-
yellow crystals, Tm 222–223°С (n-butanol). 1H NMR
spectrum (DMSO-d6): 5.90 (2 Н, s, СН2), 6.24 (2 Н, s,
СН2СО), 7.39–7.54 (5 Н, Н2''–Н6''), 7.67–7.71
(2 Н, m, Н5, Н6), 7.98 (2 Н, s, Н3', Н4'), 8.03–8.09
(2 Н, m, Н4, Н7), 9.79 (1 Н, s, Н2). Found, %:
C 53.98; H 3.48; Br and Cl 24.63; N 9.29.
C20H16BrN3O4. Calculated, %: C 54.32; H 3.65;
Br 18.07; Cl 6.86; N 9.50.
1H NMR spectrum (DMSO-d6): 1.27 (3 Н, t, J 7.2,
СН3), 3.22–3.27 (2 Н, m, СН2), 4.72 (2 Н, t, J 7.2,
СН2), 6.55 (2 Н, s, СН2СО), 8.36 (2 Н, dd, J 8.9, 2.0,
2
Н2' , Н6' or Н3', Н5'), 8.42 (1 Н, d, J 9.1, Н7), 8.48
(2 Н, dd, J 8.9, 2.0, Н3', Н5' or Н2', Н6'), 8.55 (1 Н,
dd, J 8.6, 2.1, Н6), 9.29 (1 Н, s, Н4), 10.02 (1 Н, s,
Н2). Found, %: C 48.42; H 3.68; Br 17.57; N 12.63.
C18H17BrN4O5. Calculated, %: C 48.12; H 3.81;
Br 17.79; N 12.47.
3-[2-(5-Nitrofuran-2-il)-2-oxoethyl]-1-(4-chloro-
benzyl)-1H-benzimidazole-3-ium bromide (IIk). Yield
68%, pale-yellow crystals, Tm 203–204°С (CH3CN).
2
In compounds (II), figures with a prime indicate the protons in
the aryl (hetaryl) substituting group in the acylmethyl moiety,
figures with two primes indicate protons in the position 1 of
benzimidazole.
1H NMR spectrum (DMSO-d6): 5.91 (2 Н, s, СН2),
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 44 No. 6 2018

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KUZMENKO et al.
6.25 (2 Н, s, СН2СO), 7.52 (2 Н, d, J 8.7, Н2'', Н6''), J 8.1, H2'', H6'', 8.14 (1 Н, d, J 2.7, H6'), 8.26 (1 H, dd,
J 9.3, 2.4, H4'). Found, %: C 72.68; H 5.82; N 14.29.
7.57 (2 Н, d, J 8.4, Н3'', Н5''), 7.68–7.71 (2 Н, m, H5,
Н6), 7.98 (1 Н, d, J 4.2, Н3ꢀ), 7.99 (1 Н, d, J 4.2, Н4'),
8.03–8.09 (2 Н, m, Н4, H7), 9.78 (1 Н, s, Н2).
Found, %: C 50.09; H 3.48; Br and Cl 24.58; N 9.04.
C20H15BrClN3O4. Calculated, %: C 50.39; H 3.17; Br
16.76; Cl 7.44; N 8.81.
Synthesis of 1,4-diarylimidazoles (IIIa)–(IIIi) and
1-aryl-4-(5-nitrofuran-2-il)imidazoles (IIIj)–(IIIl).
General approach. The solution containing 3 mmol of
the quaternary salt (II) and 30 mmol of ammonium
acetate in 20 mL of glacial acetic acid was boiled for
4−5 h with the reaction course being monitored by
TLC. After cooling the reaction mixture, if a precipi-
tate was formed, it was separated by filtration and
washed with water. If a precipitate was not formed, the
reaction mixture was evaporated to dryness, the pellet
was treated with water, and the resulting crystals were
separated by filtration, washed with water, and puri-
fied by chromatography on the column containing
Al2O3 using chloroform as eluent.
C24H22N4O2. Calculated, %: C 72.34; H 5.57; N 14.06.
1-(2-Methylamino-5-nitrophenyl)-4-(4-trifluoro-
methylphenyl)-1H-imidazole (IIId). Yield 82%, yellow
1
crystals, Tm 209–211°C (EtOH). H NMR spectrum
(CDCl3): 2.99 (3 Н, d, J 5.1, CН3), 4.85 (1 Н, sq. br,
NH), 6.78 (1 Н, d, J 9.3, Н3'), 7.41 (1 Н, s, H5), 7.64
(2 Н, d, J 8.4, H2'', H6''), 7.67 (1 Н, s, H2), 7.86 (2 Н,
d, J 8.1, H3'', H5''), 8.12 (1 Н, d, J 2.4, H6'), 8.30 (1 Н,
dd, J 9.0, 2.4, H4'). Found, %: N 15.62.
C17H13F3N4O2. Calculated, %: N 15.46.
1-(2-Benzylaminophenyl)-4-(4-nitrophenyl)-1H-
imidazole (IIIe). Yield 67%, yellow crystals, Tm 169–
170°C (n-butanol). 1H NMR spectrum (CDCl3): 4.08
(1 Н, t, J 5.2, NH), 4.37 (2 Н, d, J 5.4, СН2), 6.77–
6.80 (2 Н, m, Н3', Н5'), 7.15 (1 Н, d, J 7.6, Н6'), 7.26–
7.32 (6 Н, m, Н4', Н2'''–Н6'''), 7.52 (1 Н, s, Н5), 7.71
(1 Н, s, Н2), 7.93 (2 Н, d, J 8.9, H2'', H6''), 8.23 (2 Н,
d, J 8.9, H3'', H5''). Found, %: C 71.47; H 4.62; N
15.48. C22H18N4O2. Calculated, %: 71.34; H 4.90; N
15.13.
1-(5-Nitro-2-propylaminophenyl)-4-(4-nitrophenyl)-
1H-imidazole (IIIа). Yield 92%, yellow crystals, Tm
207–208°C (n-butanol). 1H NMR spectrum
(DMSO-d6): 0.87 (3 Н, t, J 7.5, СН3), 1.50–1.57 (2 Н,
m, CН2СН3), 3.17–3.22 (2 Н, m, CН2NH), 6.80
1-(2-Benzylaminophenyl)-4-(4-cyanophenyl)-1H-
imidazole (IIIf). Yield 52%, yellow crystals, Tm 143–
1
144°C (EtOH). H NMR spectrum (CDCl3): 4.13
3
(1 Н, t, J 6.0, NH,), 6.95 (1 Н, d, J 9.6, H3' ), 8.01–
(1 Н, t, J 5.7, NH), 4.35 (2 Н, d, J 5.7, СН2), 6.76–
6.82 (2 Н, m, Н3', Н5'), 7.15 (1 Н, d.d, J 7.5, 1.5, Н6'),
7.27–7.36 (6 Н, m, Н4', Н2'''–Н6'''), 7.50 (1 Н, s,
Н5), 7.68 (2 Н, d, J 8.4, H2'', H6''), 7.72 (1 Н, s, Н2),
7.91 (2 Н, d, J 8.4, H3'', H5''). Found, %: C 78.47;
H 4.95; N 16.35. C23H18N4. Calculated, %: 78.83;
8.03 (2 H, m, Н5, H6'), 8.10 (2 H, d, J 9.0, H2'', H6''),
8.18 (1 H, dd, J 9.3, 2.7, H4'), 8.22 (1 Н, s, H2), 8.28
(2 H, d, J 9.0, H3'', H5''). Found, %: C 58.57; H 4.74;
N 18.71. C18H17N5O4. Calculated, %: C 58.85; H 4.66;
N 19.06.
4-(3,4-Dichlorophenyl)-1-(5-nitro-2-propylamin- H 5.18; N 15.99.
ophenyl)-1H-imidazole (IIIb). Yield 82%, yellow crys-
4-(4-Nitrophenyl)-1-[2-(4-chlorobenzyl)aminophe-
1
tals, Tm 177–178°C (n-butanol). H NMR spectrum
nyl]-1H-imidazole (IIIg). Yield 86%, yellow crystals,
Tm 191–192°C (n-butanol). 1H NMR spectrum
(CDCl3): 4.12 (1 Н, t, J 5.4, NH), 4.32 (2 Н, d, J 5.7,
СН2), 6.68 (1 Н, d, J 8.4, Н3'), 6.80 (1 Н, t, J 7.5,
Н5'), 7.14–7.17 (2 Н, m, Н4', Н6'), 7.20 (2 Н, d, J 8.4,
Н2''', Н6'''), 7.25 (2 Н, d, J 8.7, Н3''', Н5'''), 7.50 (1 Н,
s, Н5), 7.71 (1 Н, s, Н2), 7.93 (2 Н, d, J 9.0, H2'',
H6''), 8.24 (2 Н, d, J 9.0, H3'', H5''). Found, %: C
65.43; H 4.57; Cl 8.57; N 14.00. C22H17ClN4O2. Cal-
culated, %: 65.27; H 4.23; Cl 8.76; N 13.84.
(CDCl3): 0.87 (3 Н, t, J 7.5, CН3), 1.50–1.57 (2 Н, m,
CН2CH3), 3.17–3.22 (2 Н, m, CН2NH), 6.67 (1 Н,
br. t, NH), 6.93 (1 Н, d, J 9.3, H3'), 7.64 (1 H, d, J 8.4,
H5''), 7.83 (1 H, dd, J 8.4, 2.1, H6''), 7.93 (1 Н, s, H5),
7.98 (1 H, d, J 2.7, H2''), 8.03 (1 Н, s, H2), 8.06 (1 Н,
d, J 2.1, H6'), 8.16 (1 H, dd, J 9.3, 2.4, H4'). Found,
%: 55.57; H 4.50; Cl 17.93; N 14.05. C18H16Cl2N4O2.
Calculated, %: C 55.26; H 4.12; Cl 18.12; N 14.32.
4-[4-(1,1'-Biphenyl)]-1-(5-nitro-2-propylamin-
ophenyl)-1H-imidazole (IIIc). Yield 88%, yellow crys-
4-(4-Nitrophenyl)-1-{2-[2-(2-chlorophenoxy)-
1
tals, Tm 174–175°C (n-butanol). H NMR spectrum
ethyl)]aminophenyl}-1H-imidazole
(IIIh).
Yield
(DMSO-d6): 0.97 (3 Н, t, J 7.5, CН3), 1.60–1.68 (2 Н,
m, CН2CH3), 3.19–3.26 (2 Н, m, CН2NH), 4.60
(1 Н, t, J 6.0, NH), 6.77 (1 Н, d, J 9.0, H3'), 7.24–7.70
(9 H, m, Н2, Н5, Н3'', Н5'', H2'''–Н6'''), 7.89 (2 Н, d,
(94%), yellow crystals, Tm 198–200°C (n-butanol).
1H NMR spectrum (DMSO-d6): 3.52 (2 Н, sq., J 5.7,
CН2NH), 4.19 (2 Н, t, J 5.7, CН2О), 5.08 (1 Н, t,
J 5.8, NH), 6.74 (1 Н, t.d, J 7.5, 1.2, H5'), 6.91 (1 Н,
t.d, J 7.6, 1.4, H4'''), 7.02 (1 H, d, J 9.2, H3'), 7.13
(1 Н, d.d, J 8.3, 1.3, H6'''), 7.17 (1 Н, dd, J 7.7, 1.5,
H6'), 7.25 (1 Н, t, J 8.7, H4'), 7.32 (1 Н, t, J 7.9, H5'''),
7.36 (1 Н, dd, J 7.9, 1.6, H3'''), 7.90 (1 Н, s, H5), 8.06
(2 Н, d, J 8.9, H2'', H6''), 8.11 (1 Н, s, H2), 8.20 (2 Н,
d, J 8.7, H3'', H5''). Found, %: C 63.35; H 4.73; Cl
3
In compounds (III) figures with a prime indicate the protons in
the aryl substituent group in position 1, figures with two
primes—the protons in the aryl (hetaryl) substituent group in
position 4 of imidazole, figures with three primes—the protons
in the aryl substituent group in the amino group of the aniline
moiety and in the outer phenyl ring of the biphenyl fragment of
imidazole (IIIc).
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SYNTHESIS OF NEW 1,4-DIARYLIMIDAZOLES
799
8.03; N 13.13. C23H19ClN4O3. Calculated, %: C 63.52; the agar diffusion technique as described in [19–22].
A nutritive medium without bacteria served as a nega-
tive control. Furazolidone was used as a reference
product. The antibacterial activity level was deter-
mined by the size of the growth inhibition zones.
H 4.40; Cl 8.15; N 12.88.
1-{2-[2-(2,4-Dichlorophenoxy)ethyl)]aminophenyl}-
4-(4-nitrophenyl)-1H-imidazole (IIIi). Yield 91%, yel-
1
low crystals, Tm 142–143°C (EtOH). H NMR spec-
Fungistatic activity of imidazoles (III) was studied
on P. italicum cultures using the agar diffusion tech-
nique according to the modified method described in
[17]. One milliliter of the tested fungus culture suspen-
sion (5 units of bacterial optical turbidity standard)
was poured onto solidified Sabouraud nutritive
medium. Then, the suspension was uniformly distrib-
uted over the medium surface and excess suspension
was removed. Plates were dried for 20−30 min and
sectors (3−6) were outlined. A single filter paper
(GOST 6722-75) (manufactured by the Innovation
Technology Department of the Pasteur Research
Institute of Epidemiology and Microbiology) was
placed onto each sector. Twenty microliters of each
tested compound suspension in distilled water was
applied to the disks so that 20 μg of each preparation
was used for a disk. In such a way, prepared plates were
incubated in the temperature-controlled chamber at
26°C for 72 h. Culture growth was assessed each day.
The size of the fungus growth inhibition zone formed
around the disk was estimated. Benomil was used as a
reference product.
trum (DMSO-d6): 3.50 (2 Н, sq, J 5.8, CН2NH), 4.19
(2 Н, t, J 5.7, CН2О), 5.06 (1 Н, t, J 5.9, NH), 6.74 (1
Н, t.d, J 7.6, 1.14, H5'), 7.01 (1 H, d, J 8.2, H3'), 7.15–
7.17 (2 Н, m, Н4', Н6'), 7.30–7.33 (2 Н, m, H5''',
H6'''), 7.79 (1 Н, s, Н3'''), 7.90 (1 Н, s, H5), 8.06 (2 H,
d, J 8.9, H2'', H6''), 8.10 (1 Н, s, H2), 8.23 (1 H, d, J
8.9, H3'', H5''). Found, %: C 59.10; H 4.14; Cl 14.85;
N 11.67. C23H18Cl2N4O3. Calculated, %: C 58.86;
H 3.87; Cl 15.11; N 11.94.
1-(2-Benzylaminophenyl)-4-(5-nitrofuran-2-il)-1H-
imidazole (IIIj). Yield 21%, yellow crystals, Tm 185–
186°C (EtOH). 1H NMR spectrum (DMSO-d6): 4.29
(2 Н, d, J 6.0, CН2), 5.94 (1 Н, t, J 6.0, NH), 6.59
(1 Н, d, J 8.4, H3'), 6.65 (1 Н, t, J 8.1, H5'), 7.04 (1 Н,
d, J 4.2, H3''), 7.13–7.22 (3 H, m, H4', H6', Н4'''),
7.27–7.35 (4 Н, m, H2''', H3''', H5''', H6'''), 7.84 (1 Н,
d, J 3.9, H4''), 8.04 (1 Н, d, J 1.2, H5), 8.09 (1 Н, d,
J 1.2, H2). Found, %: C 66.32; H 4.59; N 15.34.
C20H16N4O3. Calculated, %: C 66.66; H 4.48; N 15.55.
4-(5-Nitrofuran-2-il)-1-[2-(4-chlorobenzyl)amin-
ophenyl]-1H-imidazole (IIIk). Yield 28%, yellow crys-
1
tals, Tm 188–189°C (n-butanol). H NMR spectrum
ACKNOWLEDGMENTS
(DMSO-d6): 4.29 (2 Н, d, J 6.0, CН2), 5.99 (1 Н, t, J
6.0, NH), 6.57 (1 Н, d, J 8.1, H3'), 6.64 (1 Н, t, J 7.5,
H5'), 7.04 (1 Н, d, J 3.9, H3''), 7.14–7.21 (2 H, m, H4',
H6'), 7.36 (4 Н, br. s, H2''', H3''', H5''', H6'''), 7.84 (1
Н, d, J 3.9, H4''), 8.03 (1 Н, d, J 1.2, H5), 8.09 (1 Н,
d, J 1.2, H2). Found, %: C 60.49; H 3.70; Cl 9.06; N
14.01. C20H15СlN4O3. Calculated, %: C 60.84; H 3.83;
Cl 8.98; N 14.19.
The work was supported by the Ministry of Educa-
tion and Science (grant no. 4.5821.2017/8.9). The
work was performed using the equipment available in
the Center for Collective Use of the Southern Federal
University.
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Translated by E. Martynova
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
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No. 6
2018