Green synthesis, characterization and antidiabetic activity of 2-substituted aryl/Alkyl-N-Aryl/Alkyl imidazo[1,2-a]pyridin-3-amine derivatives

Article abstract of DOI:10.14233/ajchem.2018.21220

Imidazo[1,2-a]pyridines containing ring junction have shown broad therapeutic properties in the drug discovery sector, such as the treatment of heart disease, migraines, digestive disease and viral disease. Imidazo[1,2-a]pyridine structure is very much pr

Full text of DOI:10.14233/ajchem.2018.21220

Asian Journal of Chemistry; Vol. 30, No. 7 (2018), 1531-1536
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2018.21220
Green Synthesis, Characterization and Antidiabetic Activity of 2-Substituted
Aryl/Alkyl-N-Aryl/Alkyl Imidazo[1,2-a]pyridin-3-amine Derivatives
1
,2,*
3
3
TATA VEERESWARA RAO KOTA , HIMA BINDU GANDHAM and PAUL DOUGLAS SANASI
1
2
3
Department of Chemistry, Bonam Venkata Chalamayya Engineering College, Odalarevu, Allavaram Mandal-533 201, India
Department of Chemistry, Jawaharlal Nehru Technological University Kakinada, Kakinada-533 003, India
Department of Engineering Chemistry, AU College of Engineering (A), Andhra University, Visakhapatnam-530 003, India
*
Corresponding author: E-mail: veresh.kota@gmail.com
Received: 10 January 2018; Accepted: 23 February 2018;
Published online: 31 May 2018;
AJC-18926
Imidazo[1,2-a]pyridines containing ring junction have shown broad therapeutic properties in the drug discovery sector, such as the
treatment of heart disease, migraines, digestive disease and viral disease. Imidazo[1,2-a]pyridine structure is very much prevalent in
several marketed drugs viz., olprinone, zolpidem, levamisole, alpidem, zolimidine etc. The present paper describes the green synthesis of
some novel imidazo[1,2-a]pyridine derivatives (6a-f/7a-f), a straight forward, isocyanide based Groebke-Blackburn-Bienayme, three
component reactions in which aldehyde, 2-aminopyridine and isocyanide are condensed in presence of green parameters such as (i) ZnO
nanoparticles/ZnFe
2
4
O nanoparticles (reusable heterogeneous catalysts), (ii) 2-methyl-tetrahydrofuran (green solvent) and (iii) microwave
irradiation (energy efficiency reducing time period of the reaction). These derivatives were evaluated for antidiabetic experiments and the
results revealed that most of the compounds were active towards antidiabetic property.
Keywords: Green synthesis, Imidazo[1,2-a]pyridine,Antidiabetic, 2-Amino-pyridine, ZnO nanoparticles, ZnFe
2
4
O nanoparticles.
[
[
4], migraines [21], digestive disease [22,23] and viral disease
24].
In this paper, we report the synthesis of some novel imidazo-
1,2-a]pyridine derivatives, a straight forward, isocyanide
INTRODUCTION
Among the nitrogen derivatives, imidazo-fused hetero-
cycles are becoming more important in medicinal and organic
chemistry, as they exhibit a broad spectrum of pharmacological
and biological activities, such as antiviral, antibacterial, anti-
fungicidal and anti-inflammatory properties [1]. The signifi-
cance of imidazopyridine scaffolds in the drug discovery sector
is well appreciated because of the appealing benefits they offer.
Imidazole fused polyheterocycles containing ring junction
nitrogen have attracted considerable interest in medicinal
chemistry in view of their uses as anti-inflammatory [2], anti-
cancer [3], antibacterial [4] and antituberculosis [5] agents.
The importance of imidazo[1,2-a]pyridine is evident from
the fact that it is prevalent in several marketed drugs such as
olprinone (cardio tonic agent, a phosphodiesterase-PDE 3
inhibitor) [6,7], zolpidem (hypnotic) [8], levamisole (anti-
cancer) [9,10], alpidem (a nonsedative anxiolytic) [11-13],
zolimidine (anti-inflammatory) [14,15]. They are also
used in molecular recognition and bio-imaging probes due
to their structural characteristics [16-18], sedative agents
[
based Groebke-Blackburn-Bienayme [25-27], three compo-
nent reactions in which aldehyde, 2-aminopyridine and
isocyanide are condensed in presence of (i) ZnO nanoparticles/
ZnFe
2
wave irradiation (energy efficiency reducing time period of the
reaction). Furthermore, these derivatives were further evaluated
for their antidiabetic studies.
2
O
4
nanoparticles (reusable heterogeneous catalysts), (ii)
-methyltetrahydrofuran (green solvent), (iii) under micro-
EXPERIMENTAL
All the chemicals were commercially procured fromAlfa
Aesar. Microwave assisted experiments were conducted using
a CEM discovery system in a closed vessel under magnetic
stirring. 5 mL reaction vial, microwave tube: 10 mL pressure
vessel, pyrex were used. Melting points were determined in
open glass capillaries on a Stuart SMP30 apparatus and are
uncorrected. FT-IR spectra were recorded as KBr pellets on a
(
saripidem & necopidem) [19,20]. Functionalized heterocyclic
scaffolds derived from imidazo[1,2-a]pyridines have shown
1
Shimadzu FTIR 8400S spectrophotometer. H NMR (400
broad therapeutic properties such as treatment of heart disease
MHz) spectra were recorded on a Bruker DPX 400 spectrophoto-

1
532 Kota et al.
Asian J. Chem.
meter using tetramethylsilane (TMS) as internal standard,
CDCl and DMSO-d as solvents. HRMS spectra were recorded
N,2-Diphenylimidazo[1,2-a]pyridin-3-amine (6a) [28,29]:
3
6
Pale yellow solid; Yield: 84 %; m.p.: 239-240 °C; IR (KBr,
–1
on a Xevo QT of mass spectrometer. Silica gel 60 F24 of Merck
pre-coated plates were employed for their thin layer chromato-
graphy (TLC) analysis to check the purity of the compounds,
the spot being located under UV light and iodine vapours.
Synthesis of ZnO nanoparticles: 2.5 g of Zinc nitrate
νmax, cm ): 3295 (-N-H str), 2919 (-C-H str), 1600 (-C=N str),
1
1437 (-C=C- str), 1182 (-C-N str); H NMR (400 MHz, CDCl ):
3
δ 5.57 (s, 1H), 6.62 (d, J = 8.4 Hz, 2H), 6.78 (t, J = 6.4 Hz,
1H), 6.88 (t, J = 7.6 Hz, 1H), 7.26-7.20 (m, 3H), 7.30 (d, J =
7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.66 (d, J = 9.2 Hz, 1H),
[
Zn(NO
3
)
2
·4H
2
O] was dissolved in 300 mL distilled water.
7.85 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H); ESI-MS:
+
The pH of the solution was brought to 8.0 by drop wise addition
of ammonium hydroxide solution (20 %). The reaction mixture
was then stirred for 1h at room temperature and transferred to
a Teflon lined steel autoclave and maintained at 100 to 120 °C
for different time periods ranging from 6 to 24 h. The autoclave
was then allowed to cool to room temperature. The product
was then washed several times with distilled water, filtered
and dried at 80 °C overnight. The reaction can be scaled up
without any change in phase and morphology of the samples.
m/z 286.5 (M+H) . Elemental analysis C19
H
15
3
N calcd. (found)
%: C 79.97 (79.95), H 5.29 (5.26), N 14.72 (14.68).
2-(p-Tolyl)-N-phenylimidazo[1,2-a]pyridin-3-amine
(6b) [28]:Yellow solid;Yield: 55 mg, 92 %; m.p.: 236-237 °C;
–1
IR (KBr, νmax, cm ): 3288 (-N-H str), 2922 (-C-H str), 1598
1
(-C=N str), 1434 (-C=C- str), 1180 (-C-N str); H NMR (400
MHz, CDCl ): δ 7.89 (d, J = 8.2 Hz, 2H), 7.82 (dd, J = 6.8,
3
1.2 Hz, 1H), 7.63 (dt, J = 9.1, 1.1 Hz, 1H), 7.24-7.14 (m,
5 H), 6.90-6.83 (m, 1H), 6.75 (td, J = 6.8, 1.1 Hz, 1H), 6.62-
Synthesis of ZnFe
2
O
4
nanoparticles: Ferric nitrate (4.87 g),
6.56 (m, 2H), 5.61 (s, 1H), 2.34 (s, 3 H); ESI-MS: m/z 300.1
+
zinc nitrate (3.75 g) and sodium hydroxide (3.28 g) were mixed
together and dissolved in 40 mL of distilled water. Then 2 mL
of polyethylene glycol (PEG) was added dropwise in the
solution under constant stirring at room temperature and the
pH level was maintained around 11. The mixture was contin-
uously stirred for 0.5 h and transferred to 50 mL of Teflon
lined autoclave. The autoclave was sealed and maintained at
(M+H) . Elemental analysis C20
H
15
3
N calcd. (found) %: C 80.23
(80.19), H 5.71 (5.68), N 14.05 (14.01).
2-(4-Methoxyphenyl)-N-phenylimidazo[1,2-a]pyridin-
3-amine (6c) [30]: Off-white solid; Yield: 80 %; m.p.: 199-
–1
200 °C; IR (KBr, νmax, cm ): 3278 (-N-H str), 2918 (-C-H
1
str), 1599 (-C=N str), 1438 (-C=C- str), 1182 (-C-N str); H
NMR (400 MHz, CDCl ): δ 5.56 (s, 1H), 6.55 (d, J = 8.4 Hz,
3
1
65 °C for 16 h in the furnace and then allowed to reach the
2H), 6.66 (t, J = 6.4 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H), 7.06-
7.11 (m, 2H), 7.22 (d, J = 7.2 Hz, 2H), 7.12 (d, J = 7.4 Hz,
2H), 7.38 (d, J = 9.2 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.82
room temperature. Finally, the brown precipitated solution was
washed several times with distilled water and absolute ethanol.
Then the brown precipitates were collected and dried at 60 °C
for 6 h in hot air oven and characterized.
+
(d, J = 8.0 Hz, 1H); ESI-MS: m/z 316.3 (M+H) . Elemental
analysis C20
H
15
3
N O calcd. (found) %: C 76.16 (76.12), H 5.42
Synthesis of 2-substituted aryl/alkyl-N-aryl/alkyl
imidazo[1,2-a]pyridin-3-amine derivatives (6a-f/7a-f) using
(5.40), N 13.31 (13.29).
2-Cyclohexyl-N-phenylimidazo[1,2-a]pyridin-3-amine
(6d) [31]: Pale yellow solid; Yield: 75 %; m.p.: 187-188 °C;
ZnO nanoparticles/ZnFe
2
O nanoparticles: To a microwave
4
–1
tube vessel containing 2-methyltetrahydrofuran (1 mL) and
ethanol (catalytic quantity), was sequentially added 2-amino-
pyridine (50 mg, 0.53 mmol), corresponding aryl-alkyl
IR (KBr, νmax, cm ): 3205 (-N-H str), 2925 (-C-H str), 1599
1
(-C=N str), 1494 (-C=C- str), 1170 (-C-N str); H NMR (400
MHz, CDCl ): δ 1.20-1.30 (m, 3H), 1.62-1.82 (m, 8H), 5.30
3
aldehydes 4a-f (0.53 mmol), ZnO-NPs/ZnFe
2
O
4
NPs (10 mol
(s, 1H), 6.50 (d, J = 8.3 Hz, 2H), 6.71 (t, J = 7.6 Hz, 1H), 6.82
(t, J = 7.4 Hz, 1H), 7.13-7.20 (m, 3H), 7.58 (d, J = 8.8 Hz, 1H),
7.77 (d, J = 6.6 Hz, 1H); ESI-MS: m/z 292.5 (M+H) . Elemental
%
) and phenyliso-cyanide (50 mg, 0.53 mmol) and then
+
screwed tightly and heated at 120 °C by microwave irradiation
for 2-5 min. The completion of the reaction was judged by the
TLC profile, after cooling, the reaction mixture is taken into
the centrifuge tube and subjected to centrifugation, the catalyst
sediments settle down at the bottom of the centrifuge tube and
analysis C19
H
21
3
N calcd. (found) %: C 78.34 (78.32), H 7.28
(7.24), N 14.44 (14.42).
2-Ethyl-N-phenylimidazo[1,2-a]pyridin-3-amine (6e)
[32]: White solid; Yield: 78 %; m.p.: 174-175 °C; IR (KBr,
–1
for ZnFe
2
O
4
catalyst is separated magnetically by placing a
νmax, cm ): 3218 (-N-H str), 2929 (-C-H str), 1594 (-C=N str),
1
strong neodymium magnet at the bottom of the microwave
dish, after which the solution containing the product was taken
off with a pipette. Diluted with 2-methyltetrahydrofuran (10
mL), washed with 10 % sodium bicarbonate followed by water
1487 (-C=C- str), 1168 (-C-N str); H NMR (400 MHz, CDCl ):
3
δ 1.36 (t, J = 6.8 Hz, 3H), 4.10 (q, J = 6.8 Hz, 2H), 5.34 (s, 1H),
6.48 (d, J = 8.3 Hz, 2H), 6.71 (t, J = 7.6 Hz, 1H), 6.82 (t, J =
7.4 Hz, 1H), 7.13-7.20 (m, 2H), 7.56 (d, J = 7.8 Hz, 1H), 7.72
+
(
2 × 5 mL), brine solution (5 mL) and the two layers were
separated. The aqueous layer was further washed twice with
-methyl- terahydrofuran (2 × 3 mL) and the combined organic
(d, J = 6.8 Hz, 1H); ESI-MS: m/z 238.5 (M+H) . Elemental
analysis C15
H
15
3
N calcd. (found) %: C 75.91 (75.89), H 6.36
2
(6.31), N 17.70 (17.69).
phases concentrated in vacuum. The product was further
purified with the help of recrystallization using isopropyl-
acetate and n-heptane to obtain the desired 2-substituted aryl/
alkyl-N-phenylimidazo-[1,2-a]pyridin-3-amine derivatives
2-Isopropyl-N-phenylimidazo[1,2-a]pyridin-3-amine
(6f): White solid; Yield: 80 %; m.p.: 216-217 ºC; IR (KBr,
–1
ν
max, cm ): 3200 (-N-H str), 2921 (-C-H str), 1600 (-C=N str),
1
1495 (-C=C- str), 1154 (-C-N str); H NMR (400 MHz, CDCl ):
3
(
6a-f) in high purity with 80-85 % yield. The catalyst is washed
1.33 (d, J = 7.0 Hz, 6H), 3.10-3.20 (m, 1H), 5.30 (s, 1H), 6.50
(d, J = 7.4 Hz, 2H), 6.70 (d, J = 7.4 Hz, 1H), 6.82 (t, J = 7.4
Hz, 1H), 7.15-7.20 (m, 3H), 7.60 (d, J = 8.7 Hz, 1H), 7.81 (d,
thrice with ethyl acetate, dried and the fresh reactants were
introduced into the microwave dish, followed by microwave
irradiation allowing the reaction to proceed for the next run.
+
J = 6.5 Hz, 1H); ESI-MS: m/z 252.5 (M+H) . Elemental

Vol. 30, No. 7 (2018)
Green Synthesis of 2-Substituted Aryl/Alkyl-N-Aryl/Alkyl Imidazo[1,2-a]pyridin-3-amine Derivatives 1533
1
analysis C16
6.79), N 16.71 (16.70).
N-Phenyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-
amine (7a) [29]: Off-white solid;Yield: 84 %; m.p.: 218-219
H
17
N
3
calcd. (found) %: C 76.45 (76.41), H 6.81
(-C=C- str), 1136 (-C-N str); H NMR (400 MHz, CDCl
3
): δ
(
1.84 (d, J = 6.5 Hz, 6H), 3.40-3.48 (m, 1H), 6.04 (d, J = 10.0
Hz, 1H), 6.75 (t, J = 6.8 Hz, 1H), 7.0-7.15 (m, 2H), 7.52 (d, J
= 9.2 Hz, 1H), 7.70-7.78 (m, 1H), 7.99 (d, J = 7.0 Hz, 1H),
8.17 (d, J = 8.2 Hz, 1H), 8.55 (d, J = 4.8 Hz, 1H); ESI-MS:
m/z 253.5 (M+H) . Elemental analysis C15
–1
°
C; IR (KBr, νmax, cm ): 3435 (-N-H str), 2929 (-C-H str),
1
+
1
597 (-C=N str), 1494 (-C=C- str), 1148 (-C-N str); H NMR
400 MHz, CDCl ): δ 6.66 (d, J = 7.9 Hz, 2H), 6.76 (t, 7.6 Hz,
H), 6.92 (t, J = 6.8 Hz, 1H), 7.12-7.25 (m, 5H), 7.60-7.65
H
16
4
N calcd. (found)
(
1
3
%: C 71.41 (71.37), H 6.41 (6.39), N 22.19 (22.17).
Experimental Procedure for antidiabetic studies [34-37]
(
(
m, 2H), 7.77 (t, J = 6.0 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 8.30
s, 1H, D O exchangeable), 8.56 (d, J = 4.4 Hz, 1H); ESI-MS:
Acute toxicity: These studies were undertaken as per the
standard experimental procedures. The LD50 cut-off value of
the test compounds was fixed as 50 mg/kg, as screening dose
for evaluation of antidiabetic activity. All the animal experi-
ments were conducted by the approval of InstitutionalAnimal
Ethics Committee, Anurag Group of Institutions (formerly
Lalitha College of Pharmacy), Hyderabad, India. During the
study period, guidelines of Committee for the Purpose of Control
and Supervision of Experiments on Animals (CPCSEA),
InstitutionalAnimals Ethics Committee (IAEC) were followed
for the maintenance of animals. The research work was approved
by IAEC No: I/IAEC/LCP041/2014/SM40.
Alloxan induction of experimental diabetes: Overnight-
fasted Swiss albino mice are injected with alloxan (50 mg/kg)
in saline buffer intraperitoneally and hyperglycemia was
confirmed in animals after 72 h. Blood glucose levels were
determined and mice having blood glucose levels < 145 mg/dl
were excluded from experiment and rest were divided into 10
groups.
Experimental design: Animals were divided into 14 groups
of 6 animals (n = 6): Group 1 diabetic animals (vehicle) received
.5 % CMC (1 mL); Group 2 diabetic animals received insulin
0 mg/kg. Groups (3–14) diabetic animals received compounds
a-f/7a-f in a single dose of 50 mg/kg body weight per oral,
respectively for 7 days continuously.
Blood glucose measurement: Blood was withdrawn from
the tail vain each time. Blood glucose was measured at 0, 3
2
+
m/z 287.5 (M+H) . Elemental analysis C18
: C 75.51 (75.50), H 4.95 (4.92), N 19.56 (19.54).
N-p-Tolyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-
amine (7b): White solid; Yield: 80 %; m.p.: 168-169 °C; IR
H
14
N
4
calcd. (found)
%
–1
(KBr, νmax, cm ): 3440 (-N-H str), 2922 (-C-H str), 1594 (-C=N
1
str), 1493 (-C=C- str), 1151 (-C-N str); H NMR (400 MHz,
CDCl ): δ 2.36 (s, 3H), 6.72 (d, J = 7.2 Hz, 2H), 6.54 (d, J =
.2 Hz, 2H), 6.70 (t, 7.6 Hz, 2H), 6.86 (t, J = 6.8 Hz, 1H),
.64-7.66 (m, 2H), 7.72 (t, J = 6.0 Hz, 1H), 8.19 (d, J = 7.9
O exchangeable), 8.52 (d, J = 5.4 Hz,
3
7
7
Hz, 1H), 8.28 (s, 1H, D
H); ESI-MS: m/z 301.3 (M+H) . Elemental analysis C19
calcd. (found) %: C 75.97 (75.94), H 5.36 (5.32), N 18.64
18.62).
N-(4-Methoxy-phenyl)-2-(pyridin-2-yl)imidazo[1,2-
a]pyridin-3-amine (7c): Brown solid;Yield: 82 %; m.p.: 183-
2
+
1
H
16
N
4
(
–1
1
85 °C; IR (KBr, νmax, cm ): 3434 (-N-H str), 2928 (-C-H
1
str), 1598 (-C=N str), 1496 (-C=C- str), 1156 (-C-N str); H
NMR (400 MHz, CDCl ): δ 3.78 (s, 3H), 6.68 (d, J = 6.8 Hz,
H), 6.82 (d, J = 7.0 Hz, 2H), 6.78 (t, 7.6 Hz, 2H), 6.90 (t, J =
.8 Hz, 1H), 7.71-7.68 (m, 2H), 7.76 (t, J = 6.6 Hz, 1H), 8.22
O exchangeable), 8.48 (d,
3
2
6
0
5
6
(
d, J = 7.8 Hz, 1H), 8.31 (s, 1H, D
J = 5.8 Hz, 1H); ESI-MS: m/z 317.1 (M+H) . Elemental analysis
O calcd. (found) %: C 72.15 (72.13), H 5.12 (5.10),
N 17.70 (17.67).
N-Cyclohexyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-
-amine (7d) [33]: Off-white solid; Yield: 84 %; m.p.: 113-
2
+
C
16
H
16
N
4
rd
3
1
1
th
rd
th
and 7 days interval. At the end of 0, 3 and 7 day, blood
samples were withdrawn from a tail vein by snipping the tip
of the tail and the blood glucose level was measured by Accu
Sure Blood Glucose Monitoring System (Dr. Gene Health &
Wellness).
–1
14 °C; IR (KBr, νmax, cm ): 3265 (-N-H str), 2928 (-C-H str),
1
586 (-C=N str), 1476 (-C=C- str), 1147 (-C-N str); H NMR
(
400 MHz, CDCl ): δ 8.58 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H),
3
7
9
.96 (d, J = 6.8 Hz, 1H), 7.75 (t, J = 6.4 Hz, 1H), 7.53 (d, J =
.2 Hz, 1H), 7.18-7.08 (m, 2H), 6.76 (s, 1H), 6.21 (brs, 1H,
RESULTS AND DISCUSSION
2
D Oexchangeble), 3.10 (brs, 1H), 1.98 (brs, 2H), 1.70 (brs,
2
H), 1.54 (brs, 1H), 1.36-1.12 (m, 5H); ESI-MS: m/z 293.5
Xu et al. [28] reported the synthesis of compounds 6a,
6b using zinc iodide catalyzed conditions, Lacerda et al. [29]
synthesized compound 6c, 7a using AcOH catalyzed reaction
condition, Shinde et al. [31] reported the synthesis of compound
+
(M+H) . Elemental analysis C18
H
20
4
N calcd. (found) %: C 73.92
(
73.90), H 6.91 (6.89), N 19.14 (19.11).
N-Ethyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-
amine (7e): Yellow oily liquid; Yield: 78 %; IR (KBr, νmax
,
6d using LaCl
3
·7H O. Kiselyov [32] reported the synthesis of
2
–1
cm ): 3268 (-N-H str), 2971 (-C-H str), 1597 (-C=N str), 1472
compound 6e using N-fluoropyridinium salts, Dam et al. [33]
reported the synthesis of 7d using Montmorillonite K-10 clay
as catalyst. To the best of our knowledge, the synthesis of
compounds 6f, 7b, 7c, 7e-7f are new and have not been
reported in the literature so far.Apart from the above mentioned
reagents, in general imidazo[1,2-a]pyridines have been
reported to be synthesized by different methodologies for this
1
(
-C=C- str), 1141 (-C-N str); H NMR (400 MHz, CDCl
3
): δ
1
1
7
.38 (t, J = 6.8 Hz, 3H), 4.14 (q, J = 6.8 Hz, 2H), 6.08 (d, J =
0.0 Hz, 1H), 6.71 (t, J = 6.8 Hz, 1H), 7.04-7.13 (m, 2H),
.50 (d, J = 9.2 Hz, 1H), 7.68-7.72 (m, 1H), 7.95 (d, J = 7.0
Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.52 (d, J = 4.8 Hz, 1H);
+
ESI-MS: m/z 239.3 (M+H) . Elemental analysis C14
found) %: C 70.56 (70.51), H 5.93 (5.90), N 23.49 (23.47).
N-Isopropyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-
amine (7f):Yellow syrupy liquid;Yield: 80 %; IR (KBr, νmax
H
14
N
4
calcd.
(
type of condensation reactions such as Sc(OTf)
3
[38], ZnCl
[27],
2
[39], MgCl [40], ZrCl [41], SnCl ·2H O [42], HClO
2
4
2
2
4
,
AcOH [28], p-TSA [43], montmorillonite K-10 [44], cellulose
sulfuric acid [26], catalyst free and solvent free reaction condi-
–1
cm ): 3284 (-N-H str), 2964 (-C-H str), 1591 (-C=N str), 1476

1
534 Kota et al.
Asian J. Chem.
N
CN
R
ZnO NPs/
N
R-CHO
a-f
ZnFe O NPs
2
4
+
+
NH
6a-f
4
H N
N
2
2
1
+
ZnO NPs/
N
R-NC
a-f
ZnFe O NPs
2
4
OHC
N
3
5
N
N
NH
R
7
a-f
R =
e
f
d
OMe
c
a
b
Scheme-I: Green synthesis of novel imidazo[1,2-a]pyridine derivative (6a-f/7a-f)
tions [45,46]. Most of these methods have many limitations in
terms of lower product yields, toxicity, longer reaction time,
higher energetic reaction conditions or use of hazardous and
volatile organic solvents like acetonitrile, toluene, chloroform
etc. Moreover, most of those catalysts are not reusable.
Our primary objective is to develop a green synthetic pro-
tocol using recyclable and reusable heterogeneous catalyst,
green solvent and energy efficiency methods with benign
reaction condition. The synthesis of final targets imidazo[1,2-
a]pyridines derivatives (6a-f and 7a-f) is illustrated in Scheme-
I. These compounds were synthesized via three component
condensation reaction between aryl-alkyl-aldehydes (4a-f), 2-
aminopyridines and aryl-alkyl isocyanides (5a-f) utilizing
7.60 ppm (d, 1H), 7.15-7.20 ppm (m, 3H, with overlap of
phenyl proton) is assigned to the pyridine ring while the protons
resonating at 6.50 ppm (d, 2H), 6.70 ppm (d, 1H), 6.82 ppm (t,
1H) and 7.15-7.20 (m, 1H) corresponds to the phenyl ring
protons. The protons resonating in the aliphatic region 1.33
ppm (d, 6H) and 3.10-3.20 ppm (m, 1H) is assigned to the
isopropyl group while the proton resonating at 5.30 (s, 1H,
D
2
O exchangeable) is assigned to the –NH group, respectively.
Mass: The m/z, 252.5 with (M+H) corresponds to the
+
molecular weight of the desired compound i.e. compound 6f.
IR: The stretching frequencies in the region 3200, 2921,
-1
1600, 1495, 1154 cm corresponds to –NH, -CH, -C=N, -C-N
groups, respectively. The above analytical interpretation thus
confirms the structure of the compound 6f. Similarly, the struc-
ture of the remaining compounds in the series was charac-
terized as described above.
reusable nanocrystalline ZnO/ZnFe
2
O as catalyst in presence
4
of green solvent 2-methyltetrahydrofuran and catalytic quantity
of ethanol (Scheme-I) under microwave irradiation conditions.
The condensation reaction was successful (in presence of
ZnO NPs) even without microwave irradiation but took longer
reaction time (10-18 h) for the completion of the reaction [29].
In order to reduce the reaction time, attempted microwave
Antidiabetic activity: Compilation of the antidiabetic
activity results of the synthesized imidazo[1,2-a]pyridine
derivatives (6a-f/7a-f)is tabulated inTable-1.All these derivatives
exhibited significant hypoglycemic property, but with a certain
degree of variation.A major increase in blood glucose was deter-
mined in diabetic rats.All the compounds 6a-f/7a-f had shown a
significant reduction in blood glucose as compared to control
conditions in presence of ZnO NPs/ZnFe
2
O NPs was success-
4
ful by reducing the reaction time to 2-5 min. The yields and
quality of the products improved to a greater extent than the
previously reported literature procedures. The salient features
of our work lies in establishing the essential green principle
rd
th
diabetic rats at 50 mg/kg body weight for 3 and 7 days.
Insulin was used as a standard drug for the purpose of the
study and showed 68.88 % blood glucose lowering activity at
the dose of 50 mg/kg.p.o. From Table-1, it is observed that
7a-f imidazo[1,2-a]pyridine series of compounds exhibited
significant hypoglycemic activity when compare to 6a-f series
of imidazo[1,2-a]pyridine. Compounds 7d (67.0 %), 7e (65.54
%) and 7f (64.64 %) with substitution R = cyclohexyl, ethyl
and isopropyl showed nearly equivalent hypoglycemic activity
similar to the standard drug insulin (50 mg/kg b.w) in reducing
the blood glucose level, while the compounds 7a (58.06 %),
ingredients such as usage of ZnO NPs/ZnFe
2
O a reusable
4
heterogeneous catalyst, 2-methyltetrahydrofuran, a green
solvent and energy efficiency methods by utilizing microwave
irradiation technique. The structural elucidation of the synthe-
sized imidazo[1,2-a]pyridine derivatives was established by
1
H NMR, IR and mass spectroscopic techniques.As an example,
the structural interpretation of 2-isopropyl-N-phenyl-
imidazo[1,2-a]pyridin-3-amine (6f) is discussed here.
1
H NMR: The proton resonating at 7.81 ppm (d, 1H),

Vol. 30, No. 7 (2018)
Green Synthesis of 2-Substituted Aryl/Alkyl-N-Aryl/Alkyl Imidazo[1,2-a]pyridin-3-amine Derivatives 1535
TABLE-1
RESULTS OF HYPOGLYCEMIC EFFECTS OF HYDRAZONE DERIVATIVES (6a-f/7a-f)
Blood glucose level (mg/dl)
Treatment (mg/kg b.w p.o)
Day-0
Day-3
Day-7
Hyperglycemic activity (%)
Control (0.5 % CMC)
Insulin
345.0 ± 2.48
354.0 ± 1.96
346.5 ± 2.46
343.0 ± 3.25
353.4 ± 2.27
352.6 ± 2.26
354.3 ± 2.46
342.4 ± 1.88
357.3 ± 2.37
325.8 ± 2.25
334.6 ± 2.05
348.5 ± 2.86
338.6 ±2.40
339.3 ± 3.39
376.30 ± 3.54**
146.30 ± 2.74**
262.10 ± 2.26**
255.10 ± 2.72**
282.3 ± 3.65**
280.20 ± 3.80**
246.50 ± 3.13**
292.30 ± 3.06**
262.35 ± 1.68**
207.21 ± 3.13**
183.50 ± 1.94**
239.44 ± 2.16**
225.28 ± 2.46**
239.22 ± 2.13**
395.1 ± 3.03**
110.14 ± 2.46**
157.40 ± 3.46**
154.64 ± 2.46**
159.20 ± 1.69**
154.42 ± 1.92**
157.30 ± 1.46**
154.30 ± 1.46**
149.84 ± 3.01**
120.42 ± 2.19**
125.30 ± 2.66**
114.72 ± 1.98**
117.35 ± 1.60**
116.50 ± 3.99**
–
68.88
54.57
55.02
54.95
56.20
55.64
54.93
58.06
63.03
62.55
67.08
65.54
64.64
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
Values are represented as mean ± SEM. Data were analyzed using analysis of variance and group means were compared with Tukey-Kramer Post
ANOVA test. The values were considered when P < 0.01. **P < 0.001; Tabulated data are expressed as mean ± SEM; (n = 6).
7
b (63.03 %) and 7c (62.55 %) with substitution R = phenyl,
REFERENCES
para-methoxy phenyl, p-methyl-phenyl showed considerably
good hypoglycemic activity. In case of imidazo[1,2-a]pyridine
series, all the compounds viz., compounds 6a (54.57 %), 6b
1
.
K. Gudmundsson and S.D. Boggs, PCT Int. Appl., WO 2006026703,
CAN, 274, 144 (2006).
2. K.C. Rupert, J.R. Henry, J.H. Dodd, S.A. Wadsworth, D.E. Cavender,
G.C. Olini, B. Fahmy and J. Siekierka, Bioorg. Med. Chem. Lett., 13,
(
55.02 %), 6c (54.95 %), 6d (56.20 %), 6e (R = 55.64 %) and
3
47 (2003);
6
f (54.93 %) displayed moderate hypoglycemic activity.
https://doi.org/10.1016/S0960-894X(02)01020-X.
A.T. Baviskar, C. Madaan, R. Preet, P. Mohapatra, V. Jain, A. Agarwal,
S.K. Guchhait, C.N. Kundu, U.C. Banerjee and P.V. Bharatam, J. Med.
Chem., 54, 5013 (2011);
In general from the determined results, it is concluded that
3
.
in the main scaffold of imidazo[1,2-a]pyridine nucleus, inclusion
of pyridine ring in the second position and N-substituted aryl/
alkyl moieties viz., compounds (7a-f) reduced the glucose level
in diabetic rats. However, the impact of 7d, 7e and 7f is more
pronounced in alloxan induced diabetic rats.
Further exploration of the above established results
towards the synthesis, toxicity studies and mode of action of
hypoglycemic activity may lead to the development of an
efficient drug candidate for diabetes mellitus.
https://doi.org/10.1021/jm200235u.
4
5
6
7
.
.
.
.
N.M. Shukla, D.B. Salunke, E. Yoo, C.A. Mutz, R. Balakrishna and
S.A. David, Bioorg. Med. Chem., 20, 5850 (2012);
https://doi.org/10.1016/j.bmc.2012.07.052.
G.C. Moraski, L.D. Markley, P.A. Hipskind, H. Boshoff, S. Cho, S.G.
Franzblau and M.J. Miller, ACS Med. Chem. Lett., 2, 466 (2011);
https://doi.org/10.1021/ml200036r.
T. Ueda, K. Mizushige, K.Yukiiri, T. Takahashi and M. Kohno, Cerebrovasc.
Dis., 16, 396 (2003);
https://doi.org/10.1159/000072563.
Conclusion
K. Mizushige, T. Ueda, K. Yukiiri and H. Suzuki, Cardiovasc. Drug Rev.,
The present paper illustrates the green synthesis of imidazo-
2
0, 163 (2002);
[
1,2-a]pyridine derivatives (6a-f/7a-f) using the green para-
meters such as (i) ZnO nanoparticle/ZnFe (a magnetically
separable heterogeneous catalyst), (ii) 2-methyltetrahydrofuran
green solvent) and (iii) microwave irradiation (energy efficiency
https://doi.org/10.1111/j.1527-3466.2002.tb00085.x.
T. Swainston Harrison and G.M. Keating, CNS Drugs, 19, 65 (2005);
https://doi.org/10.2165/00023210-200519010-00008.
8
9
.
.
O
2 4
R.F. Holcombe, C.E. McLaren and T. Milovanovic, Cancer Detect. Prev.,
(
3
0, 94 (2006);
reducing time period of the reaction) utilizing the raw materials
viz., such as aryl/alkyl-aldehydes, 2-aminopyridine and aryl/
alkyl isocyanides. Evaluation of antidiabetic activity of the synth-
esized imidazo[1,2-a]pyridine derivatives 6a-f/7a-f revealed
that most of the compounds exhibited significant hypogly-
cemic property when compare to insulin as the reference drug.
In general, it is concluded that in the main scaffold of imidazo-
https://doi.org/10.1016/j.cdp.2005.08.002.
0. E.C. Mun, J.M. Mayol, M. Riegler, T.C. O’Brien, O.C. Farokhzad, J.C.
1
Song, C. Pothoulakis, B.J. Hrnjez and J.B. Matthews, Gastroenterology,
1
14, 1257 (1998);
https://doi.org/10.1016/S0016-5085(98)70432-9.
11. S.Z. Langer, S. Arbilla, J. Benavides and B. Scatton, Adv. Biochem.
Psychopharmacol., 46, 61 (1990).
2. A. Berson, V. Descatoire, A. Sutton, D. Fau, B. Maulny, N. Vadrot, G.
Feldmann, B. Berthon, T. Tordjmann and D. Pessayre, J. Pharmacol.
Exp. Ther., 299, 793 (2001).
1
[1,2-a]pyridine nucleus, inclusion of pyridine ring in the second
position and N-substituted aryl/alkyl moieties such as comp-
ounds 7d (67.0 %), 7e (65.54 %) and 7f(64.64 %) with substitution
R = cyclohexyl, ethyl and isopropyl reduced the glucose level
in diabetic rats.
13. B. Saletu, J. GrNberger and L. Linzmayer, Int. Clin. Psychopharmacol.,
1, 145 (1986);
https://doi.org/10.1097/00004850-198604000-00006.
1
1
4. J.J. Kaminski, B. Wallmark, C. Briving and B.M. Andersson, J. Med.
Chem., 34, 533 (1991);
https://doi.org/10.1021/jm00106a008.
ACKNOWLEDGEMENTS
5. Y. Jin, M.C. Rho, K. Gajulapati, H.Y. Jung, S.K. Boovanahalli, J.H.
Lee, G.-Y. Song, J.H. Choi,Y.K. Kim, K. Lee andY. Choi, Bull. Korean
Chem. Soc., 30, 1297 (2009);
The authors are thankful to Advanced Analytical Lab,
Andhra University, Visakhapatnam, India for conducting the
https://doi.org/10.5012/bkcs.2009.30.6.1297.
1
H NMR and Mass spectral analysis.

1
536 Kota et al.
Asian J. Chem.
1
1
6. M.H. Wiegand, Drugs, 68, 2411 (2008);
32. A.S. Kiselyov, Tetrahedron Lett., 46, 4487 (2005);
https://doi.org/10.2165/0003495-200868170-00001.
7. K.S. Gudmundsson, J.D. Williams, J.C. Drach and L.B. Townsend, J.
Med. Chem., 46, 1449 (2003);
https://doi.org/10.1016/j.tetlet.2005.04.124.
33. J. Dam, Z. Ismail, T. Kurebwa, N. Gangat, L. Harmse, H.M. Marques,
A. Lemmerer, M.L. Bode and C.B. de Koning, Eur. J. Med. Chem., 126,
353 (2017);
https://doi.org/10.1021/jm020339r.
1
8. J.J. Kaminski and A.M. Doweyko, J. Med. Chem., 40, 427 (1999);
https://doi.org/10.1021/jm950700s.
9. R.J. Boerner and H.J. Moller, Psychopharmakotherapie, 4, 145 (1997).
0. D.J. Sanger, Behav. Pharmacol., 6, 116 (1995).
1. T.H. Al-Tel and R.A. Al-Qawasmeh, Eur. J. Med. Chem., 45, 5848
https://doi.org/10.1016/j.ejmech.2016.10.041.
34. J.T. Litchfield and E.J.A. Wilcoxon, J. Pharmacol. Exp. Ther., 96, 99
(1949).
35. P.V. Raghavan, Expert Consultant, CPCSEA, OECD, Guideline No. 420
(2000).
1
2
2
(
2010);
36. R.J. Jarrett, H. Keen and C. Hardwick, Diabetes, 19, 724 (1970);
https://doi.org/10.2337/diab.19.10.724.
37. C.R. Mackerer, R.N. Saunders, J.R. Haettinger and M.A. Mehlman, J.
Toxicol. Environ. Health, 2, 139 (1976);
https://doi.org/10.1016/j.ejmech.2010.09.049.
2. J.E. Starrett, T.A. Montzka,A.R. Crosswell and R.L. Cavanagh, J. Med.
Chem., 32, 2204 (1989);
2
2
2
https://doi.org/10.1021/jm00129a028.
https://doi.org/10.1080/15287397609529422.
3
3
4
8. A. Shaabani,A. Maleki, J. Moghimi Rad and E. Soleimani, Chem. Pharm.
Bull. (Tokyo), 55, 957 (2007);
https://doi.org/10.1248/cpb.55.957.
9. A.L. Rousseau, P. Matlaba and C.J. Parkinson, Tetrahedron Lett., 48,
3. B. Mirmashhori, N. Azizi and M.R. Saidi, J. Mol. Catal. Chem., 247,
1
59 (2006);
https://doi.org/10.1016/j.molcata.2005.11.042.
4. A. Gueiffier, S. Mavel, M. Lhassani,A. Elhakmaoui, R. Snoeck, G.Andrei,
O. Chavignon, J.C. Teulade, M. Witvrouw, J. Balzarini, E. De Clercq
and J.-P. Chapat, J. Med. Chem., 41, 5108 (1998);
https://doi.org/10.1021/jm981051y.
5. K. Groebke, L. Weber and F. Mehlin, Synlett, 661 (1998);
https://doi.org/10.1055/s-1998-1721.
6. H. Bienayme and K. Bouzid, Angew. Chem. Int. Ed., 37, 2234 (1998);
https://doi.org/10.1002/(SICI)1521-3773(19980904)37:16<2234::
AID-ANIE2234>3.0.CO;2-R.
7. C. Blackburn, B. Guan, P. Fleming, K. Shiosaki and S. Tsai, Tetrahedron
Lett., 39, 3635 (1998);
https://doi.org/10.1016/S0040-4039(98)00653-4.
8. H. Xu, C. Ma, Z. Wu and G. Haung, Synthesis, 48, 351 (2016);
https://doi.org/10.1055/s-0035-1560375.
4079 (2007);
https://doi.org/10.1016/j.tetlet.2007.04.008.
0. L.R. Odell, M. Nilsson, J. Gising, O. Lagerlund, D. Muthas,A. Nordqvist,
A. Karlen and M. Larhed, Bioorg. Med. Chem. Lett., 19, 4790 (2009);
https://doi.org/10.1016/j.bmcl.2009.06.045.
1. S. Guchhait and C. Madaan, Synlett, 628 (2009);
https://doi.org/10.1055/s-0028-1087915.
2. A. Shaabani, E. Soleimani, A. Sarvary, H. Rezayan and A. Maleki, Chin.
J. Chem., 27, 369 (2009);
https://doi.org/10.1002/cjoc.200990060.
3. A. Shaabani, E. Soleimani,A. Maleki and J. Moghimi-Rad, Synth. Commun.,
2
2
4
4
2
4
3
8, 1090 (2008);
2
2
https://doi.org/10.1080/00397910701862931.
4
4
4. R.S. Varma and D. Kumar, Tetrahedron Lett., 40, 7665 (1999);
https://doi.org/10.1016/S0040-4039(99)01585-3.
5. M.Adib, M. Mahdavi, M.A. Noghani and P. Mirzaei, Tetrahedron Lett.,
9. R.B. Lacerda, C.K. de Lima, L.L. da Silva, N.C. Romeiro,A.L. Miranda,
E.J. Barreiro and C.A. Fraga, Bioorg. Med. Chem., 17, 74 (2009);
https://doi.org/10.1016/j.bmc.2008.11.018.
0. L.B.E. De Jesus De, F. Carlos, A. Manssour, S.G. Zapata, S. Roberto
and T.R. Menegatti, Pharmaceutical Compositions containing 1-Methyl-
4
8, 7263 (2007);
3
3
https://doi.org/10.1016/j.tetlet.2007.08.049.
4
6. S.Vidyacharan,A.H. Shinde, B. Satpathi and D.S. Sharada, Green Chem.,
3
,6,7,8-Tetrahydropirazolo[3,4-b]pyrrolo[4,3-d]Pyridine-6,8-dione
Derivatives, Use and Process for Preparing Them, WO2006092032A2
2006).
1
6, 1168 (2014);
https://doi.org/10.1039/c3gc42130a.
(
1. H.A. Shinde, M. Srilaxmi, B. Satpathi and D.S. Sharada, Tetrahedron
Lett., 55, 5915 (2014);
https://doi.org/10.1016/j.tetlet.2014.08.126.