Synthesis and Anticholinesterase Activity of [(4Z)-2-Aryl-4-(arylmethylidene)-5-oxo-4,5-dihydro-1H-imidazol-1-yl]alkanoic Acids

Article abstract of DOI:10.1134/S1070428018090178

ω-[(4Z)-2-Aryl-4-arylmethylidene-5-oxo-4,5-dihydro-1H-imidazol-1-yl]alkanoic acids were synthesized by reaction of N-substituted α,β-dehydropeptides with chloro(trimethyl)silane or 1,1,1,3,3,3-hexamethyldisilazane. Both initial peptides and (4H)-imidazol-

Full text of DOI:10.1134/S1070428018090178

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 9, pp. 1369–1377. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © V.O. Topuzyan, V.M. Kazoyan, R.A. Tamazyan, A.G. Aivazyan, L.Kh. Galstyan, 2018, published in Zhurnal Organicheskoi Khimii,
2018, Vol. 54, No. 9, pp. 1355–1363.
Synthesis and Anticholinesterase Activity
of [(4Z)-2-Aryl-4-(arylmethylidene)-5-oxo-4,5-dihydro-
1H-imidazol-1-yl]alkanoic Acids
V. O. Topuzyana,* V. M. Kazoyana, R. A. Tamazyana, A. G. Aivazyana, and L. Kh. Galstyanb
a Scientific Technological Center of Organic and Pharmaceutical Chemistry, National Academy of Sciences of Armenia,
pr. Azatutyan 26, Yerevan, 0014 Armenia
*e-mail: vtop@web.am
b Yerevan State University, ul. Aleka Manukyana 1, Yerevan, 0025 Armenia
Received April 9, 2018
Abstract—ω-[(4Z)-2-Aryl-4-arylmethylidene-5-oxo-4,5-dihydro-1H-imidazol-1-yl]alkanoic acids were syn-
thesized by reaction of N-substituted α,β-dehydropeptides with chloro(trimethyl)silane or 1,1,1,3,3,3-hexa-
methyldisilazane. Both initial peptides and (4H)-imidazol-5-one derivatives based thereon were tested for
anticholinesterase activity.
DOI: 10.1134/S1070428018090178
(4H)-Imidazol-5-ones are known as physiologically
active compounds [1–4]. We previously proposed
a procedure for the synthesis of (4H)-imidazol-5-ones
from α,β-dehydroamino acid derivatives with the use
of silylating agents [5–9], and this procedure was
subsequently utilized in [10, 11].
reaction of N-substituted α,β-dehydropeptides 9‒24
with chloro(trimethyl)silane or hexamethyldisilazane
(HMDS) (Scheme 1).
Initial unsaturated dipeptides 9‒24 were prepared
by the azlactone method [12]. The reaction of
{[(2Z)-2-benzamido-3-phenylprop-2-enoyl]amino}-
acetic acid (9) with 3 equiv of chloro(trimethyl)silane
was carried out in DMF under reflux in the presence of
ω-(4-Arylmethylidene-5-oxo-4,5-dihydro-1H-imid-
azol-1-yl)alkalnoic acids 25‒40 were synthesized by
Scheme 1.
O
Ar
Ar
O
(1) NaOH
(2) HCl
H
H2N
COOH
+
41–44
N
COOH
N
O
( )n
( )n
R
N
H
O
R
1–4
5–8
9–24
Me3SiCl
or (Me3Si)2NH
(Me3Si)2NH
O
O
Ar
Ar
COOH
N
( )n
N
NH
R
N
R
41–44
25–40
1, 9‒12, 25–28, 41, R = Ph, Ar = Ph; 2, 13‒16, 29‒32, 42, R = Ph, Ar = C6H4OMe-4; 3, 17‒20, 33–36, 43, R = Ph, Ar = C6H4Br-4;
4, 21‒24, 37‒40, 44, R = 4-BrC6H4, Ar = Ph; 5, 9, 13, 17, 21, 25, 29, 33, 37, n = 1; 6, 10, 14, 18, 22, 26, 30, 34, 38, n = 2; 7, 11, 15,
19, 23, 27, 31, 35, 39, n = 3; 8, 12, 16, 20, 24, 28, 32, 36, 40, n = 5.
1369

TOPUZYAN et al.
1370
Scheme 2.
O
OH
O
Ph
Ph
Ph
H
COOH
N
N
N
N
N
NH
–CH2=CHCOOH
Ph
Ph
Ph
26
41
triethylamine. After 2 h, imidazolone 25 was formed in
48% yield. In analogous reaction with 3 equiv of hexa-
methyldisilazane compound 25 was formed in 97%
yield after 1 h. Therefore, the other ω-(4-arylmethyli-
dene-5-oxo-4,5-dihydro-1H-imidazol-1-yl)alkanoic
acids were synthesized with the use of HMDS.
According to the TLC data, the reactions were
complete in 1 h.
reaction of 10 with HMDS imidazolone 41 is formed
as a by-product as a result of thermal decomposition of
initially formed acid 26 (Scheme 2).
This assumption was confirmed by the identifica-
tion of acrylic acid (Rf 0.60; the chromatogram was
treated with potassium permanganate) in the reaction
mixture obtained by heating acid 26 in DMF. If the
initial peptide contained a β-alanine residue (com-
pounds 14, 18, and 22), its reaction with HMDS was
accompanied by the formation of the corresponding
imidazolone (compounds 42‒44). The latter were also
obtained by reacting oxazolones 1‒4 with HMDS.
3-{[(2Z)-2-Benzamido-3-phenylprop-2-enoyl]-
amino}propanoic acid (10) reacted with HMDS to
produce in 10 min 81% of 3-[(4Z)-4-benzylidene-5-
oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]propanoic
acid (26). The yield of acid 26 decreased on further
heating of the reaction mixture. TLC analysis of the
reaction mixture revealed formation of a compound
with Rf 0.65 in addition to acid 26 (Rf 0.40). Its amount
increased with time, and after 3 h we isolated
(5Z)-5-benzylidene-2-phenyl-3,5-dihydro-4H-imid-
azol-4-one (41) in 57% yield. If the reaction was
carried out with 5 equiv of HMDS, the yield of 41 was
55% in 2 h. According to the TLC data, imidazolone
41 was also formed when acid 26 was heated in boiling
DMF. These findings led us to presume that in the
1
In the H NMR spectra of dipeptides 9‒24 and
imidazolones 25‒40 the vinylic proton resonated as
a singlet at δ 7.07‒7.33 and 7.06‒7.16 ppm, respec-
tively, which indicated Z configuration of the exocyclic
double bond. In fact, the X-ray diffraction data for
compound 32 confirmed its Z configuration (Fig. 1).
All cyclic fragments in molecule 32 are planar; the
maximum deviation of atoms from the mean-square
planes does not exceed 0.0172(5) Å. Molecules 32 in
crystal are linked to form dimers through intermolec-
ular hydrogen bonds O14‒H14···O6i and O6···H14i‒N14i;
C24
C23
O28
C25
C22
O6
C21
C29
C5
C27
C4
N3
C26
O13
C12
N1
C8
C7
C2
C15
C10
C9
C20
C11
O14
C16
C17
C19
C18
Fig. 1. Structure of the molecule of 6-[(4Z)-4-(4-methoxybenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]hexanoic acid
(32) according to the X-ray diffraction data (arbitrary atom numbering). Non-hydrogen atoms are shown as thermal vibration
ellipsoids with a probability of 50%.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

SYNTHESIS AND ANTICHOLINESTERASE ACTIVITY
D···A 2.708(3) Å (Fig. 2). The dimers are linked to
1371
each other through mainly van der Waals interactions.
The anticholinesterase activity of dipeptides 9‒24
and imidazolones 25‒44 was estimated with respect to
acetylcholinesterase (AChE, EC 3.1.1.7) and butyryl-
cholinesterase (BuChE, EC 3.1.1.8). The results are
collected in Tables 1‒3. N-Substituted α,β-dehydro-
dipeptides 9‒24 either showed no activity or their
inhibitory activity against both cholinesterases was
weak (0‒8% against AChE and 0‒15% against BuChE;
Table 1). Imidazolones 25‒40 containing a carboxylic
acid residue on N1 turned out to be more active
(1–97% against AChE and 2–73% against BuChE;
Table 2). Compounds 27 and 28 exhibited a high
inhibitory activity toward AChE (97% and 83%,
respectively), and butanoic acid 31 inhibited BuChE
by 73%. Imidazolones 41‒44 were also found to in-
hibit cholinesterases (Table 3); in particular, 5-ben-
zylidene-2-phenyl-3,5-dihydro-4H-imidazol-4-one
(41) showed a high activity with respect to BuChE.
Fig. 2. Dimer formed by molecules of 6-[(4Z)-4-(4-methoxy-
benzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-
hexanoic acid (32) in crystal. Intermolecular hydrogen bonds
are shown as dashed lines.
pound 32 (CIF file) were deposited to the Cambridge
Crystallographic Data Centre (CCDC entry
no. 1819058).
EXPERIMENTAL
Oxazolones 1–4 were synthesized according to the
procedure described in [14].
The IR spectra were recorded on a Specord M-80
spectrometer from samples dispersed in mineral oil.
α,β-Dehydrodipeptides 9–24 (general procedure).
Oxazolone 1‒4, 15 mmol, was added to a solution of
15 mmol of amino acid 5‒8 and 0.6 g (15 mmol) of
1
The H and 13C NMR spectra were measured on
a Varian Mercury 300 spectrometer from solutions in
DMSO-d6 using hexamethyldisiloxane as internal stan-
dard. The progress of reactions was monitored, and the
purity of the isolated compounds was checked, by TLC
on Alugram Xtra SIL G/UV plates using benzene–
methanol (5:2, A) or propan-1-ol‒water (7:3, B) as
eluent. Spots were detected under UV light or by
spraying with a 5% solution of potassium perman-
ganate followed by heating to 100‒120°C for 2‒3 min.
The melting points were determined with a Boetius
hot stage.
Table 1. Anticholinesterase activity of N-substituted α,β-de-
hydrodipeptides 9‒24 at a concentration of 80 μM
I, %
Compound no.
AChE
BuChE
09
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2
6
2
0
0
6
8
0
0
6
0
7
2
2
2
2
08
09
05
00
00
11
08
00
00
13
00
02
06
04
04
04
The X-ray diffraction data for compound 32
(Table 4) were obtained at room temperature on
an Enraf–Nonius CAD-4 automated diffractometer
(MoKα radiation, graphite monochromator, θ/2θ scan-
ning). The unit cell parameters (triclinic crystal sys-
tem) were determined and refined from 24 reflections
in the range 13.9 < θ < 15.8°. The structure was solved
by the direct method. The coordinates of hydrogen
atoms were determined by the difference Fourier
syntheses. The structure was refined by the full-matrix
least-squares method in anisotropic approximation for
non-hydrogen atoms and isotropic approximation for
hydrogens. All calculations were performed using
SHELXTL [13]. The crystallographic data for com-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

TOPUZYAN et al.
1372
Table 2. Anticholinesterase activity of ω-[(4Z)-2-aryl-4-
arylmethylidene-5-oxo-4,5-dihydro-1H-imidazol-1-yl]al-
kanoic acids 25‒40 at a concentration of 80 μM
7.43‒7.58 m (5H, Harom), 7.99‒8.04 m (2H, Harom),
8.09 t (1H, NH, J = 5.7 Hz), 9.77 s (1H, NH), 12.29
br.s (1H, COOH). Found, %: C 66.46; H 5.07; N 8.75.
C18H16N2O4. Calculated, %: C 66.66; H 4.97; N 8.64.
I, %
Compound no.
3-{[(2Z)-2-Benzamido-3-phenylprop-2-enoyl]-
amino}propanoic acid (10). Reaction time 24 h. Yield
96%, mp 222‒224°C, Rf 0.22 (A). IR spectrum, ν,
cm–1: 3300, 3253 (NH), 1734 (COOH), 1645 (C=O,
AChE
BuChE
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
02
18
97
83
04
19
03
41
37
06
12
04
20
05
01
02
28
18
02
07
12
23
73
05
30
08
30
06
06
10
09
02
1
amide). H NMR spectrum, δ, ppm: 2.47 t (2H, CH2,
J = 6.7 Hz), 3.44 t.d (2H, NCH2, J = 6.7, 6.0 Hz),
7.19 s (1H, C=CH), 7.21‒7.33 m (3H, Harom), 7.42‒
7.55 m (5H, Harom), 7.89 t (1H, NH, J = 6.0 Hz), 7.98‒
8.03 m (2H, Harom), 9.72 s (1H, NH), 11.90 br.s
(1H, COOH). Found, %: C 67.69; H 5.49; N 8.04.
C19H18N2O4. Calculated, %: C 67.45; H 5.36; N 8.28.
4-{[(2Z)-2-Benzamido-3-phenylprop-2-enoyl]-
amino}butanoic acid (11). Reaction time 24 h. Yield
85%, mp 215‒218°C, Rf 0.30 (A). IR spectrum, ν,
cm–1: 3265 (NH), 1654 (C=O, amide), 1639 (COOH).
1H NMR spectrum, δ, ppm: 1.73‒1.83 m (2H CH2),
2.28 t (2H, CH2COOH, J = 7.3 Hz), 3.22‒3.29 m (2H,
NHCH2), 7.14 s (1H, C=CH), 7.20‒7.33 m (3H,
Harom), 7.42‒7.56 m (5H, Harom), 7.96 t (1H, NH, J =
5.8 Hz), 7.99‒8.04 m (2H, Harom), 9.70 s (1H, NH),
11.71 br.s (1H, COOH). Found, %: C 68.44; H 6.03;
N 7.80. C20H20N2O4. Calculated, %: C 68.17; H 5.72;
N 7.95.
Table 3. Anticholinesterase activity of (5Z)-2-aryl-5-aryl-
methylidene-3,5-dihydro-4H-imidazol-4-ones 41–44 at
a concentration of 80 μM
6-{[(2Z)-2-Benzamido-3-phenylprop-2-enoyl]-
amino}hexanoic acid (12). Reaction time 48 h. Yield
85%, mp 147‒149°C, Rf 0.56 (A). IR spectrum, ν,
cm–1: 3305, 3272 (NH), 1739 (COOH), 1640 (C=O,
I, %
Compound no.
AChE
BuChE
41
42
43
44
0
6
9
5
62
11
10
03
1
amide). H NMR spectrum, δ, ppm: 1.32‒1.43 m (2H,
CH2), 1.50‒1.65 m (4H, CH2), 2.20 t (2H, CH2COOH,
J = 7.3 Hz), 3.17‒3.25 m (2H, NHCH2), 7.12 s (1H,
C=CH), 7.20‒7.33 m (3H, Harom), 7.42‒7.56 m (5H,
Harom), 7.84 t (1H, NHCH2, J = 5.7 Hz), 7.98‒8.03 m
sodium hydroxide in 50 mL of aqueous acetone (1:1),
and the mixture was stirred for 12‒46 h at room
temperature. The mixture was diluted with 100 mL of
water, unreacted initial compound 1‒4 was filtered off,
and the filtrate was acidified to pH 2 with aqueous
HCl. The precipitate was filtered off, washed with
water until neutral washings, dried, and recrystallized
from 50% ethanol.
(2H, Harom), 9.68 s (1H, NH), 11.63 br.s (1H, COOH).
Found, %: C 69.59; H 6.70; N 7.00. C22H24N2O4. Cal-
culated, %: C 69.46; H 6.36; N 7.36.
{[(2Z)-2-Benzamido-3-(4-methoxyphenyl)prop-2-
enoyl]amino}acetic acid (13). Reaction time 48 h.
Yield 66%, mp 215‒218°C, Rf 0.64 (A), Rf 0.64 (B).
IR spectrum, ν, cm–1: 3305, 3232 (NH), 1738 (COOH),
1639 (C=O, amide). 1H NMR spectrum, δ, ppm: 3.78 s
(3H, OCH3), 3.86 d (2H, NHCH2, J = 5.5 Hz), 6.81‒
6.86 m (2H, Harom), 7.32 s (1H, C=CH), 7.43‒7.55 m
(5H, Harom), 7.98 t (1H, NHCH2, J = 5.5 Hz), 8.01‒
8.08 m (2H, Harom), 9.71 s (1H, NH), 12.17 br.s
(1H, COOH). Found, %: C 64.57; H 5.30; N 8.09.
C19H18N2O5. Calculated, %: C 64.40; H 5.12; N 7.90.
{[(2Z)-2-Benzamido-3-phenylprop-2-enoyl]-
amino}acetic acid (9). Reaction time 48 h. Yield 87%,
mp 182‒184°C, Rf 0.22 (A). IR spectrum, ν, cm–1:
3325, 3225 (NH), 1740 (COOH), 1640 (C=O, amide).
1H NMR spectrum, δ, ppm: 3.87 d (2H, NCH2, J =
5.8 Hz), 7.21‒7.34 m (3H, Harom), 7.31 s (1H, C=CH),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

SYNTHESIS AND ANTICHOLINESTERASE ACTIVITY
1373
Table 4. Principal crystallographic parameters of 6-[(4Z)-4-
(4-methoxybenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-
imidazol-1-yl]hexanoic acid (32)
3-{[(2Z)-2-Benzamido-3-(4-methoxyphenyl)prop-
2-enoyl]amino}propanoic acid (14). Reaction time
48 h. Yield 97%, mp 248‒250°C, Rf 0.68 (B). IR spec-
trum, ν, cm–1: 3262 (NH), 1735 (COOH), 1639 (C=O,
Parameter
Value
1
amide). H NMR spectrum, δ, ppm: 2.46 t (2H, CH2,
Formula
C23H24N2O4
392.44
J = 6.9 Hz), 3.39‒3.47 m (2H, NHCH2), 3.78 s (3H,
OCH3), 6.80‒6.86 m (2H, Harom), 7.20 s (1H, C=CH),
7.43‒7.55 m (5H, Harom), 7.77 t (1H, NHCH2, J =
5.8 Hz), 7.99‒8.05 m (2H, Harom), 9.65 s (1H, NH),
11.90 br.s (1H, COOH). Found, %: C 65.50; H 5.67;
N 7.43. C20H20N2O5. Calculated, %: C 65.21; H 5.47;
N 7.60.
Molecular weight
Crystal system
Space group
a, b, c, Å
Triclinic
P-1
8.8299(18), 10.646(2),
12.139(2)
α, β, γ, deg
110.29(3), 94.42(3),
103.82(3)
4-{[(2Z)-2-Benzamido-3-(4-methoxyphenyl)prop-
2-enoyl]amino}butanoic acid (15). Reaction time
48 h. Yield 90%, mp 236‒239°C; Rf 0.18 (A), 0.70 (B).
IR spectrum, ν, cm–1: 3266 (NH), 1733 (COOH), 1641
V, Å3
1023.2(4)
2
Z
calc, g/cm3
1.274
1
d
(C=O, amide). H NMR spectrum, δ, ppm: 1.71‒
μ(MoKa), mm–1
0.088
1.82 m (2H, CH2), 2.27 t (2H, CH2COOH, J = 7.3 Hz),
3.20‒3.28 q (2H, NHCH2), 3.78 s (3H, OCH3), 6.81‒
6.86 m (2H, Harom), 7.16 s (1H, C=CH), 7.43‒7.55 m
(5H, Harom), 7.86 t (1H, NHCH2, J = 5.8 Hz), 8.01‒
8.06 m (2H, Harom), 9.63 s (1H, NH), 11.72 br.s
(1H, COOH). Found, %: C 66.11; H 5.93; N 7.10.
C21H22N2O5. Calculated, %: C 65.96; H 5.80; N 7.32.
F(000)
416
Crystal dimensions, mm
Temperature, K
0.25×0.30×0.36
293
Radiation wavelength, Å
0.71073
1.8, 30.0
θmin/max, deg
6-{[(2Z)-2-Benzamido-3-(4-methoxyphenyl)prop-
2-enoyl]amino}hexanoic acid (16). Reaction time
48 h. Yield 89%, mp 157‒159°C, Rf 0.78 (B). IR spec-
trum, ν, cm–1: 3242 (NH), 1639 (C=O, amide), 1726
Scan range
0 ≤ h ≤ 12, –14 ≤ k ≤ 14,
–17 ≤ l ≤ 17
Total number of reflections
6315
Number of reflections
with I > 2.0σ(I)
1
(COOH). H NMR spectrum, δ, ppm: 1.31‒1.43 m
3175
5955
(2H, CH2), 1.48‒1.65 m (4H, CH2), 2.20 t (2H,
CH2COOH, J = 7.3 Hz), 3.16‒3.24 m (2H, NHCH2),
3.78 s (3H, OCH3), 6.81‒6.86 m (2H, Harom), 7.13 s
(1H, C=CH), 7.43‒7.56 m (5H, Harom), 7.72 t (1H,
NHCH2, J = 5.7 Hz), 8.00‒8.06 m (2H, Harom), 9.61 s
(1H, NH), 11.64 br.s (1H, COOH). Found, %: C 67.51;
H 6.62; N 7.03. C23H26N2O. Calculated, %: C 67.30;
H 6.39; N 6.82.
Number of independent
reflections
Number of variables
358
R, wR2, S
0.0658, 0.2085, 1.01
trum, ν, cm–1: 3249 (NH), 1733 (COOH), 1642 (C=O,
1
amide). H NMR spectrum, δ, ppm: 2.47 t (2H, CH2,
J = 6.9 Hz), 3.39‒3.47 m (2H, NHCH2), 7.18 s (1H,
C=CH), 7.21‒7.33 m (3H, Harom), 7.50‒7.57 m (2H,
Harom), 7.58‒7.63 m (2H, Harom), 7.85‒8.03 m (3H,
NH), 9.76 s (1H, NH), 11.64 br.s (1H, COOH). Found,
%: C 54.38; H 4.36; Br 19.33; N 6.87. C19H17BrN2O4.
Calculated, %: C 54.69; H 4.11; Br 19.15; N 6.71.
{[(2Z)-2-Benzamido-3-(4-bromophenyl)prop-2-
enoyl]amino}acetic acid (17). Reaction time 48 h.
Yield 82%, mp 215‒217°C, Rf 0.75 (B). IR spectrum,
ν, cm–1: 3342, 3235 (NH), 1739 (COOH), 1638 (C=O,
amide). 1H NMR spectrum, δ, ppm: 3.87 d (2H, NCH2,
J = 5.8 Hz), 7.27 s (1H, C=CH), 7.42‒7.55 m (7H,
Harom), 7.98‒8.03 m (2H, Harom), 8.17 t (1H, NHCH2,
J = 5.8 Hz), 9.77 s (1H, NH), 17.15 br.s (1H, COOH).
Found, %: C 53.36; H 3.90; Br 19.67; N 7.17.
C18H15BrN2O4. Calculated, %: C 53.62; H 3.75;
Br 19.81; N 6.95.
4-{[(2Z)-2-Benzamido-3-(4-bromophenyl)prop-2-
enoyl]amino}butanoic acid (19). Reaction time 24 h.
Yield 88%, mp 250‒252°C, Rf 0.67 (B). IR spectrum,
ν, cm–1: 3381, 3227 (NH), 1735 (COOH), 1647 (C=O,
1
amide). H NMR spectrum, δ, ppm: 1.73‒1.83 m (2H,
NHCH2CH2), 2.28 t (2H, CH2COOH, J = 7.3 Hz),
3.21‒3.28 q (2H, NHCH2), 7.10 s (1H, C=CH), 7.41‒
7.55 m (7H, Harom), 7.97‒8.04 m (3H, Harom, NH),
3-{[(2Z)-2-Benzamido-3-(4-bromophenyl)prop-
2-enoyl]amino}propanoic acid (18). Reaction time
24 h. Yield 87%, mp 158‒161°C, Rf 0.64 (B). IR spec-
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TOPUZYAN et al.
1374
9.69 s (1H, NH), 11.71 br.s (1H, COOH). Found, %:
C 55.91; H 4.69; Br 18.21; N 6.63. C20H19BrN2O4.
Calculated, %: C 55.70; H 4.44; Br 18.53; N 6.49.
Yield 88%, mp 168‒170°C, Rf 0.79 (B). IR spectrum,
ν, cm–1: 3238 (NH), 1727 (COOH), 1639 (C=O,
amide). H NMR spectrum, δ, ppm: 1.32‒1.43 m (2H,
1
CH2), 1.49‒1.66 m (4H, CH2), 2.20 t (2H, CH2COOH,
J = 7.3 Hz), 3.16‒3.24 m (2H, NHCH2), 7.11 s (1H,
C=CH), 7.20‒7.33 m (3H, Harom), 7.49‒7.54 m (2H,
Harom), 7.58‒7.63 m (2H, Harom), 7.87 t (1H, NHCH2,
J = 5.6 Hz), 7.92‒7.99 m (2H, Harom), 9.77 s (1H, NH),
11.63 br.s (1H, COOH). Found, %: C 57.82; H 5.29;
Br 17.02; N 6.34. C22H23BrN2O4. Calculated, %:
C 57.53; H 5.05; Br 17.39; N 6.10.
6-{[(2Z)-2-Benzamido-3-(4-bromophenyl)prop-2-
enoyl]amino}hexanoic acid (20). Reaction time 24 h.
Yield 92%, mp 206‒209°C, Rf 0.74 (B). IR spectrum,
ν, cm–1: 3238 (NH), 1727 (COOH), 1639 (C=O,
1
amide). H NMR spectrum, δ, ppm: 1.32‒1.44 m (2H,
CH2), 1.49‒1.66 m (4H, CH2), 2.20 t (2H, CH2COOH,
J = 7.3 Hz), 3.17‒3.24 m (2H, NHCH2), 7.07 s (1H,
C=CH), 7.41‒7.55 m (7H, Harom), 7.91 t (1H, NHCH2,
J = 5.7 Hz), 7.96‒8.02 m (2H, Harom), 9.68 s (1H, NH),
11.62 br.s (1H, COOH). Found, %: C 57.78; H 5.21;
Br 17.03; N 6.28. C22H23BrN2O4. Calculated, %:
C 57.53; H 5.05; Br 17.39; N 6.10.
[(4Z)-4-Benzylidene-5-oxo-2-phenyl-4,5-dihydro-
1H-imidazol-1-yl]acetic acid (25). a. A mixture of
1 g (0.0031 mol) of compound 9, 1.0 g (1.17 mL,
0.0093 mol) of chloro(trimethyl)silane, and 0.9 g
(1.1 mL, 0.0093 mol) of triethylamine in 10 mL of
DMF was refluxed for 2 h. The mixture was cooled
and diluted with 60 mL of water, and the precipitate
was filtered off, dried in air, and recrystallized from
ethyl acetate. Yield 0.44 g (48%).
{(Z)-2-(4-Bromobenzamido)-3-phenylprop-
2-enoyl]amino}acetic acid (21). Reaction time 48 h.
Yield 70%, mp 135‒138°C, Rf 0.71 (B). IR spectrum,
ν, cm–1: 3342, 3235 (NH), 1739 (COOH), 1638 (C=O,
1
amide). H NMR spectrum, δ, ppm: 3.87 d (2H,
NHCH2, J = 5.8 Hz), 7.22‒7.34 m (4H, Harom), 7.51‒
7.55 m (2H, Harom), 7.58‒7.64 m (2H, Harom), 7.93‒
7.99 m (2H, Harom), 8.14 t (1H, NHCH2, J = 5.8 Hz),
9.85 s (1H, NH), 11.97 br.s (1H, COOH). Found, %:
C 53.90; H 4.03; Br 19.60; N 7.09. C18H15BrN2O4.
Calculated, %: C 53.62; H 3.75; Br 19.81; N 6.95.
b. A mixture of 1 g (0.0031 mol) of compound 9
and 1.45 g (1.87 mL, 0.009 mol) of HMDS in 10 mL
of DMF was refluxed for 1 h. The mixture was cooled,
diluted with 60 mL of water, and acidified to pH 2 with
aqueous HCl, and the precipitate was filtered off, dried
in air, and recrystallized from ethyl acetate. Yield
0.89 g (97%), mp 198–201°C, Rf 0,33 (A). IR spec-
trum, ν, cm–1: 1740 (COOH), 1675 (C5=O), 1637
(C=C). 1H NMR spectrum, δ, ppm: 4.41 s (2H, NCH2),
7.15 s (1H, C=CH), 7.34‒7.45 m (3H, Harom), 7.52‒
7.61 m (3H, Harom), 7.78‒7.83 m (2H, Harom), 8.23–
8.27 m (2H, Harom), 12.94 br.s (1H, COOH). 13C NMR
spectrum, δC, ppm: 42.5 (NCH2), 127.3 (CH), 127.9
(2C, CH), 128.0 (2C, CH), 128.3 (2C, CH), 129.0,
129.5 (CH), 130.7 (CH), 132.0 (2C, CH), 133.9, 138.2,
161.6, 168.6, 169.9. Found, %: C 70.81; H 4.93;
N 9.01. C18H14N2O3. Calculated, %: C 70.58; H 4.61;
N 9.14.
3-{(Z)-2-(4-Bromobenzamido)-3-phenylprop-
2-enoyl]amino}propanoic acid (22). Reaction time
24 h. Yield 84%, mp 177‒180°C, Rf 0.67 (B). IR spec-
trum, ν, cm–1: 3390, 3249 (NH), 1733 (COOH), 1640
1
(C=O, amide). H NMR spectrum, δ, ppm: 2.47 t (2H,
CH2, J = 6.9 Hz), 3.40‒3.47 m (2H, NHCH2), 7.14 s
(1H, C=CH), 7.41‒7.55 m (7H, Harom), 7.94 t (1H,
NHCH2, J = 5.6 Hz), 7.95‒8.01 m (2H, Harom), 9.71 s
(1H, NH), 11.94 br.s (1H, COOH). Found, %: C 54.86;
H 4.33; Br 19.35; N 6.53. C19H17BrN2O4. Calculated,
%: C 54.69; H 4.11; Br 19.15; N 6.71.
4-{(Z)-2-(4-Bromobenzamido)-3-phenylprop-2-
enoyl]amino}butanoic acid (23). Reaction time 24 h.
Yield 76%, mp 175‒178°C, Rf 0.73 (B). IR spectrum,
ν, cm–1: 3227 (NH), 1735 (COOH), 1647 (C=O,
Acids 26‒40 were synthesized as described above
for compound 25 (method b).
3-[(4Z)-4-Benzylidene-5-oxo-2-phenyl-4,5-dihy-
dro-1H-imidazol-1-yl]propanoic acid (26). Reaction
time 10 min. Yield 81%, mp 200‒203°C, Rf 0.40 (A).
IR spectrum, ν, cm–1: 1739 (COOH), 1681 (C5=O),
1
amide). H NMR spectrum, δ, ppm: 1.73–1.83 m (2H,
CH2), 2.78 t (2H, CH2COOH, J = 7.3 Hz), 3.21–
3.29 m (2H, NHCH2), 7.14 s (1H, C=CH), 7.20–
7.33 m (3H, Harom), 7.42–7.57 m (2H, Harom), 7.58–
7.63 m (2H, Harom), 7.92–8.04 m (3H, Harom, NH),
9.69–9.78 s (1H, NH), 11.80 br.s (1H, COOH). Found,
%: C 55.91; H 4.67; Br 18.42; N 6.30. C20H19BrN2O4.
Calculated, %: C 55.70; H 4.44; Br 18.53; N 6.49.
1
1645 (C=C). H NMR spectrum, δ, ppm: 2.53‒2.58 m
(2H, CH2CO), 3.94‒4.00 m (2H, NCH2), 7.10 s (1H,
C=CH), 7.32‒7.44 m (3H, Harom), 7.50‒7.62 m (3H,
Harom), 7.81‒7.87 m (2H, Harom), 8.18‒8.26 m (2H,
Harom), 12.11 br.s (1H, COOH). Found, %: C 71.45;
H 5.31; N 853. C19H16N2O3. Calculated, %: C 71.24;
H 5.04; N 8.74.
6-{(Z)-2-(4-Bromobenzamido)-3-phenylprop-2-
enoyl]amino}hexanoic acid (24). Reaction time 24 h.
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SYNTHESIS AND ANTICHOLINESTERASE ACTIVITY
1375
(2C, CH), 129.4, 130.4 (CH), 133.9 (2C, CH), 136.5,
138.5, 160.4, 160.7, 170.1, 171.1. Found, %: C 68.79;
H 5.34; N 8.21. C20H18N2O4. Calculated, %: C 68.56;
H 5.18; N 7.99.
4-[(4Z)-4-Benzylidene-5-oxo-2-phenyl-4,5-dihy-
dro-1H-imidazol-1-yl]butanoic acid (27). Reaction
time 70 min. Yield 91%, mp 148‒150°C, Rf 0.47 (A).
IR spectrum, ν, cm–1: 1720 (COOH), 1702 (C5=O),
1
1645 (C=C). H NMR spectrum, δ, ppm: 1.79‒1.89 m
4-[(4Z)-4-(4-Methoxybenzylidene)-5-oxo-2-
phenyl-4,5-dihydro-1H-imidazol-1-yl]butanoic acid
(31). Reaction time 45 min. Yield 87%, mp 171‒
174°C, Rf 0.50 (A). IR spectrum, ν, cm–1: 1730
(2H, CH2), 2.22 t (2H, CH2CO, J = 7.0 Hz), 3.78‒
3.83 m (2H, NCH2), 7.09 s (1H, C=CH), 7.32–7.43 m
(3H, Harom), 7.53‒7.61 m (3H, Harom), 7.86‒7.92 m
(2H, Harom), 8.20‒8.25 m (2H, Harom), 11.87 br.s
(1H, COOH). Found, %: C 72.05; H 5.33; N 8.42.
C20H18N2O3. Calculated, %: C 71.84; H 5.43; N 8.38.
1
(COOH), 1703 (C5=O), 1641 (C=C). H NMR spec-
trum, δ, ppm: 1.78‒1.88 m (2H, CH2), 2.21 t (2H,
CH2CO, J = 7.0 Hz), 3.76‒3.82 m (2H, NCH2), 3.85 s
(3H, OCH3), 6.91‒6.96 m (2H, Harom), 7.06 s (1H,
C=CH), 7.51‒7.60 m (3H, Harom), 7.84‒7.90 m (2H,
6-[(4Z)-4-Benzylidene-5-oxo-2-phenyl-4,5-dihy-
dro-1H-imidazol-1-yl]hexanoic acid (28). Reaction
time 90 min. Yield 94%, mp 140‒142°C, Rf 0,53 (A).
IR spectrum, ν, cm–1: 1720 (COOH), 1682 (C5=O),
H
arom), 8.18‒8.23 m (2H, Harom), 11.80 br.s (1H,
COOH). Found, %: C 69.56; H 5.72; N 7.49.
C21H20N2O4. Calculated, %: C 69.25; H 5.53; N 7.69.
1
1641 (C=C). H NMR spectrum, δ, ppm: 1.21‒1.32 m
(2H, CH2), 1.45‒1.59 m (4H, CH2), 2.11 t (2H,
CH2CO, J = 7.3 Hz), 3.72‒3.77 m (2H, NCH2), 7.09 s
(1H, C=CH), 7.32‒7.43 m (3H, Harom), 7.53‒7.62 m
(3H, Harom), 7.79‒7.84 m (2H, Harom), 8.19‒8.24 m
(2H, Harom), 11.63 br.s (1H, COOH). Found, %:
C 73.07; H 6.31; N 7.54. C22H22N2O3. Calculated, %:
C 72.91; H 6.12; N 7.73.
6-[(4Z)-4-(4-Methoxybenzylidene)-5-oxo-2-
phenyl-4,5-dihydro-1H-imidazol-1-yl]hexanoic acid
(32). Reaction time 45 min. Yield 88%, mp 126‒
127°C, Rf 0.55 (A). IR spectrum, ν, cm–1: 1735
1
(COOH), 1706 (C5=O), 1633 (C=C). H NMR spec-
trum, δ, ppm: 1.20‒1.31 m (2H, CH2), 1.45‒1.58 m
(4H, CH2), 2.11 t (2H, CH2CO, J = 7.3 Hz), 3.71‒
3.76 m (2H, NCH2), 3.85 s (3H, OCH3), 6.91‒6.96 m
(2H, Harom), 7.06 s (1H, C=CH), 7.53–7.58 m (3H,
[(4Z)-4-(4-Methoxybenzylidene)-5-oxo-2-phenyl-
4,5-dihydro-1H-imidazol-1-yl]acetic acid (29).
Reaction time 30 min. Yield 92%, mp 216‒218°C,
Rf 0.22 (A). IR spectrum, ν, cm–1: 1733 (COOH), 1678
Harom), 7.77‒7.83 m (2H, Harom), 8.17‒8.22 m (2H,
Harom), 11.62 br.s (1H, COOH). Found, %: C 70.51;
1
(C5=O), 1633 (C=C). H NMR spectrum, δ, ppm:
H 6.24; N 7.30. C23H24N2O4. Calculated, %: C 70.39;
H 6.16; N 7.14.
3.86 s (3H, OCH3), 4.39 s (2H, NCH2), 6.92–6.97 m
(2H, Harom), 7.11 s (1H, C=CH), 7.50–7.59 m (3H,
2-[(4Z)-4-(4-Bromobenzylidene)-5-oxo-2-phenyl-
4,5-dihydro-1H-imidazol-1-yl]acetic acid (33). Reac-
tion time 25 min. Yield 93%, mp 251‒254°C, Rf 0.24
(A). IR spectrum, ν, cm–1: 1738 (COOH), 1688
H
H
arom), 7.76–7.82 m (2H, Harom), 8.20–8.25 m (2H,
arom), 11.90 br.s (1H, COOH). 13C NMR spectrum,
δC, ppm: 42.5 (NCH2), 54.7 (OCH3), 113.7 (2C, CH),
126.7, 127.6 (CH), 127.8 (2C, CH), 128.2 (2C, CH),
129.2, 130.4 (CH), 134.0 (2C, CH), 136.3, 160.1,
160.8, 168.8, 169.8. Found, %: C 67.45; H 4.39;
N 8.51. C19H16N2O4. Calculated, %: C 67.85; H 4.80;
N 8.33.
1
(C5=O), 1640 (C=C). H NMR spectrum, δ, ppm:
4.41 s (2H, CH2), 7.12 s (1H, C=CH), 7.52‒7.62 m
(5H, Harom), 7.77‒7.82 m (2H, Harom), 8.16‒8.21 m
(2H, Harom), 12.97 br.s (1H, COOH). 13C NMR spec-
trum, δC, ppm: 42.5 (CH2), 123.7, 125.8 (CH), 127.9
(2C, CH), 128.3 (2C, CH), 128.8, 130.9 (CH), 131.2
(2C, CH), 133.0, 133.5 (2C, CH), 138.6, 162.0, 168.6,
169.7. Found, %: C 56.41; H 3.55; Br 20.62; N 7.14.
C18H13BrN2O3. Calculated, %: C 56.13; H 3.40;
Br 20.74; N 7.27.
3-[(4Z)-4-(4-Methoxybenzylidene)-5-oxo-
2-phenyl-4,5-dihydro-1H-imidazol-1-yl]propanoic
acid (30). Reaction time 35 min. Yield 81%, mp 238‒
241°C, Rf 0.25 (A). IR spectrum, ν, cm–1: 1735
1
(COOH), 1703 (C5=O), 1640 (C=C). H NMR spec-
trum, δ, ppm: 2.52‒2.57 m (2H, CH2CO), 3.85 s (3H,
OCH3), 3.93‒3.99 m (2H, NCH2), 6.91‒6.96 m (2H,
3-[(4Z)-4-(4-Bromobenzylidene)-5-oxo-2-phenyl-
4,5-dihydro-1H-imidazol-1-yl]propanoic acid (34).
Reaction time 30 min. Yield 65%, mp 220‒223°C,
Rf 0.34 (A). IR spectrum, ν, cm–1: 1734 (COOH), 1692
Harom), 7.07 s (1H, C=CH), 7.53‒7.59 m (3H, Harom),
7.79‒7.85 m (2H, Harom), 8.17‒8.22 m (2H, Harom),
12.09 br.s (1H, COOH). 13C NMR spectrum, δC, ppm:
32.4 (CH2), 37.2 (NCH2), 54.6 (OCH3), 113.7 (2C,
CH), 126.8, 127.2 (CH), 127.9 (2C, CH), 128.2
1
(C5=O), 1644 (C=C). H NMR spectrum, δ, ppm:
2.52–2.57 m (2H, CH2CO), 3.94‒3.99 m (2H, NCH2),
7.07 s (1H, C=CH), 7.51‒7.63 m (5H, Harom), 7.80‒
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TOPUZYAN et al.
1376
7.86 m (2H, Harom), 8.13‒8.18 m (2H, Harom), 12.11 br.s
(1H, COOH). Found, %: C 57.42; H 3.91; Br 19.84;
N 7.31. C19H15BrN2O3. Calculated, %: C 57.16;
H 3.79; Br 20.01; N 7.02.
138.3, 161.2, 170.1, 171.2. Found, %: C 57.32; H 3.99;
Br 19.63; N 7.24. C19H15BrN2O3. Calculated, %:
C 57.16; H 3.79; Br 20.01; N 7.02.
4-[(4Z)-4-Benzylidene-2-(4-bromophenyl)-5-oxo-
4,5-dihydro-1H-imidazol-1-yl]butanoic acid (39).
Reaction time 40 min. Yield 98%, mp 155‒158°C,
Rf 0.55 (A). IR spectrum, ν, cm–1: 1726 (COOH), 1688
4-[(4Z)-4-(4-Bromobenzylidene)-5-oxo-2-phenyl-
4,5-dihydro-1H-imidazol-1-yl]butanoic acid (35).
Reaction time 30 min, yield 61%, mp 190‒192°C,
Rf 0.50 (A). IR spectrum, ν, cm–1: 1741 (COOH), 1691
1
(C5=O), 1642 (C=C). H NMR spectrum, δ, ppm:
1
(C5=O), 1636 (C=C). H NMR spectrum, δ, ppm:
1.78‒1.89 m (2H, CH2), 2.24 t (2H, CH2CO, J =
6.8 Hz), 3.76‒3.82 m (2H, NCH2), 7.11 s (1H, C=CH),
7.33‒7.44 m (3H, Harom), 7.69‒7.74 m (2H, Harom),
7.83‒7.88 m (2H, Harom), 8.19‒8.23 m (2H, Harom),
11.85 br.s (1H, COOH). 13C NMR spectrum, δ, ppm:
23.7 (CH2), 30.4 (CH2), 40.6 (NCH2), 125.1, 127.3
(CH), 128.0 (2C, CH), 128.1, 129.6 (CH), 130.0 (2C,
CH), 131.5 (2C, CH), 132.0 (2C, CH), 134.0, 138.3,
161.1, 170.2, 173.0. Found, %: C 58.40; H 4.26;
Br 19.10; N 6.59. C20H17BrN2O3. Calculated, %:
C 58.13; H 4.15; Br 19.33; N 6.78.
1.78–1.88 m (2H, CH2), 2.22 t (2H, CH2CO, J =
7.0 Hz), 3.77‒3.82 m (2H, NCH2), 7.07 s (1H, C=CH),
7.52‒7.62 m (5H, Harom), 7.86‒7.91 m (2H, Harom),
8.14‒8.19 m (2H, Harom), 11.82 br.s (1H, COOH).
Found, %: C 58.39; H 4.42; Br 19.04; N 6.53.
C20H17BrN2O3. Calculated, %: C 58.13; H 4.15;
Br 19.33; N 6.78.
6-[(4Z)-4-(4-Bromobenzylidene)-5-oxo-2-phenyl-
4,5-dihydro-1H-imidazol-1-yl]hexanoic acid (36).
Reaction time 30 min. Yield 88%, mp 151‒154°C,
Rf 0.44 (A). IR spectrum, ν, cm–1: 1709 (COOH), 1695
6-[(4Z)-4-Benzylidene-2-(4-bromophenyl)-5-oxo-
4,5-dihydro-1H-imidazol-1-yl]hexanoic acid (40).
Reaction time 20 min. Yield 97%, mp 147‒149°C,
Rf 0.62 (A). IR spectrum, ν, cm–1: 1713 (COOH),
1
(C5=O), 1640 (C=C). H NMR spectrum, δ, ppm:
1.21–1.31 m (2H, CH2), 1.45‒1.59 m (4H, CH2), 2.11 t
(2H, CH2CO, J = 7.3 Hz), 3.72‒3.77 m (2H, NCH2),
7.07 s (1H, C=CH), 7.52‒7.63 m (5H, Harom), 7.78‒
7.83 m (2H, Harom), 8.13‒8.18 m (2H, Harom), 11.62 br.s
(1H, COOH). Found, %: C 60.03; H 5.07; Br 18.00;
N 6.19. C22H21BrN2O3. Calculated, %: C 59.87;
H 4.80; Br 18.10; N 6.35.
1
1690 (C5=O), 1638 (C=C). H NMR spectrum, δ,
ppm: 1.21–1.33 m (2H, CH2), 1.47‒1.59 m (4H, CH2),
2.13 t (2H, CH2CO, J = 7.3 Hz), 3.74 t (2H, NCH2, J =
7.5 Hz), 7.11 s (1H, C=CH), 7.33‒7.43 m (3H, Harom),
7.69‒7.80 m (4H, Harom), 8.18‒8.23 m (2H, Harom),
11.65 br.s (1H, COOH). 13C NMR spectrum, δC, ppm:
23.7 (CH2), 25.4 (CH2), 28.3 (CH2), 33.1 (CH2), 40.8
(CH2), 125.1, 127.4 (CH), 128.0 (2C, CH), 128.3,
129.5 (CH), 129.7 (2C, CH), 131.5 (2C, CH), 132.0
(2C, CH), 133.9, 138.3, 161.1, 170.0, 173.5. Found, %:
C 60.03; H 5.12; Br 17.96; N 6.17. C22H21BrN2O3.
Calculated, %: C 59.87; H 4.80; Br 18.10; N 6.35.
[(4Z)-4-Benzylidene-2-(4-bromophenyl)-5-oxo-
4,5-dihydro-1H-imidazol-1-yl]acetic acid (37). Reac-
tion time 25 min. Yield 83%, mp 202‒205°C, Rf 0.25
(A). IR spectrum, ν, cm–1: 1741 (COOH), 1697
1
(C5=O), 1643 (C=C). H NMR spectrum, δ, ppm:
4.43 s (2H, CH2), 7.16 s (1H, C=CH), 7.35‒7.45 m
(3H, Harom), 7.68‒7.78 m (4H, Harom), 8.21‒8.26 m
(2H, Harom), 12.80 br.s (1H, COOH). Found, %:
C 56.32; H 3.67; Br 20.48; N 7.39. C18H13N2O3Br.
Calculated, %: C 56.13; H 3.40; Br 20.74; N 7.27.
(5Z)-5-Benzylidene-2-phenyl-3,5-dihydro-4H-
imidazol-4-one (41). a. A mixture of 1.0 g (3 mmol) of
{[(2Z)-2-benzamido-3-phenylprop-2-enoyl]amino}-
acetic acid (9) and 1.45 g (1.87 mL, 9 mmol) of
HMDS in 10 mL of DMF was refluxed for 3 h. The
mixture was cooled, diluted with 60 mL of water, and
acidified to pH 3 with aqueous HCl, and the precipitate
was filtered off, dried in air, and recrystallized from
benzene. Yield 0.42 g (57%). When the ratio 9–HMDS
was 1:5 (reaction time 2 h), the yield of 41 was
0.41 g (55%).
b. A mixture of 1.0 g (4 mmol) of 4-benzylidene-2-
phenyl-1,3-oxazol-5(4H)-one 1 and 1.6 g (2.87 mL,
10 mmol) of HMDS in 10 mL of DMF was refluxed
for 0.5 h. The mixture was then treated as described
above in a. Yield 91%, mp 295‒298°C, Rf 0.65 (A). IR
3-[(4Z)-4-Benzylidene-2-(4-bromophenyl)-5-oxo-
4,5-dihydro-1H-imidazol-1-yl]propanoic acid (38).
Reaction time 35 min. Yield 58%, mp 214‒217°C,
Rf 0.39 (A). IR spectrum, ν, cm–1: 1730 (COOH), 1685
1
(C5=O), 1641 (C=C). H NMR spectrum, δ, ppm:
2.54–2.60 m (2H, CH2CO), 3.93‒3.99 m (2H, NCH2),
7.11 s (1H, C=CH), 7.33‒7.44 m (3H, Harom), 7.69–
7.74 m (2H) and 7.77‒7.82 m (2H) (Harom), 8.18‒
8.23 m (2H, Harom), 12.15 br.s (1H, COOH). 13C NMR
spectrum, δC, ppm: 32.3 (CH2), 37.4 (NCH2), 125.1,
127.4 (CH), 128.0 (2C, CH), 128.2, 129.6 (CH), 130.0
(2C, CH), 131.5 (2C, CH), 132.0 (2C, CH), 133.9,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

SYNTHESIS AND ANTICHOLINESTERASE ACTIVITY
1377
spectrum, ν, cm–1: 3128 (NH), 1720 (C4=O), 1643
(C=C). H NMR spectrum, δ, ppm: 6.93 s (1H,
C=CH), 7.32‒7.45 m (3H, Harom), 7.47‒7.58 m (3H,
Harom), 8.17‒8.21 m (2H, Harom), 8.23‒8.27 m (2H,
Harom), 11.91 s (1H, NH). Found, %: C 77.59; H 5.03;
N 11.01. C16H12N2O. Calculated, %: C 77.40; H 4.87;
N 11.28.
0.02 mL of a 0.01 M solution of compound 9–44 in
ethanol. In control experiments, a solution containing
AChE or BChE and 3,3′-disulfanediylbis(6-nitroben-
zoic acid) was incubated for 10 min at 25°C, its
absorbance was measured, acetylthiocholine was then
added, the solution was incubated for 20 min at 25°C,
and its absorbance was measured again. Test experi-
ments were carried out in a similar way in the presence
of compound 9–44. The inhibitory activity (%) was
calculated by the formula I = [(Acontrol ‒ Atest)/Acontrol]×
100, where Acontrol is the difference between the two
absorbances measured in control experiment, and
Atest is the difference between the two absorbances
measured in test experiment.
1
Compounds 42–44 were synthesized as described
above for imidazolone 41 (method b).
(5Z)-5-(4-Methoxybenzylidene)-2-phenyl-3,5-di-
hydro-4H-imidazol-4-one (42). Reaction time 60 min.
Yield 72%, mp 298‒301°C, Rf 0.49 (A). IR spectrum,
ν, cm–1: 3130 (NH), 1702 (C4=O), 1643 (C=C).
1H NMR spectrum, δ, ppm: 3.87 s (3H, OCH3), 6.91 s
(1H, C=CH), 6.93‒6.98 m (2H, Harom), 7.45‒7.55 m
(3H, Harom), 8.14‒8.19 m (2H, Harom), 8.20‒8.25 m
(2H, Harom), 11.81 br.s (1H, NH). Found, %: C 73.58;
H 5.45; N 9.84. C17H14N2O2. Calculated, %: C 73.37;
H 5.07; N 10.06.
REFERENCES
1. Sadula, A., Peddabiona, U.R., and Subhashini, P.N.,
J. Med. Chem. Res., 2015, vol. 24, p. 851.
2. Voosala, C., Yaria, N.S., Nakka, M.R., and Vidava-
luri, S., Med. Chem., 2013, vol. 4, p. 303.
3. Solankee, A., Patel, G., and Patel, K., Indian J. Chem.,
Sect. B, 2011, vol. 50, p. 949.
4. Kaila, V.J., Desai, D.J., Patel, K.D., and Chuda-
sama, C.J., Orient. J. Chem., 2008, vol. 24, p. 589.
5. Topuzyan, V.O., Oganesyan, A.A., and Panosyan, G.A.,
(5Z)-5-(4-Bromobenzylidene)-2-phenyl-3,5-dihy-
dro-4H-imidazol-4-one (43). Reaction time 60 min.
Yield 68%, mp 333‒337°C, Rf 0.53 (A). IR spectrum,
ν, cm–1: 3155 (NH), 1706 (C4=O), 1640 (C=C).
1H NMR spectrum, δ, ppm: 6.89 s (1H, C=CH), 7.47‒
7.58 m (5H, Harom), 8.16‒8.21 m (4H, Harom), 11.96 br.s
(1H, NH). Found, %: C 58.91; H 3.55; Br 24.03;
N 8.39. C16H11BrNO2. Calculated, %: C 58.74; H 3.39;
Br 24.42; N 8.56.
Russ. J. Org. Chem., 2004, vol. 40, p. 1644.
6. Topuzyan, V.O., Arutyunyan, L.G., and Ogane-
syan, A.A., Russ. J. Org. Chem., 2007, vol. 43, p. 868.
7. Topuzyan, V.O., Arutyunyan, L.G., Oganesyan, A.A.,
and Panosyan, G.A., Russ. J. Org. Chem., 2007, vol. 43,
p. 936.
8. Topuzyan, V.O., Arutyunyan, L.G., Oganesyan, A.A.,
and Panosyan, G.A., Russ. J. Org. Chem., 2008, vol. 44,
p. 474.
9. Topuzyan, V.O., Kazandzhyan, M.M., Tamazyan, R.A.,
and Aivazyan, A.G., Russ. J. Org. Chem., 2009, vol. 45,
p. 215.
10. Tosunyan, S.R., Khim. Zh. Arm., 2012, vol. 66, p. 316.
11. Muselli, M., Colombeau, L., Hedouin, J., Hoarau, C.,
and Bischoff, L., Synlett, 2016, vol. 27, p. 2819.
(5Z)-5-Benzylidene-2-(4-bromophenyl)-3,5-dihy-
dro-4H-imidazol-4-one (44). Reaction time 60 min.
Yield 56%, mp 330‒333°C, Rf 0.55 (A). IR spectrum,
ν, cm–1: 3156 (NH), 1698 (C4=O), 1642 (C=C).
1H NMR spectrum, δ, ppm: 6.96 s (1H, C=CH), 7.32‒
7.44 m (3H, Harom), 7.63‒7.68 m (2H, Harom), 8.08‒
8.13 m (2H, Harom), 8.20‒8.26 m (2H, Harom), 11.94 br.s
(1H, NH). Found, %: C 58.59; H 3.62; Br 24.09;
N 8.67. C16H11BrNO2. Calculated, %: C 58.74; H 3.39;
Br 24.42; N 8.56.
The anticholinesterase activity of compounds 9–
44 against human erythrocyte acetylcholinesterase and
plasma butyrylcholinesterase was evaluated according
to the procedure described in [15]. The measurements
were performed by spectrophotometry with a Specord
UV-Vis instrument at λ 412 nm in a cell maintained at
a constant temperature. The final sample volume was
2.5 mL; samples contained 1.25 mL of distilled water,
1 mL of 0.1 M phosphate buffer (pH 7.6 ± 0.1);
0.02 mL (0.005 mol) of 3,3′-disulfanediylbis(6-nitro-
benzoic acid), 0.005 mL (0.005 mol) of acetylthio-
choline, 0.01 mL of the corresponding enzyme, and
12. Topuzyan, V.O., Akopyan, A.Z., Durgaryan, L.K.,
Vlasenko, E.V., Paronikyan, R.G., Paronikyan, R.V., and
Ter-Zakharyan, Yu.Z., Pharm. Chem. J., 1995, vol. 29,
no. 3, p. 200.
13. Sheldrick, G.M., Acta Crystallogr., Sect. C, 2015,
vol. 71, p. 3.
14. Topuzyan, V.O. and Tosunyan, S.R., Khim. Zh. Arm.,
2012, vol. 65, p. 369.
15. Aziz-ur-Rehman, Afroz, S., Abbasi, M.A., Tanveer, W.,
Khan, K.M., Ashraf, M., Ahmad, I., Afzal, I., and
Ambreen, N., Pak. J. Pharm. Sci., 2012, vol. 25, no. 4,
p. 809.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018