Design, Synthesis, Anti-Cancer Activity, and in silico Studies of Novel Imidazo[1,2-a]pyridine Derivatives

Article abstract of DOI:10.1134/S1070363220090212

Abstract: A novel series of imidazo [1,2-a]pyridinederivatives has been designed, synthesized and tested for the anti-proliferativeactivity against three different human cancer cell lines. Most of thesynthesized compounds exhibit anti-proliferative activi

Full text of DOI:10.1134/S1070363220090212

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 9, pp. 1727–1736. © Pleiades Publishing, Ltd., 2020.
Design, Synthesis, Anti-Cancer Activity, and in silico Studies
of Novel Imidazo[1,2-a]pyridine Derivatives
a
a
a
b
a,
S. Endoori , K. C. Gulipalli , S. Bodige , J. N. Narendra Sharath Chandra , and N. Seelam *
a
Department of Chemistry, Koneru Lakshmaiah Education Foundation, Green Fields, Vaddeswaram, Guntur, 522502 India
b
Department of Pharmaceutical Chemistry, Gurukrupa Institute of Pharmacy, Maharashtra, 431129 India
*
e-mail: nareshvarma.klu@gmail.com
Received July 27, 2020; revised August 18, 2020; accepted September 9, 2020
Abstract—A novel series of imidazo [1,2-a]pyridine derivatives has been designed, synthesized and tested for
the anti-proliferative activity against three different human cancer cell lines. Most of the synthesized compounds
exhibit anti-proliferative activity with IC50 values ranging from 5.35–59.8 μM. Six compounds demonstrate ef-
ficient inhibition of growth of all cell lines with IC50 values close to that of standard drug, and the compound 16h
is more potent than the standard drug cisplatin for the HeLa cell line.
Keywords: synthesis, imidazo[1,2-a]pyridine, anticancer activity, molecular docking
DOI: 10.1134/S1070363220090212
INTRODUCTION
isoindoline-1,3-dione (6). Reduction of the intermediate
in presence of Na S O led to the crucial intermediate 7
6
2
2
4
Imidazopyridine derivatives possess a vast variety
which was used in reductive amination with compounds
and 13 followed by pathalimide deprotection with
of biological activities [1] including antifungal, anti-
inflammatory, antitumor, and many more [2–5]. Various
drugs containing imidazo[1,2-a]pyridine scaffold are
currently available on the market [6–9].
8
hydrazine hydrate which gave intermediates 9 and 15,
respectively. Finally, the latter compounds 9 and 15
reacted with aryl isocyanates 11a–11j in presence of TEA
with formation of the corresponding target compounds
Urea derivatives have attracted close attention as
building blocks in the molecules of anticancer agents
due to their significant inhibitory activity against protein
tyrosine kinases (PTKs), DNAtopoisomerase, Raf kinase,
and NADH oxidase, that play a vital role in the cell
proliferation [10]. Sorafenib, a diaryl urea derivative has
been reported to inhibit several kinases, such as VEGFR
1
2a–12j (Scheme 1) and 16a–16j (Scheme 2).
Anticancer activity. In vitro anti-proliferative activity
of all synthesized compounds 12a–12j and 16a–16j
was assessed by the MTT colorimetric assay [12, 13]
against MCF-7 (human breast adenocarcinoma) cell
line, HeLa (human cervix) cell line and HT-29 (human
colorectal adenocarcinoma) cell lines (Table 1) using
the anticancer drug cisplatin as a reference. Among the
tested compounds, the product 16h containing 4-CF3-
phenyl ring exhibited potent inhibitory activity against
HeLa, MCF-7, and HT-29 cell lines with IC values of
(
vascular endotheliael growth factor receptor), Raf and
platelet derived growth factor receptor [11].
Shuch important chemotherapeutic activities of
both pharmacophores (imidazo[1,2-a]pyridine and urea
moieties) gave an impulse to our design and synthesys of
anticancer agents with enhanced potency and/or reduced
toxicity.
50
11.26, 5.35, and 9.30 μM, respectively. Replacement of
4-CF -phenyl ring with 4-OCF -phenyl ring in 16i led
3
3
to decreased anticancer activity, but the activity was still
RESULTS AND DISCUSSION
essentially retained. Replacement of 4-OCF -phenyl ring
3
Synthesis of target molecules was achieved in seven
steps, starting with treatment of 2-amino pyridine
with 4-OCH -phenyl in 16c led to further decrease in
3
anticancer activity. Compounds with 4-OCH , 2-OCH ,
3
3
(
2
1) by 1,3-dichloroacetone (2) and formation of
-(chloromethyl)imidazo[1,2-a]pyridine (3), which upon
nitration followed by coupling with potasium pthalimide
5) gave 2-[(3-nitroimidazo[1,2-a]pyridin-2-yl)methyl]-
and 4-OCF substituents (12c, 12d and, 12i) displayed
3
moderate antiproliferative activity against all three tested
cancer cell lines. It is important to note that compound
16h was more potent than the standard drug cisplatin
(
1
727

1728
ENDOORI et al.
Scheme 1. Synthesis of the title compounds 12a–12j.
for the HeLa cell line with IC value of 11.26 μM. The
were docked on the active site of PI3K . This provided
5
0
α
accumulated data, would be a basis of the following
SAR studies.
guidance for selection of derivatives to be synthesized for
better PI3K inhibitors. The selective protein retrieved
α
Molecular docking. The possible binding mode
from the data bank (PDB: 4EPW) was used for this
purpose. All docking procedures were carried out by
MOE (Molecular Operating Environment) software
2008.10. All synthesized compounds were fit into the
of designed compounds in the PI3K active site was
α
approached by molecular docking studies. Imidazo [1,2-
a]pyridine derivatives selected from chemexper studies
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 9 2020

DESIGN, SYNTHESIS, ANTI-CANCER ACTIVITY, AND IN SILICO STUDIES
Scheme 2. Synthesis of the title compounds 16a–16j.
1729
1
3
active site of PI3K enzyme and demonstrated good in
C NMR spectra were measured on a Bruker AMX
α
1
vitro PI3K inhibitory activity, suggesting high potency of
300 spectrometer operating at 400/300 MHz for H and
1
Mass spectra were measured on an Agilent technologies
Mass spectrometer.
α
13
the synthesized compounds. The sample docking results
are presented in Fig. 1.
00 MHz for C NMR using TMS as an internal standard.
EXPERIMENTAL
2
-(Chloromethyl)imidazo[1,2-a]pyridine (3). A
mixture of compounds 1 (30.0 g, 0.319 mol) and 2
40.19 g, 0.319 mol) in ethanol (160 mL) was refluxed
All chemicals were purchased from Sigma–Aldrich
and Combi-blocks and used without further purification.
Melting points were uncorrected and determined in one
end open capillary tubes using a Guna Digital Melting
Point apparatus. Elemental analyses were carried out on
(
for 16 h, then cooled down to room temperature and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (100–
1
a Perkin-Elmer 240 CHN elemental analyzer. H and
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 9 2020

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ENDOORI et al.
Table 1. In vitro anti-proliferative activity of the synthesized compounds 12a–12j and 16a–16j
IC , ꢀg/mL
IC , ꢀg/mL
5
0
50
Compound
2a
2b
2c
2d
2e
2f
2g
Compound
HeLa
36.25
25.82
13.58
15.23
16.35
18.29
21.68
18.21
14.56
15.22
MCF-7
42.28
38.26
7.28
HT-29
59.83
42.25
11.57
14.25
16.51
26.85
18.25
13.86
12.25
12.23
HeLa
32.89
20.89
13.68
14.25
19.23
22.52
25.36
11.26
12.82
29.19
11.56
MCF-7
36.56
25.63
7.56
10.89
15.36
25.38
28.36
5.35
HT-29
42.36
29.25
11.85
13.58
19.34
29.51
31.67
9.30
1
1
1
1
1
1
1
16a
16b
16c
16d
16e
9.57
11.69
22.39
23.58
11.34
10.05
10.31
16f
16g
1
2h
16h
1
2i
16i
6.25
30.26
4.05
13.23
32.66
8.07
1
2j
16j
Cisplatin
2
2
00 mesh), eluted by EtOAc : hexanes (1 : 1) to afford
(98%) (30.0 mL, 0.72 mol) dropwise over a period of
60 min. The resulting reaction mixture was warmed up
to ambient temperature and stirred for another 2 h then
poured onto crushed ice (600 mL). The aqueous layer
was extracted with dichloromethane (500×2 mL), the
combined organic layers were washed with saturated
-(chloromethyl)imidazo[1,2-a]pyridine (3) as a alight
1
brown solid, yield 82%. H NMR (CDCl ) spectrum, δ,
ppm: 4.77 s (2H, CH Cl), 6.79 t (1H, J = 6.6 Hz, H ),
7
3
2
Ar
.18 t (1H, J = 7.8 Hz, H ), 7.57 d (1H, J = 9.0 Hz, H ),
Ar Ar
7.61 s (1H, H ), 8.07 d (1H, J = 6.9 Hz, H ). Found, %: C
Ar Ar
5
7.61; H 4.15; Cl 21.22, N 16.79. C H ClN Calculated,
8 7 2.
NaHCO solution (300 mL), brine (300 mL), dried over
3
%
: C 57.67; H 4.23; Cl 21.28, N 16.81. MS (m/z): 167.1
Na SO and concentrated under reduced pressure. The
residue was triturated in MeOH (150 mL), filtered off and
2
4
+
[М + Н] .
2
-(Chloromethyl)-3-nitroimidazo[1,2-a]pyridine
dried under vaccum to afford pure product 4 as a yellow
1
(
4). To a solution of compound 3 (40.0 g, 0.240 mol) in
solid, yield 67%. H NMR (CDCl ) spectrum, δ, ppm:
3
H SO (100 mL) cooled to 0°C was added fuming HNO
5.13 s (2H, CH Cl), 7.33 t (1H, J = 7.2 Hz, H ), 7.69 t
2
4
3
2
Ar
Fig. 1. (a) Three-dimensional representation of the interacting mode of 16h on PI3K enzyme and (b) two-dimensional representation
of the interacting mode of 16h on PI3K enzyme.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 9 2020

DESIGN, SYNTHESIS, ANTI-CANCER ACTIVITY, AND IN SILICO STUDIES
1731
(
1H, J = 7.2 Hz, H ), 7.87 d (1H, J = 8.7 Hz, H ), 9.45 d
layer was extracted with dichloromethane (300×2 mL),
the combined organic layers were washed with brine
(100 mL), dried over Na SO and concentrated under
Ar
Ar
(1H, J = 7.2 Hz, H ). Found, %: C 45.39; H 2.89; Cl
Ar
1
6.79, N 19.79; O 15.06. C H ClN O . Calculated, %:
8 6 3 2
2
4
C 45.41; H 2.86; Cl 16.75, N 19.86; O 15.12. MS (m/z):
reduced pressure. The residue was purified by column
chromatography by silica gel (100–200 mesh, MeOH :
+
2
12.1 [М + H] .
-[(3-Nitroimidazo[1,2-a]pyridin-2-yl)methyl]-
isoindoline-1,3-dione (6). A mixture of compound 4
19.0 g, 0.09 mol) with potassium 1,3-dioxoisoindolin-2-
DCM = 2 : 98) to afford the pure product 9 as yellow solid,
2
1
yield 68%. H NMR spectrum (DMSO-d ), δ, ppm: 0.00
6
br. s (4H, 2CH ), 0.27 br. s (4H, 2CH ) 0.85 m (2H, 2CH),
(
2
2
3
.08 d (4H, J = 6.9 Hz, 2CH N), 4.89 s (2H, CH N), 6.85 t
ide (5) (18.3 g, 0.10 mol) in DMF(100 mL) was heated
at 90°C for 3 h. The reaction mixture was cooled down
to room temperature and diluted with water (800 mL),
the resulted solids were filtered off, washed with water
2 2
(
1H, J = 6.9 Hz, H ), 7.13 t (1H, J = 6.9 Hz, H ), 7.32 d
Ar Ar
(
1H, J = 8.7 Hz, H ), 7.85–7.90 m (4H, H ), 8.31 d (1H,
Ar
Ar
J = 6.6 Hz, H ). Found, %: C 71.91; H 5.96; N 13.05;
Ar
O 7.88. C H N O . Calculated, %: C 71.98; H 6.04; N
(
500 mL) and dried under vaccum to afford pure
24 24
4
2
+
1
1
3.99; O 7.99. MS (m/z): 401.1 [М + H] .
compound 6 as a brown solid, yield 79%. H NMR
spectrum (DMSO-d ), δ, ppm: 5.30 s (2H, CH N), 7.48 t
6
2
2-(Aminomethyl)-N,N-bis(cyclopropylmethyl)
(
(
5
%
1H, J = 6.9 Hz, H ), 7.76–7.88 m (2H, H ), 7.90–7.99 m
imidazo[1,2-a]pyridin-3-amine (10). A suspension of
compound 9 (4.50 g, 0.012 mol) in ethanol (90 mL) was
mixed with hydrazine hydrate (98%) (5.8 mL, 0.12 mol)
at room temperature and heated at 90°C for 1 h, then
cooled down to room temperature. The solids formed
were filtered off, the filtered cake was washed with DCM
Ar
Ar
4H, H ), 9.39 d (1H, J = 6.9 Hz, H ). Found, %: C
Ar Ar
9.58; H 3.11; N 17.32; O 19.88. C H N O Calculated,
16
10
4
4.
: C 59.63; H 3.13; N 17.38; O 19.86. MS (m/z): 323.1
+
[
М + H] .
-[(3-Aminoimidazo[1,2-a]pyridin-2-yl)methyl]-
isoindoline-1,3-dione (7). A suspension of compound 6
20.0 g, 0.062 mol) in a mixture of MeOH (200 mL) with
THF (100 mL) was charged with a solution of Na S O in
2
(50 mL), the combined filtrate was concentrated under
reduced pressure to give compound 10 as yellow gel, yield
(
1
8
6%. H NMR spectrum (DMSO-d ), δ, ppm: –0.10 br. s
6
2
2
4
water (100 mL) at room temperature and heated to 85°C
for 16 h. The reaction mixture was cooled down to room
temperature and concentrated under reduced pressure
until MeOH and THF were evaporated. The residue was
diluted with an excess of water (600 mL), the resulted
solids were filtered off, washed with an excess of water
(4H, 2CH2), 0.24 br. s (4H, 2CH2), 0.73–0.80 m (2H,
2HC), 2.97 d (4H, J = 6.8 Hz, 2CH2N), 3.77 s (2H, CH2N),
6.82–6.86 m (1H, HAr), 7.12–7.16 m (1H, HAr), 7.39 d
(1H, J = 9.2 Hz, HAr), 8.28 d (1H, J = 6.8 Hz, HAr). Found,
%: C 71.11; H 8.26; N 20.59. C16H22N4. Calculated, %:
+
C 71.08; H 8.20; N 20.72. MS (m/z): 271.1 [М + H] .
and dried under vaccuum to afford pure compound 7 as a
2
-{[3-(Isobutylamino)imidazo[1,2-a]pyridin-2-yl]-
1
brown solid, yield 85%. H NMR spectrum (DMSO-d ),
6
methyl}isoindoline-1,3-dione (14). A suspension of
compound 7 (5.00 g, 0.0171 mol, ) with isobutyraldehyde
13 (1.35 g, 0.0188 mol) in DCE (100 mL) was mixed with
AcOH (1.95 mL, 0.0342 mol) at room temperature and
stirred for 1 h. The reaction mixture was cooled down to
δ, ppm: 4.88 s (2H, CH N), 4.92 s (2H, NH ), 6.79 t (1H,
2
2
J = 6.6 Hz, H ), 6.97 t (1H, J = 7.2 Hz, H ), 7.26 d (1H,
Ar
Ar
J = 9.0 Hz, H ), 7.83–7.90 m (4H, H ), 8.04 d (1H, J =
Ar
Ar
6
1
1
.9 Hz, H ). Found, %: C 65.71; H 4.08; N 19.11; O
Ar
0.89. C H N O . Calculated, %: C 65.75; H 4.14; N
1
6
12
4
2
0°C and Na(OAc) BH (10.87 g, 0.0513 mol) was added
3
+
9.17; O 10.95. MS (m/z): 293.1 [М + H] .
-({3-[Bis(cyclopropylmethyl)amino]imi-
dazo[1,2-a]pyridin-2-yl}methyl)isoindoline-1,3-dione
9). A suspension of compounds 7 (5.00 g, 0.0171 mol)
portions wise. Upon completion of addition the reaction
mixture was warmed up to ambient temperature and
stirred for 16 h, then cooled down to 0°C and diluted
2
(
with saturated NaHCO solution (60.0 mL). The aqueous
3
and 8 (3.63 g, 0.0376 mol) in DCE (100 mL) was charged
with AcOH (1.95 mL, 0.0342 mol) at room temperature
and stirred for 1 h. The reaction mixture was cooled to
layer was extracted with dichloromethane (300×2 mL),
the combined organic layers were washed with brine
(100 mL), dried over Na SO and concentrated under
2
4
0
°C and Na(OAc) BH (10.87 g, 0.0513 mol) was added
reduced pressure. The residue was purified by column
chromatography(silicagel100–200mesh,MeOH:DCM=
3
portion wise. Upon completion of the addition reaction
the mixture was warmed up to ambient temperature and
stirred for 16 h, then cooled down to 0°C and diluted
2 : 98) to afford pure compound 14 as a yellow solid, yield
1
65%. H NMR (CDCl ) spectrum, δ, ppm: 1.11 d (6H,
3
with saturated NaHCO solution (60.0 mL). The aqueous
J = 6.6 Hz, 2CH ), 1.88–1.97 m (1H, HC), 2.84 t (2H,
3
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 9 2020

1732
ENDOORI et al.
J = 6.6 Hz, CH NH), 4.20 t (1H, J = 6.6 Hz, NH), 4.99 s
H 6.88; N 17.11; O 4.08. C H N O. Calculated, %: C
23 27 5
70.92; H 6.99; N 17.98; O 4.11. MS (m/z): 390.2 [М + H] .
2
+
(
2H, CH N), 6.74 t (1H, J = 6.6 Hz, H ), 7.06 t (1H, J =
2
Ar
6
.9 Hz, H ), 7.48 d (1H, J = 10.5 Hz, H ), 7.67 q (2H,
Ar Ar
1-({3-[Bis(cyclopropylmethyl)amino]imidazo-
J = 3.3 Hz, H ), 7.82 t (2H, J = 4.8 Hz, H ), 7.98 d (d,
J = 6.3 Hz, H ). Found, %: C 68.91; H 5.68; N 16.11;
Ar
Ar
[1,2-a]pyridin-2-yl}methyl)-3-(4-bromophenyl)urea
1
Ar
(12b). Yield 76%, mp 170-172°C. H NMR spectrum
O 9.11. C H N O . Calculated, %: C 68.95; H 5.79; N
(DMSO-d ), δ, ppm: –0.00 br. s (4H, 2CH ), 0.28 br. s
20
20
4
2
6
2
+
1
6.08; O 9.18. MS (m/z): 349.1 [М + H] .
-(Aminomethyl)-N-isobutylimidazo[1,2-a]-
pyridin-3-amine (15). A suspension of compound 14
3.50 g, 0.010 mol) in ethanol (90 mL) was mixed with
(4H, 2CH ), 0.81–0.83 m (2H, 2CH), 3.07 d (4H, J =
2
4
.8 Hz, 2CH N), 4.46 d (2H, J = 4.8 Hz,ArCH ), 6.59 br. s
2
2
2
(
1H, NH), 6.94 t (1H, J = 6.6 Hz, H ), 7.26 t (1H, J =
Ar
7
6
.2 Hz, H ), 7.43–7.50 m (5H, H ), 8.38 d (1H, J =
Ar Ar
(
1
3
.9 Hz, H ), 8.90 s (1H, NH). C NMR spectrum
hydrazine hydrate (98%) (4.8 mL, 0.10 mol) at room
temperature and heated at 90°C for 1 h. The reaction
mixture was cooled down to room temperature, the
precipitated solids were filtered off, the filter cake was
washed with DCM (50 mL), the combined filtrate was
Ar
(
DMSO-d ), δ , ppm: 3.0, 10.1, 36.6, 58.5, 111.3, 112.2,
6 C
1
1
1
16.3, 119.3, 123.5, 123.8, 127.7, 131.3, 136.8, 139.9,
40.6, 154. Found, %: C 59.11; H 5.56; Br, 17.01; N
4.88; O 3.39. C H BrN O. Calculated, %: C 58.98;
2
3
26
5
H 5.60; Br, 17.06; N 14.95; O 3.42. MS (m/z): 468.1
concentrated under reduced pressure to afford compound
+
1
[М + 2H] .
1
5 as a yellow gel, yield 87%. H NMR (CDCl ) spectrum,
3
1
-({3-[Bis(cyclopropylmethyl)amino]imidazo-
δ, ppm: 1.10 d (6H, J = 6.6 Hz, 2CH ), 1.88–1.97 m (1H,
3
[
(
(
(
1,2-a]pyridin-2-yl}methyl)-3-(4-methoxyphenyl)urea
12c). Yield 78%, mp 150–152°C. H NMR spectrum
CH), 2.84 t (J= 7.2 Hz, CH NH), 3.90 s (2H, CH N), 4.20 t
2
2
1
(
1H, J = 6.6 Hz, NH), 6.82–6.85 m (1H, H ), 7.12–7.16 m
Ar
DMSO-d ), δ, ppm: –0.00 br. s (4H, 2CH ), 0.28 br. s
(
1H, H ), 7.39 d (1H, J = 6.9 Hz, H ), 8.28 d (1H,
6
2
Ar
Ar
4H, 2CH ), 0.77–0.83 m (2H, 2CH), 3.06 d (4H, J =
J = 5.1 Hz, H ). Found, %: C 66.11; H 8.52; N 25.11.
2
Ar
6
.3 Hz, 2CH N), 3.74 s (3H, OCH ), 4.44 d (2H, J =
C H N . Calculated, %: C 66.02; H 8.31; N 25.67. MS
2 3
1
2
18
4
+
4.8 Hz, ArCH ), 6.41 br. s (1H, NH), 6.86 d (2H, J =
(
m/z): 219.1 [М + H] .
2
8
.7 Hz, H ), 6.93 t (1H, J = 6.6 Hz, H ), 7.25 t (1H,
Ar Ar
Synthesis of title compounds 12a–12j and 16a–16j.
J = 7.2 Hz, H ), 7.33 d (2H, J = 8.7 Hz, H ), 7.48 d (1H,
Ar
Ar
To an ice cold solution of an appropriate amine
1.00 mmol) in dichloromethane (10 mL) were added
TEA (3.00 mmol) and a solution of an aryl isocyanate
1.10 mmol) in dichloromethane (4.0 mL), and the mixture
J = 4.5 Hz, H ), 8.37 d (1H, J = 6.9 Hz, H ), 8.54 s
Ar
Ar
(
1
3
(
1H, NH). C NMR (CDCl ) spectrum, δ , ppm: 3.4,
3 C
1
0.3, 14.1, 22.7, 29.3, 29.7, 31.9, 37.5, 55.5, 59.6, 111.6,
(
114.1, 116.4, 121.7, 123.3, 124.5, 129.0, 132.7, 136.9,
was stirred at room temperature for 2 h, then diluted
with water (20 mL) and extracted with dichloromethane
1
7
1
41.5, 155.3. Found, %: C 68.79; H 6.93; N 16.58; O
.58. C H N O . Calculated, %: C 68.71; H 6.97; N
2
4
29
5
2
(
(
3×20 mL). The organic layer was washed with H O
+
2
6.69; O 7.63. MS (m/z): 420.2 [М + H] .
20 mL), brine solution (10 mL), dried over Na SO , and
2
4
1
-({3-[Bis(cyclopropylmethyl)amino]imidazo-
concentrated. The obtained crude product was purified
by flash column chromatography (MeOH : DCM =
[
(
(
(
1,2-a]pyridin-2-yl}methyl)-3-(2-methoxyphenyl)urea
12d). Yield 72%, mp 120–122°C. H NMR spectrum
1
2
: 98) to afford the corresponding pure title compounds
as off white solids.
-({3-[Bis(cyclopropylmethyl)amino]imidazo-
1,2-a]pyridin-2-yl}methyl)-3-phenylurea (12a). Yield
DMSO-d ), δ, ppm: –0.05 br. s (4H, 2CH ), 0.22 br. s
6
2
4H, 2CH ), 0.76–0.79 m (2H, 2CH), 3.01 d (4H, J =
2
1
6
.4 Hz, 2CH N), 3.81 s (3H, OCH ), 4.39 d (2H, J =
2 3
[
8
5
.2 Hz, ArCH ), 6.80–6.89 m (3H, H ), 6.94 d. d (1H,
2
Ar
1
7%, mp 160–162°C. H NMR spectrum (DMSO-d ),
6
J = 8.0 Hz, J = 2.4 Hz, H ), 7.17–7.21 m (1H, H ),
1 2 Ar Ar
δ, ppm: –0.05 br. s (4H, 2CH ), 0.23 br. s (4H, 2CH ),
2
2
7.25 t (1H, J = 4.8 Hz, NH), 7.42 d (1H, J= 9.2 Hz, HAr),
8.08 d. d (1H, J = 7.2 Hz, J = 2.0 Hz, H ), 8.16 s (1H,
0
4
6
.75–0.79 m (2H, 2CH), 3.01 d (4H, J = 4.8 Hz, 2CH N),
2
1
2
Ar
1
3
.40 d (2H, J = 4.8 Hz,ArCH ), 6.48 br. s (1H, NH), 6.86–
NH), 8.33 d (1H, J = 7.2 Hz, H ). C NMR (CDCl )
2
Ar 3
.90 m (2H, H ), 7.17–7.24 m (3H, H ), 7.36–7.45 m
spectrum, δ , ppm: 3.4, 10.3, 29.7, 37.4, 55.2, 59.7, 109.8,
Ar
Ar
C
(
3H, H ), 8.32 d (1H, J = 6.9 Hz, H ), 8.69 br. s (1H,
111.4, 116.6, 118.9, 120.9, 121.3, 123.2, 124.0, 128.9,
129.5, 136.8, 141.5, 147.7, 156.0. Found, %: C 68.76;
H 6.91; N 16.56; O 7.56. C H N O . Calculated, %: C
Ar
3
Ar
1
NH). C NMR spectrum (DMSO-d ), δ , ppm: 3.0, 10.1,
3
1
6
C
6.6, 58.6, 111.3, 116.3, 117.4, 120.9,123.5, 123.8, 127.7,
28.6, 137.0, 140.5, 140.6, 155.0. Found, %: C 70.86;
2
4
29
5
2
+
68.71; H 6.97; N 16.69; O 7.63. MS (m/z): 420.2 [М + H] .
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 9 2020

DESIGN, SYNTHESIS, ANTI-CANCER ACTIVITY, AND IN SILICO STUDIES
1733
1
-({3-[Bis(cyclopropylmethyl)amino]imidazo-
%: C 72.36; H 7.71; N 16.23; O 3.71. MS (m/z): 432.3
[М + H] .
+
[
(
(
(
6
4
1,2-a]pyridin-2-yl}methyl)-3-(3-methoxyphenyl)urea
12e). Yield 77%, mp 130–132°C. H NMR spectrum
DMSO-d ), δ, ppm: –0.03 br. s (4H, 2CH ), 0.24 br. s
4H, 2CH ), 0.78–0.82 m (2H, 2CH), 3.03 d (4H, J =
.4 Hz, 2CH N), 3.82 s (3H, OCH ), 4.42 d (2H, J =
2 3
.8 Hz,ArCH ), 6.84–6.91 m (3H, H ), 6.91–6.97 m (1H,
1
1
-({3-[Bis(cyclopropylmethyl)amino]imidazo-
6
2
[1,2-a]pyridin-2-yl}methyl)-3-[4-(trifluoromethyl)-
1
2
phenyl]urea (12h). Yield 78%, mp 160–162°C. H NMR
spectrum (DMSO-d ), δ, ppm: –0.01 br. s (4H, 2CH ),
6
2
2
Ar
0.27 br. s (4H, 2CH ), 0.81–0.84 m (2H, 2CH), 3.05 d
2
H ), 7.19–7.21 m (1H, H ), 7.23 t (1H, J = 14.8 Hz, NH),
Ar
Ar
(4H, J = 6.0 Hz, 2CH N), 4.46 d (2H, J = 4.5 Hz,ArCH ),
2
2
7
.44 d (1H, J = 8.8 Hz, H ), 8.10 d. d (1H, J = 7.2 Hz,
Ar 1
J = 2.0 Hz, H ), 8.18 s (1H, NH), 8.34 d. d (1H, J =
6.70 br. s (1H, NH), 6.93 t (1H, J = 6.6 Hz, H ), 7.25 t
Ar
2
Ar
1
(1H, J = 6.9 Hz, H ), 7.48 d (1H, J = 9.0 Hz, H ),
Ar
Ar
1
3
6
.8 Hz, J = 1.2 Hz, H ). C NMR (CDCl ) spectrum,
2 3
Ar
δC, ppm: 3.8, 10.7, 37.8, 55.6, 60.1, 110.2, 111.8, 117.0,
7.59 br. s (4H, H ), 8.36 d (1H, J = 6.6 Hz, H ), 9.15 s
Ar Ar
13
(1H, NH). C NMR spectrum (DMSO-d ), δ , ppm: 3.8,
6
C
1
1
19.2, 121.3, 121.6, 123.5, 124.4, 129.3, 129.9,137.1,
41.9, 148.1, 156.4. Found, %: C 68.67; H 6.90; N 16.55;
O 7.59. C H N O . Calculated, %: C 68.71; H 6.97; N
1
1
0.9, 37.4, 59.3, 112.1,113.6, 117.1, 118.9, 124.3, 124.7,
28.5, 128.9, 131.9, 137.5, 138.2, 141.4, 144.5, 155.4.
24
29
5
2
Found, %: C 62.98; H 5.69; F 12.40; N 15.29; O 3.48.
C H F N O. Calculated, %: C 63.01; H 5.73; F 12.46;
+
1
6.69; O 7.63. MS (m/z): 420.2 [М + H] .
-({3-[Bis(cyclopropylmethyl)amino]imidazo-
1,2-a]pyridin-2-yl}methyl)-3-(3,4-dimethylphenyl)-
2
4
26
3
5
+
1
N 15.31; O 3.5. MS (m/z): 458.2 [М + H] .
-({3-[Bis(cyclopropylmethyl)amino]imidazo-
1,2-a]pyridin-2-yl}methyl)-3-[4-(trifluoromethoxy)-
phenyl]urea (12i). Yield 82%, mp 140–142°C. H NMR
spectrum (DMSO-d ), δ, ppm: –0.05 br. s (4H, 2CH ),
[
1
1
urea (12f). Yield 79%, mp125–127°C. H NMR spectrum
DMSO-d ), δ, ppm: –0.05 br. s (4H, 2CH ), 0.22 br. s (4H,
CH ), 0.75–0.79 m (2H, 2CH), 2.12 s (3H,ArCH ), 2.15 s
[
1
(
2
6
2
2
3
6
2
(3H, ArCH ), 3.01 d (4H, J = 5.6 Hz, 2CH N), 4.39 d
3 2
0.22 br. s (4H, 2CH ), 0.75–0.79 m (2H, 2CH), 3.01 d (4H,
2
(
2H, J = 4.8 Hz, ArCH ), 6.41 t (1H, J = 4.8 Hz, NH),
2
J = 5.6 Hz, 2CH N), 4.41 d (2H, J = 4.8 Hz,ArCH ), 6.55 t
2
2
6
.88 d. t (1H, J = 6.8 Hz, J = 1.2 Hz, H ), 6.96 d (1H,
2 2 Ar
(1H, J = 4.8 Hz, NH), 6.87–6.91 m (1H, H ), 7.18–7.23 m
Ar
J = 8.0 Hz, H ), 7.09–7.13 m (2H, H ), 7.18–7.22 m
(3H, H ), 7.43–7.50 m (3H, H ), 8.33 d (J = 6.8 Hz,
Ar
Ar
Ar
Ar
1
3
(
1H, H ), 7.43 d (1H, J = 9.2 Hz, H ), 8.32 d (1H,
H ), 8.92 s (1H, NH). C NMR (CDCl ) spectrum, δ ,
Ar
Ar
Ar 3 C
1
3
J = 6.8 Hz, H ), 8.48 s (1H, NH). C NMR spectrum
ppm: 3.3, 10.3, 37.1, 59.5, 111.9, 116.0, 116.7, 119.2,
121.4, 121.8, 123.4, 124.3, 124.9, 129.1, 137.1, 138.8,
141.6, 143.4, 156.4. Found, %: C 60.82; H 5.48; F 12.09;
N 14.82; O 6.73. C H F N O . Calculated, %: C 60.88;
Ar
(
DMSO-d ), δ , ppm: 3.5, 10.6, 19.0,20.1, 37.1, 59.1,
6 C
111.8, 115.6, 116.8, 119.4, 124.0,124.3, 128.2, 128.9,
1
7
30.0, 136.5, 137.6, 138.7, 141.1, 155.5. Found, %: C
1.83; H 7.42, N 16.68; O 3.81. C H N O. Calculated,
24
26
3
5
2
2
5
31
5
H 5.53; F 12.04; N 14.79; O 6.76. MS (m/z): 474.2
+
%
: C 71.91; H 7.48; N 16.77; O 3.83. MS (m/z): 418.3
[М + H] .
+
[М + H] .
1
-({3-[Bis(cyclopropylmethyl)amino]imidazo-
1
-({3-[Bis(cyclopropylmethyl)amino]imidazo-
[1,2-a]pyridin-2-yl}methyl)-3-{4-[(trifluoromethyl)-
thio]phenyl}urea (12j). Yield 80%, mp 120–122°C. H
1
[
1,2-a]pyridin-2-yl}methyl)-3-(2-isopropylphenyl)-
urea (12g). Yield 72%, mp 90–92°C. H NMR spectrum
1
NMR spectrum (DMSO-d ), δ, ppm: –0.23 br. s (4H,
6
(
DMSO-d ), δ, ppm: –0.06 br. s (4H, 2CH ), 0.21 br. s
2CH ), 0.00 br. s (4H, 2CH ), 0.53–0.57 m (2H, 2CH),
6
2
2
2
(
4H, 2CH ), 0.75–0.78 m (2H, 2CH), 1.13 d (6H, J =
2.78 d (4H, J = 5.6 Hz, 2CH N), 4.21 d (2H, J = 4.8 Hz,
2
2
6
.8 Hz, 2CH ), 3.00 br. s (4H, 2CH N), 3.07–3.13 m (1H,
ArCH ), 6.46 t (1H, J = 4.8 Hz, NH), 6.66 d. t (1H, J =
3
2
2
1
ArCH), 4.41 d (2H, J = 4.8 Hz, ArCH ), 6.86–6.90 m
6.8 Hz, J = 0.8 Hz, H ), 6.98 d. t (1H, J = 6.4 Hz, J =
2
2 Ar 1 2
(
2H, H ), 6.96 t (1H, J = 7.6 Hz, NH), 7.07 t (1H, J =
0.8 Hz, H ), 7.22 d (1H, J = 9.2 Hz, H ), 7.35 d (4H,
Ar Ar
Ar
7
8
.2 Hz, H ), 7.18–7.22 m (2H, H ), 7.43 d (1H, J =
J = 8.8 Hz, H ), 8.10 d (1H, J = 6.8 Hz, H ), 8.91 s
Ar Ar
Ar
Ar
1
3
.8 Hz, H ), 7.67 d (1H, J = 8.0 Hz, H ), 7.88 s (1H,
(NH). C NMR spectrum (DMSO-d ), δ , ppm: 3.0,
Ar
Ar
6 C
1
3
NH), 8.33 d (1H, J = 6.8 Hz, H ). C NMR spectrum
10.1, 36.6, 58.5, 111.3, 112.8, 116.3, 118.1, 123.5, 123.9,
127.7, 128.1, 131.15, 136.7, 137.4, 140.6, 143.7, 154.8.
Found, %: C 58.76; H 5.31; F 11.61; N 14.34; O 3.25; S
6.47. C H F N OS. Calculated, %: C 58.88; H 5.35; F
Ar
(DMSO-d ), δ , ppm: 3.0, 10.1, 23.1, 26.5, 36.8, 58.7,
6 C
1
1
7
11.3, 116.3, 122.6, 122.8, 123.5, 123.8, 124.9, 125.5,
27.8, 136.4, 137.1, 138.2, 140.6, 155.5. Found, %: C
2.28; H 7.76; N 15.63; O 3.68. C H N O. Calculated,
2
4
26
3
5
+
11.64; N 14.31; O 3.27; S 6.55. MS (m/z): 490.2 [М + H] .
2
6
33
5
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 9 2020

1734
ENDOORI et al.
1
-{[3-(Isobutylamino)imidazo[1,2-a]pyridin-
(2H, J = 5.1 Hz, ArCH ), 4.74 t (1H, J = 6.6 Hz, NH),
2
2
1
0
2
-yl]methyl}-3-phenylurea (16a). Yield 82%, mp
6.83–6.95 m (4H, H ), 7.13 t (1H, J = 6.6 Hz, NH), 7.27 t
Ar
1
60–162°C. H NMR spectrum (DMSO-d ), δ, ppm:
(1H, J = 5.1 Hz, H ), 7.40 d (1H, J = 9.0 Hz, H ),
6
Ar
Ar
1
3
.97 d (6H, J = 6.8 Hz, 2CH ), 1.68–1.78 m (1H, CH),
8.06–8.12 m (3H, H ). C NMR spectrum (DMSO-d ),
3
Ar 6
.75 t (2H, J = 6.8 Hz, CH N), 4.38 d (2H, J = 5.2 Hz,
δC ppm: 20.3, 28.7, 36.2, 55.6, 55.8, 110.5, 111.2, 116.5,
118.1, 120.4, 120.9, 122.7, 122.8, 127.6, 129.4, 133.2,
139.8, 147.3, 155.3. Found, %: C 65.33; H 6.82; N 19.03;
O 8.62. C H N O . Calculated, %: C 65.37; H 6.86; N
2
ArCH ), ), 4.77 t (1H, J = 6.8 Hz, NH), 6.54 t (1H, J =
2
4
.8 Hz, NH), 6.86–6.90 m (2H, H ), 7.12–7.14 m (1H,
Ar
Ar), 7.16–7.22 m (2H, H ), 7.24–7.42 m (3H, H ),
Ar
Ar
20 25
5
2
1
3
+
8
.13 d (1H, J = 6.8 Hz, H ), 8.65 s (1H, NH). C NMR
19.06; O 8.71. MS (m/z): 368.2 [М + H] .
Ar
spectrum (DMSO-d ), δ C ppm: 20.3, 28.7, 36.3, 55.8,
6
1-{[3-(Isobutylamino)imidazo[1,2-a]pyridin-2-yl]-
1
1
11.3, 116.5, 117.5, 121.0, 122.7, 122.9, 127.5, 128.6,
33.0, 139.8, 140.4, 155.3. Found, %: C 67.54; H 6.77;
N 20.71; O 4.66. C H N O. Calculated, %: C 67.63; H
methyl}-3-(3-methoxyphenyl)urea (16e). Yield 72%,
1
mp 150–152°C. H NMR spectrum (DMSO-d ), δ, ppm:
6
1
9
23
5
0.97 d (6H, J = 6.8 Hz, 2CH ), 1.68–1.77 m (1H, CH),
3
+
6
.87; N 20.76; O 4.74. MS (m/z): 338.2 [М + H] .
-(4-Bromophenyl)-3-{[3-(isobutylamino)imidazo-
1,2-a]pyridin-2-yl]methyl}urea (16b). Yield 74%, mp
2
.75 t (2H, J = 6.6 Hz, CH N), 3.70 s (3H,ArCH ), 4.37 d
2 3
1
(2H, J = 4.8 Hz, ArCH ), 4.77 t (1H, J = 6.4 Hz, NH),
2
[
6.46–6.53 m (2H, H ), 6.84–6.89 m (2H,Ar), 7.09–7.15 m
Ar
1
1
0
2
55–157°C. H NMR spectrum (DMSO-d ), δ, ppm:
(3H, H ), 7.41 d (1H, J = 8.8 Hz, H ), 8.13 d (1H, J =
6
Ar
Ar
1
3
.94 d (6H, J = 6.4 Hz, 2CH ), 1.65–1.75 m (1H, CH),
6.8 Hz, H ), 8.67 s (1H, NH). C NMR spectrum
3
Ar
.72 t (2H, J = 6.8 Hz, CH N), 4.32 d (2H, J = 5.2 Hz,
(DMSO-d ), δ , ppm: 20.3, 28.7, 36.3, 54.8, 55.8, 103.4,
2
6
C
ArCH ), 4.74 t (1H, J = 6.8 Hz, NH), 6.38 t (1H, J =
106.3, 109.9, 111.3, 116.5, 122.7, 122.9, 127.4, 129.3,
133.0, 139.8, 141.6, 155.2, 159.6. Found, %: C 65.31;
H 6.80; N 19.11; O 8.58. C H N O . Calculated, %: C
2
5
.2 Hz, NH), 6.77–6.86 m (3H, H ), 7.08–7.12 m
Ar
(
1H, H ), 7.24 t (2H, J = 8.8 Hz, H ), 7.37 d (1H, J =
Ar Ar
20 25
5
2
+
9
.2 Hz, H ), 8.09 d (1H, J = 6.8 Hz, H ), 8.41 s (1H,
65.37; H 6.86; N 19.06; O 8.71. MS (m/z): 368.2 [М + H] .
Ar
Ar
1
3
NH). C NMR spectrum (DMSO-d ), δ , ppm: 21.7,
6
C
1-(3,4-Dimethylphenyl)-3-{[3-(isobutylamino)-
3
1
5
0.2, 37.8, 57.2, 112.7, 115.3, 118.0, 120.7, 124.2, 124.3,
28.9, 134.7, 135.0, 141.2, 155.3, 157.0. Found, %: C
imidazo[1,2-a]pyridin-2-yl]methyl}urea (16f). Yield
1
7
6%, mp 155–157°C. H NMR spectrum (DMSO-d ), δ,
6
4.78; H 5.25; Br 19.11; N 16.85; O 3.79. C H BrN O.
1
9
22
5
ppm: 0.97 d (6H, J = 6.8 Hz, 2CH ), 1.67–1.77 m (1H,
3
Calculated, %: C 54.82; H 5.33; Br 19.19; N 16.82; O
.84.
-{[3-(Isobutylamino)imidazo[1,2-a]pyridin-2-yl]-
CH), 2.12 s (3H,ArCH ), 2.15 s (3H,ArCH ), 2.75 t (2H,
3
3
3
J = 6.8 Hz, CH N), 4.35 d (2H, J = 5.2 Hz,ArCH ), 4.76 t
2
2
1
(1H, J = 6.8 Hz, NH), 6.45 t (1H, J = 5.2 Hz, NH), 6.87 d. t
(1H, J = 6.4 Hz, J = 0.8 Hz, H ), 6.96 d (1H, J =
methyl}-3-(4-methoxyphenyl)urea (16c). Yield 75%,
1
2
Ar
1
mp 115–117°C. H NMR spectrum (DMSO-d ), δ, ppm:
7.6 Hz, H ), 7.10–7.16 m (3H, H ), 7.41 d (1H, J =
6
Ar Ar
0
.97 d (6H, J = 6.8 Hz, 2CH ), 1.70–1.77 m (1H, CH),
8.8 Hz, H ), 8.12 d (1H, J = 6.8 Hz, H ), 8.43 s (1H,
Ar Ar
3
1
3
2.75 t (2H, J = 6.8 Hz, CH N), 3.70 s (3H,ArCH ), 4.37 d
NH). C NMR spectrum (DMSO-d ), δ , ppm: 18.6,
2
3
6 C
(
6
7
2H, J = 5.2 Hz, ArCH ), 4.79 t (1H, J = 6.8 Hz, NH),
19.6, 20.3, 28.7, 36.3, 55.8, 111.3, 115.1, 116.5, 118.9,
122.7, 122.9, 127.4, 128.5, 129.5, 133.1, 136.0, 138.1,
139.7, 155.3. Found, %: C 69.10; H 7.41; N 19.22; O 4.35.
C H N O. Calculated, %: C 69.01; H 7.45; N 19.16; O
2
.44 t (1H, J = 5.2 Hz, NH), 6.46–6.89 m (3H, H ), 7.11–
Ar
.16 m (1H, H ), 7.29 d (2H, J = 9.2 Hz, H ), 7.41 d
Ar
Ar
(1H, J = 8.8 Hz, H ), 8.12 d (1H, J = 6.8 Hz, H ), 8.47 s
Ar Ar
21 27
5
1H, NH). 13C NMR spectrum (DMSO-d ), δ , ppm:
4.38. MS (m/z): 366.1 [М + H] .
-{[3-(Isobutylamino)imidazo[1,2-a]pyridin-2-yl]-
methyl}-3-(2-isopropylphenyl)urea (16g). Yield 74%,
+
(
2
1
6
C
0.3, 28.7, 36.3, 55.1, 55.8, 111.3, 113.8, 116.5, 119.2,
22.7, 122.8, 127.5, 133.2, 133.5, 139.8, 153.9, 155.5.
1
Found, %: C 65.31; H 6.83; N 19.15; O 8.64. C H N O .
Calculated, %: C 65.37; H 6.86; N 19.06; O 8.71. MS
1
20
25
5
2
mp 125–127°C. H NMR spectrum (DMSO-d ), δ, ppm:
6
0
2
.97 d (6H, J = 6.8 Hz, 2CH ), 1.13 d (6H, J = 6.8 Hz,
3
+
(m/z): 368.2 [М + H] .
CH ), 1.67–1.77 m (1H, CH), 2.75 t (2H, J = 6.4 Hz,
3
1-{[3-(Isobutylamino)imidazo[1,2-a]pyridin-2-yl]-
CH N), 3.06–3.13 m (1H,ArCH), 4.37 d (2H, J = 4.8 Hz,
2
methyl}-3-(2-methoxyphenyl)urea (16d). Yield 69%,
ArCH ), 4.79 t (1H, J = 6.4 Hz, NH), 6.87–7.00 m (3H,
2
1
mp 180–182°C. H NMR spectrum (DMSO-d ), δ, ppm:
H ), 7.06–7.22 m (3H, H ), 7.41 d (1H, J = 8.8 Hz,
6
Ar
Ar
13
0
.97 d (6H, J = 6.6 Hz, 2CH ), 1.67–1.80 m (1H, CH),
H ), 7.86 s (1H, NH), 8.14 d (1H, J = 6.8 Hz, H ). C
Ar Ar
3
2
.75 t (2H, J = 6.6 Hz, CH N), 3.79 s (3H,ArCH ), 4.35 d
NMR spectrum (DMSO-d ), δ , ppm: 20.3, 23.0, 26.5,
6 C
2
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 9 2020

DESIGN, SYNTHESIS, ANTI-CANCER ACTIVITY, AND IN SILICO STUDIES
1735
55.8, 28.7, 36.4, 111.3, 122.6, 122.8, 122.9, 125.0, 125.5,
16.06; O 3.69; S 7.28. C H F N OS. Calculated, %:
20 22 3 5
1
6
%
27.5, 133.0, 136.3, 138.3, 139.8, 155.8. Found, %: C
9.58; H 7.66; N 18.52; O 4.25. C H N O. Calculated,
22 29 5
C 54.91; H 5.07; F 13.03; N 16.01; O 3.66; S 7.33. MS
(m/z): 438.1 [М + H] .
+
: C 69.63; H 7.70; N 18.45; O 4.22. MS (m/z): 380.2
In vitro evaluation of anticancer activity. The
MCF-7 (human breast adenocarcinoma) cell line, HeLa
+
[М + H] .
1
-{[3-(Isobutylamino)imidazo[1,2-a]pyridin-
(human cervix) cell line and HT-29 (human colorectal
2
-yl]methyl}-3-[4-(trifluoromethyl)phenyl]urea
adenocarcinoma) cell lines were purchased from NCCS,
Pune. The procedure was carried out according to the well
documented method [12, 13]. The percentage growth
inhibition was calculated and concentration of test drugs
needed to inhibit cell growth by 50% was generated from
the dose-response curves for each cell line using with
origin software.
1
(16h). Yield 78%, mp 190–192°C. H NMR spectrum
(
DMSO-d ), δ, ppm: 0.98 d (6H, J = 6.8 Hz, 2CH ),
6
3
1
.68–1.77 m (1H, CH), 2.76 t (2H, J = 6.4 Hz, CH N),
2
4
.42 d (2H, J = 5.2 Hz, ArCH ), 4.77 t (1H, J = 6.8 Hz,
2
NH), 6.72 t (1H, J = 5.2 Hz, NH), 6.89 d. t (1H, J =
6
1
.8 Hz, J = 0.8 Hz, H ), 7.13–7.17 m (1H, H ), 7.43 d
2 Ar Ar
(1H, J = 8.8 Hz, H ), 7.59 q (4H, J = 9.2 Hz, H ), 8.14
Ar Ar
1
3
d (1H, J = 6.8 Hz, H ), 9.12 s (1H, NH). C NMR
Ar
Molecular docking. Docking was performed on
Windows 2002 using MOE 2008.10 version. Phospho-
inositide 3-kinasewas retrieved from the protein data
bank (PDB code: 4EPW) and the enzyme was visualized
using sequence option and further co-factors were
deleted. The partial charge of protein was adjusted with
the help of force field method AMBER 99. Later, the
protein was subjected to 3D protonation at cut off 12.0,
and further hydrogen was added according to standard
geometry and the receptor energy was minimized using
force field MMFF94x at 0.01 kJ/mol gradients. The
ligand structures were generated according to the routine
procedure. Docking was performed using the option
simulation followed by docking on selected active site
amino acids using sequence option, and eventually
docked using setting options such as receptor and solvent,
alpha triangle, selected residues, affinity dG, force field
refinement, and best 30 poses. The resulting best pose
score values in the series were used for analysis of
docking and interactions.
spectrum (DMSO-d ), δ , ppm: 20.3, 28.7, 36.3, 55.8,
6
C
111.3, 117.1, 122.7, 122.9, 126.0, 127.4, 132.7, 139.8,
1
1
5
44.1, 154.8. Found, %: C 59.33; H 5.42; F 14.01; N
7.19; O 3.90. C H F N O. Calculated, %: C 59.25; H
2
0
22
3
5
+
.47; F 14.06; N 17.27; O 3.95. MS (m/z): 406.2 [М + H] .
-{[3-(Isobutylamino)imidazo[1,2-a]pyridin-
-yl]methyl}-3-[4-(trifluoromethoxy)phenyl]urea
1
2
1
(
(
16i). Yield 82%, mp 110–112°C. H NMR spectrum
DMSO-d ), δ, ppm: 0.97 d (6H, J = 6.6 Hz, 2CH ),
6
3
1
.66–1.79 m (1H, CH), 2.75 t, (2H, J = 6.6 Hz, CH N),
2
4
.38 d (2H, J = 4.8 Hz, ArCH ), 4.75 t (1H, J = 6.3 Hz,
2
NH), 6.58 t (1H, J = 5.1 Hz, NH), 6.88 t (1H, J = 6.6 Hz,
H ), 7.14 t (1H, J = 6.6 Hz, H ), 7.22 d (2H, J = 8.4 Hz,
Ar
Ar
H ), 7.41 d (1H, J = 9.0 Hz, H ), 7.48 d (2H, J = 9.0 Hz,
Ar
Ar
1
3
H ), 8.12 d (1H, J = 6.6 Hz, H ), 8.87 s (1H, NH). C
Ar
Ar
NMR spectrum (DMSO-d ), δ , ppm: 20.3, 28.7, 36.3,
6
C
5
1
5.8, 111.3, 116.5, 118.5, 118.9, 121.4, 121.6, 122.7,
22.9, 127.4, 132.8, 139.7, 139.8, 141.9, 155.1. Found, %:
C 57.21; H 5.21; F 13.48; N 16.66; O 7.51. C H F N O .
20
22
3
5
2
Calculated, %: C 57.00; H 5.26; F 13.52; N 16.62; O 7.59.
+
MS (m/z): 422.1 [М + H] .
CONCLUSIONS
1-{[3-(Isobutylamino)imidazo[1,2-a]pyridin-2-yl]-
methyl}-3-{4-[(trifluoromethyl)thio]phenyl}urea
We report the synthesis of novel imidazo[1,2-a]-
pyridine derivatives starting from commercially available
1
(
(
16j). Yield 80%, mp 155–157°C. H NMR spectrum
DMSO-d ), δ, ppm: 0.97 d (6H, J = 6.6 Hz, 2CH ),
6
3
2
-aminopyridine and 1,3-dichloroacetone. All the newly
1
.68–1.77 m (1H, CH), 2.75 t (2H, J = 6.6 Hz, CH N),
2
1
synthesized compounds have been characterized by H
4
.39 d (2H, J = 4.8 Hz, ArCH ), 4.75 t (1H, J = 6.3 Hz,
2
13
and C NMR and MS spectra and evaluated for in vitro
NH), 6.69 t (1H, J = 4.8 Hz, NH), 6.89 t (1H, J = 6.9 Hz,
anticancer activity against three human cancer cell lines
HeLa, MCF-7, and HT29. The compounds 12c, 12d,
12i, 16c, 16h, and 16i demonstrate moderate to high
anti-proliferative activity against all tested cell lines. The
compound 16h is determined to be more potent than the
standard drug cisplatin for the HeLa cell line.
NH), 7.16 t (1H, J = 6.9 Hz, H ), 7.42 d (1H, J = 9.0 Hz,
Ar
H ), 7.55 t (4H, J = 9.3 Hz, H ), 8.14 d (1H, J = 6.6 Hz,
Ar
Ar
1
3
H ), 9.08 s (1H, NH). C NMR spectrum (DMSO-d ),
Ar
6
δC, ppm: 20.3, 28.7, 36.3, 55.7, 111.4, 112.9, 116.4, 118.2,
1
1
22.8, 123.1, 127.5, 128.0, 131.1, 132.6, 137.4, 139.8,
43.6, 154.8. Found, %: C 54.82; H 5.01; F 13.13; N
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 9 2020

1736
ENDOORI et al.
Adv. Biochem. Psychopharmacol, 1990, vol. 46, p. 61.
ACKNOWLEDGMENTS
PMID: 1981304.
The authors would like to thank the management of AMRI
Hyderabad research centre for giving an opportunity to carry
out this research. The authors are also thankful to SaiInnotech
labs Pvt.Ltd.for providing synthesis facility.
7. Mizushige, K., Ueda, T., Yukiiri, K., and Suzuki, H.,
Cardiovasc. Drug Rev., 2002, vol. 20, p. 163.
https://doi.org/10.1111/j.1527-3466.2002.tb00085.x
8
. Almirante, L., Polo, L., Mugnaini, A., Provinciali, E.,
Rugarli, P., Biancotti, A., Gamba, and Murmann, W.,
J. Med. Chem., 1965, vol. 8, p. 305.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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