New imidazo[1,2-a]pyridines carrying active pharmacophores: Synthesis and anticonvulsant studies

Article abstract of DOI:10.1016/j.bmcl.2012.12.035

Five new series of imidazo[1,2-a]pyridines carrying biologically active pyrazoline (4a-e), cyanopyridone (5a, b), cyanopyridine (6a-f), 2-aminopyrimidine (7a-f) and pyrimidine-2-thione (8a-d) systems were designed and synthesized as prominent anticonvulsant agents. The target compounds were screened for their in vivo anticonvulsant activity following maximal electroshock (MES) and subcutaneous pentylene tetrazole (scPTZ) methods at a small test dose of 10 mg/kg. Further, Rotarod toxicity method was used to study the toxicity profile of selected compounds. Compounds 4b, 5a, 5b, 6a, 7e and 8d possessing 4-fluorophenyl substituent at 2nd position of imidazo[1,2-a]pyridine ring displayed potent anticonvulsant activity without displaying any toxicity. Enhanced activity profile was observed for new compounds in PTZ method over MES method.

Full text of DOI:10.1016/j.bmcl.2012.12.035

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1502–1506
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
New imidazo[1,2-a]pyridines carrying active pharmacophores:
Synthesis and anticonvulsant studies
Shrikanth Ulloora a, Ramakrishna Shabaraya b, Syed Aamir b, Airody Vasudeva Adhikari a,
⇑
a Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Mangalore 575 025, Karnataka, India
b Srinivas College of Pharmacy, Valachil, Mangalore, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Five new series of imidazo[1,2-a]pyridines carrying biologically active pyrazoline (4a–e), cyanopyridone
(5a, b), cyanopyridine (6a–f), 2-aminopyrimidine (7a–f) and pyrimidine-2-thione (8a–d) systems were
designed and synthesized as prominent anticonvulsant agents. The target compounds were screened
for their in vivo anticonvulsant activity following maximal electroshock (MES) and subcutaneous pentyl-
ene tetrazole (scPTZ) methods at a small test dose of 10 mg/kg. Further, Rotarod toxicity method was
used to study the toxicity profile of selected compounds. Compounds 4b, 5a, 5b, 6a, 7e and 8d possessing
4-fluorophenyl substituent at 2nd position of imidazo[1,2-a]pyridine ring displayed potent anticonvul-
sant activity without displaying any toxicity. Enhanced activity profile was observed for new compounds
in PTZ method over MES method.
Received 11 September 2012
Revised 29 November 2012
Accepted 12 December 2012
Available online 20 December 2012
Keywords:
Imidazo[1,2-a]pyridine
Anticonvulsant activity
Toxicology
Ó 2012 Elsevier Ltd. All rights reserved.
Epilepsy is a collective term used for about 40 different types of
human seizure disorders.1 It is a major health problem that affects
approximately 1% of world population.2 Also, the cellular mecha-
nism of human epilepsy is still uncertain and hence the present
drug therapy is rather concerned only with control of epilepsy
symptoms than curing.3 Moreover, about 40% of patients are found
to experience uncontrolled seizure and is resistant to present anti-
epileptic drugs (AEDs),4 which are the only choice of medication
for epilepsy. Further, an ideal AED should keep the patient free
from any seizures without any considerable adverse effects. How-
ever, present therapy for seizure is associated with various adverse
side effects such as ataxia, hyperplasia and anaemia.5,6 Conse-
quently, development of new antiepileptic agents having improved
seizure control along with better tolerability is a major goal in epi-
lepsy research.
The non-benzodiazepines are generally used as sedatives, anti-
convulsants, hypnotics, anxiolytics and muscle relaxants as they
show less adverse effects compared to classical benzodiazepines.7
In fact, imidazopyridines are the major class of non-benzodiaze-
pines, acting upon various central nervous systems (CNS) disor-
ders. Interestingly, several imidazopyridine based drugs such as
Zolpidem, Alpidem, Saripidem, etc. exhibit potency against penty-
lenetetrazole (PTZ) induced seizures.8 The chemical structure of
some important imidazo[1,2-a]pyridine based CNS agents are gi-
ven in Figure 1. In addition to their CNS activity, recent literatures
also revealed various other applications of imidazopyridine
derivatives in medicinal chemistry. They were reported as poten-
tial antiprotozoal,9 antimicrobial,10 antiherpetic,11 anti-HIV,12 anti-
viral,13 anticancer14 and anti-inflammatory15 agents.
Design of new synthetic compounds with appropriate thera-
peutic importance is a major challenge in medicinal chemistry.
Molecular modification could be a productive source for new bio-
logically active molecules.16 Recently, imidazopyridines containing
an aryl substituent at 2nd position were reported as highly CNS ac-
tive scaffolds.17 Further, it is also revealed that, selectivity of imi-
dazo[1,2-a]pyridines towards benzodiazepine receptors can be
enhanced by incorporating a 4-halophenyl ring at 2nd position
and a hydrophobic unit at 8th position.18 Inspired by this observa-
tion, it has been planned to design new series of imidazo[1,2-
a]pyridines containing 4-fluoro substituted aryl ring at 2nd posi-
tion and a methyl group as a hydrophobic unit at 8th position of
the ring, with the expectation of improved pharmacological
activity.
The reaction sequence involving the synthesis of required imi-
dazo[1,2-a]pyridine-3-carboxaldehydes and subsequent final com-
pounds are given in Schemes 1 and 2, respectively. The compounds
1a, b and 2a, b were synthesized following reported procedure.19
These aldehydes 2a, b were stirred at 50 °C for about 4 h with dif-
ferent acetophenones under alcoholic NaOH media to obtain the
key chalcone intermediates 3a–h. Later on, these chalcones were
used as active scaffolds for the synthesis of target compounds
4a–e, 5a, b, 6a–f, 7a–f and 8a–d carrying different heterocyclic sys-
tems. Pyrazolines 4a–e were synthesized by refluxing appropriate
chalcones 3a–h with hydrazine hydrate under ethanolic media.
Further, 3-cyano-2-pyridones 5a, b were conveniently obtained
⇑
Corresponding author. Tel.: +91 8242474000x3203; fax: +91 8242474033.
E-mail addresses: avadhikari123@yahoo.co.in, avchem@nitk.ac.in (A.V. Adhikari).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.12.035

S. Ulloora et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1502–1506
1503
Cl
Br
O
Br
N
N
N
N
N
N
O
N
O
N
N
O
N
NH
N
S
Cl
Cl
Cl
Zolpidem
Alpidem
DS-1
Saripidem
Figure 1. Important imidazo[1,2-a]pyridines acting as CNS agents.
O
Br
DMF-POCl3, 0-5 °C
, 6 hrs
N
Ethanol
, 6 hrs
N
N
N
+
O
Δ
Δ
N
NH2
R1
R1=H, F
R1
R1
[2a, b]
[1a, b]
Scheme 1. Synthesis of imidazo[1,2-a]pyridine-3-carboxaldehydes.
by refluxing chalcones with ethyl cyanoacetate and ammonium
acetate under alcoholic media for about 12 h. Similarly, 2-meth-
oxy-3-cyano pyridines 6a–f were synthesized with good yield by
stirring chalcones 3a–h with malononitrile at room temperature
in sodium methoxide solution. The latter two reactions involve
the Michael addition of active methylene compounds to conju-
gated double bond, followed by internal cyclization. Finally, 2-ami-
no pyrimidines 7a–f and pyrimidin-2-thiones 8a–d were obtained
by refluxing chalcones 3a–h with guanidine hydrochloride and
thiourea, respectively in presence of alc. NaOH. Further, all the
newly synthesised final compounds were purified by either recrys-
tallization or column chromatographic techniques.
The structures of new intermediates and final compounds syn-
thesized by above mentioned routes were confirmed by various
spectral techniques like FTIR, 1H NMR, 13C NMR, mass spectroscopy
followed by elemental analysis. Synthesis of core imidazo[1,2-
a]pyridine derivative 1a, was confirmed by its FTIR spectrum,
where the peak corresponding to amine group of 2-amino-3-pico-
line and carbonyl functionality of phenacyl bromide disappeared.
Also, a new characteristic peak at 1638 cmÀ1 corresponding to
C@N stretching of the ring was observed, which clearly demon-
strate the cyclization. Similarly, the 1H NMR spectrum of 1a dis-
played a singlet at d 2.65 ppm corresponding to CH3 group
attached to pyridine ring along with other required aromatic peaks,
but no peaks corresponding to amine group was observed. Formy-
lation of core ring was clearly established by the observation of
new carbonyl stretching peak at 1678 cmÀ1 in FTIR spectrum of
2a. This was further confirmed by its 1H NMR spectrum, wherein
it displayed a singlet at d 9.98 ppm, corresponding to aldehydic
proton. Moreover, a peak at d 8.34 ppm that corresponds to CH
proton at 3rd position of the ring disappeared upon formylation,
indicating the electrophilic attack at 3rd position. The shift in car-
bonyl stretching frequency from 1678 to 1647 cmÀ1 upon reacting
aldehyde 2a with acetophenone, confirmed the formation of chal-
cone 3a. Also, appearance of two doublets in 1H NMR spectrum at d
7.95 and 7.83 ppm correspond to protons of conjugated alkenes,
further supported the proposed structure of chalcone. The coupling
constant value (J) for these olifinic protons was found to be
15.2 Hz. Similarly, for all other chalcones (3b–h), the ‘J’ values
are in the range of 14.4–16 Hz, indicating that they are stereo-
selective and attained trans (E) configuration.
FTIR spectrum of pyrazoline analogue 4a showed a new peak at
3241 cmÀ1 for NH stretching. Also, its 1H NMR spectrum displayed
a singlet at d 9.34 ppm, corresponding to pyrazoline NH proton.
Moreover, three doublets of doublets (dd) were observed for ABX
type of pyrazoline ring protons at d 5.63, 3.38 and 3.03 ppm, which
is a characteristic feature of pyrazoline systems that reveals the
proposed structure. Formation of 3-cyano-2-pyridone derivative
5a was well documented from its FTIR spectrum, which showed
characteristic peaks at 2213 cmÀ1 corresponding to nitrile func-
tionality and at 1637 cmÀ1 for cyclic amide carbonyl group. Simi-
larly, FTIR spectrum of 3-cyano-2-methoxypyridine analogue 6a
exhibited appropriate peaks at 2220 and 1582 cmÀ1, respectively,
for nitrile and pyridine C@N stretching. Conversion of chalcone
3a into 2-amino pyrimidine derivative 7a was evidenced by the
appearance of a new peak in its FTIR spectrum at 3306 cmÀ1 corre-
sponding to amine group. Also, its 1H NMR spectrum showed a sin-
glet at d 5.24 ppm confirming the proposed structure. However,
treatment of chalcones 3a–h with thiourea resulted in non-aro-
matic pyrimidine thiones 8a–d. This was confirmed by FTIR spec-
trum of 8a wherein, a signal at 3176 cmÀ1 that corresponds to
NH stretching frequency was observed. Furthermore, its 1H NMR
spectrum displayed two singlets at d 10.02 and 9.07 ppm confirm-
ing the presence of two NH groups. Also, two doublets at d 6.06 and
5.12 ppm were observed for vinylic and allylic protons, respec-
tively of the pyrimidine ring which further supported the proposed
structure. Moreover, in all above conversions, the cyclization was
evidenced by the complete disappearance of two singlets corre-
sponding to conjugated alkenyl protons of chalcones. In the same
way, the synthesis of other derivatives was also confirmed. Addi-
tionally, the structures of all target compounds were further estab-
lished by 13C NMR, mass spectral and elemental analyses. The
detailed synthetic procedure and characterization data of all these
individual compounds are given as Supplementary data.
The preclinical discovery and development of a new bioactive
chemical entity for the treatment of epilepsy rely heavily on the
use of predictable animal models. The maximal electroshock
(MES)20 and subcutaneous pentylenetetrazole (scPTZ)21 screening
methods are the two important and routinely used in vivo animal
models for the anticonvulsant studies. These two methods are rec-
ognized as the ‘gold standards’ in the early stages of testing. They
are claimed to detect new bioactive chemical entities affording

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S. Ulloora et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1502–1506
N
N
O
R1
2a, b
R2COCH3, NaOH
Ethanol, 50 oC
N
N
N
N
N
N2H4.H2O, Ethanol
, 7 hrs
CH2(CN)2, NaOMe
N
N
H
N
N
RT, 2 hrs
Δ
O
O
N
R2
R1
R1
R1
R2
R4
R4= Me, H, NO2, F
3a-h
6a-f
4a-e
R2= p-Cl Ph, Ph, p-Tolyl,
P-F Ph, Thiophen-2-yl
Ethanol, 80 o
C
H2N
H2N
NCCH2CO2Et, NH4OAc
.HCl
NaOH
NH
S
NaOH
H2N
H2N
N
N
N
N
N
N
N
H
N
O
N
N
S
H2N
N
N
H
R1
H
R1
R5
R1
R3
R6
7a-f
5a, b
R3= NO2, Cl
8a-d
R6= Cl, F, Me, H
R5= Ph, p-Cl Ph, p-NO2 Ph, p-Tolyl, Thiophen-2-yl
Scheme 2. Synthesis of new imidazo[1,2-a]pyridine derivatives.
protection to generalized tonic–clonic seizures and generalized ab-
sence seizures, respectively. Almost all clinically significant AEDs
are protective in at least one of these two models.22 In the same
way compounds found to be effective in either of these seizure
methods are termed as potential anticonvulsants.23 In our study
also, target compounds were screened for their antiepileptic prop-
erties following these methods by administering a single dose
(10 mg/kg) of test samples, 0.5 h prior to the study. Further, their
toxicity study was carried out by Rotarod method,24 that measures
motor impairment. The toxicity profiles of tested compounds was
evaluated after 0.5 and 4 h, by taking three different test doses
(10, 50 and 100 mg/kg). The screening results of MES, scPTZ and
Rotarod toxicity studies are summarized in Table 1. The experi-
mental protocols used for these in vivo studies are described in
Supplementary data.
to 2nd position of imidazo[1,2-a]pyridine nuclei displayed en-
hanced activity with latency period of 10.97 1.74 s, which is sig-
nificant when compared with that of control (2.18 0.47).
Similarly, another fluoro derivative 4a also showed good anticon-
vulsant activity (9.15 1.01). However, replacement of fluoro by
hydrogen as in 4c, 4d and 4e resulted in decreased anti-epileptic
efficacy of the molecules. The cyanopyridone derivatives 5a, b dis-
played better activity irrespective of substituents present on the
molecule indicating that cyanopyridone is an active moiety.25 In
contrast, little less activity was observed for 2-methoxy-3-cyano-
pyridines 6a–f when compared with cyanopyridone analogues.
Here also, compounds 6a and 6b displayed good results owing to
the presence of fluoro substituent on aryl ring (halo-aryl) attached
to imidazopyridine moiety. In spite of halo-aryl group present in
6c, it resulted relatively less activity which may be attributed to
the presence of electron withdrawing nitro group.26 Further, 2-
amino pyrimidine 7a–f and pyrimidine 2-thiones 8a–d exhibited
In MES method, among pyrazoline derivatives 4a–e, compound
4b carrying fluoro substituent at para position on aryl ring attached

S. Ulloora et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1502–1506
1505
Table 1
Anticonvulsant and toxicity screening results of target compounds
Sample
R1
R2/R3/R4/R5/R6
MES testa
Duration of tonic extension (s)
scPTZ testa
Toxicity studiesb
Latency (onset of clonus)
Onset times in s (mean SEM)
0.5 h
4.0 h
Conic
Tonic
Control
Diazepam
4a
4b
4c
4d
4e
5a
5b
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
15.35 0.60
—
02.18 0.47
13.17 1.29
09.45 1.01
10.97 1.74
09.28 1.11
09.25 1.15
09.33 1.25
10.88 1.31
10.97 1.74
07.94 1.53
09.90 1.41
09.13 1.01
10.77 1.33
08.72 1.36
10.90 1.44
07.95 1.50
08.80 1.32
08.16 1.21
08.11 1.43
08.86 1.50
08.72 1.36
09.90 1.41
08.04 1.25
09.75 1.32
10.91 1.45
59.2 1.11
—
385.5 10.90
—
x
x
—
—
—
x
—
—
—
x
F
F
H
H
H
F
F
F
F
F
H
H
H
F
F
F
4-Cl Ph
Ph
4-Me Ph
4-F Ph
Thiophen-2-yl
NO2
Cl
Me
H
NO2
F
NO2
Me
4-Cl Ph
4-NO2 Ph
4-Me Ph
07.21 1.30
06.54 1.14
07.22 1.32
07.15 1.07
07.27 1.11
06.61 1.21
06.54 1.14
09.84 1.17
07.77 1.01
07.01 1.15
06.96 1.23
08.52 1.41
06.85 1.06
09.88 0.98
08.67 1.01
08.15 1.71
08.27 1.37
08.71 1.25
08.52 1.41
07.77 1.01
08.13 1.76
07.45 1.51
06.87 1.12
158.7 1.54
149.3 2.24
126.7 1.74
79.32 1.23
117.7 1.05
171.8 2.22
129.2 4.17
335.3 4.58
171.5 1.83
115.7 0.84
90.87 1.70
79.32 1.23
170.7 1.74
109.7 1.60
85.33 1.70
171.4 1.74
115.7 0.85
79.50 1.23
90.83 1.70
82.50 1.70
107.0 4.32
79.34 1.23
90.83 1.70
542.2 6.74
528.2 4.85
532.5 4.81
426.8 3.23
530.8 5.51
641.5 6.07
544.7 8.77
611.5 8.45
596.0 9.64
469.2 6.09
456.7 4.55
426.8 3.23
595.7 8.46
480.2 3.84
435.8 3.73
593.2 8.47
469.2 6.09
426.8 3.22
454.7 4.55
435.0 3.94
479.7 7.22
426.5 3.23
454.7 4.55
x
x
—
—
—
—
—
x
—
—
—
x
—
100
—
—
—
x
—
—
—
x
x
x
—
—
—
—
x
—
—
—
—
—
—
—
x
—
—
—
F
Ph
H
H
F
F
H
H
Thiophen-2-yl
4-Me Ph
Cl
H
Me
F
a
Results are expressed as mean SEM; (n = 6). MES and PTZ tests were carried out at 10 mg/kg dose. The mice were examined 0.5 h post ip injection of test samples.
Toxicity study was carried out by Rotarod method at a 10, 50 and 100 mg/kg doses. The values indicate the minimum dose required to exhibit toxicity in at least 50% of
b
mice. (—) indicates the absence of toxicity, while (x) means not tested.
similar trend in their results, wherein compounds 7e and 8d con-
taining thiophene and fluoro groups displayed enhanced activity.
On the other hand, the title compounds exhibit better results in
PTZ induced anticonvulsant screening test than that of MES meth-
od. Many compounds especially, 4a, 4b, 5a, 6a, 7e and 8d exhibit
good protection against epilepsy at tested dose (10 mg/kg). In
PTZ method also, compounds with fluoro substituent on aryl ring
displays delayed onset of clonus–tonus phases, indicating their
anticonvulsant efficacy. Particularly, a cyanopyridine derivative
6a, possessing an electron donating methyl group along with
fluoro-aryl moiety exhibit the highest activity with complete pro-
tection against seizures. Further, 2-amino pyrimidine derivatives
are found to be more active analogues than corresponding
pyrimidine-2-thiones, possibly due to more hydrogen bond donor
capacity of amine group.
The toxicity study was carried out for most of the compounds
by Rotarod method. The study was performed by observing the
mice after 0.5 and 4 h of test sample administration. None of the
tested samples exhibited toxicity at both the intervals except 5a,
which showed toxicity at a high dose of 100 mg/kg (after 4 h).
The toxicity of 5a is might be due to the presence of nitro group
in the molecule. This compound remained non-toxic at 0.5 h inter-
val, indicating that the compound has slow onset of toxicity. Other
tested compounds were non-toxic at all tested doses (10, 50 and
100 mg/kg) and at both the intervals, thereby appears to be poten-
tial candidates for anticonvulsants.
in improved activity whereas less activity has been observed for
those possessing electron withdrawing groups. Similarly, motor
impairment study shows that electron withdrawing groups such
as nitro substituent induces toxicity. Despite the good activity of
4a, 4b, 5a, 5b, 6a, 7e and 8d, they are less potent when compared
with standard drug, diazepam. Nevertheless, the compounds dis-
play prominent activity at a small dose of 10 mg/kg without pro-
ducing toxicity. This clearly indicates that there is a good scope
for the development of new imidazo[1,2-a]pyridine based potent
antiepileptic agents through suitable structural modifications.
In conclusion, new series of imidazo[1,2-a]pyridines carrying
various heterocyclic systems were conveniently designed and syn-
thesized. These target compounds were confirmed by FTIR, 1H
NMR, 13C NMR, mass spectral followed by elemental analyses stud-
ies. The final compounds were screened for their in vivo anticon-
vulsant activities following MES and scPTZ methodologies.
Additionally, toxicity study was carried out following Rotarod
method and they are found to be non-toxic at all tested doses.
Many compounds such as 4a, 4b, 5a, 5b, 6a, 7e and 8d exhibit
the prominent anticonvulsant activity in very small dose, that is
at 10 mg/kg. Particularly, compounds possessing 4-fluorophenyl
ring attached at 2nd position of imidazo[1.2-a]pyridine moiety re-
sulted in enhanced activity. These results confirms that imi-
dazo[1,2-a]pyridines carrying 4-fluorophenyl substituent at 2nd
position is an appropriate structural feature for significant anticon-
vulsant properties and it can be used as a template for further
modifications and investigations to get new active analogues.
When we correlate the structures of the test samples and their
activity, it appears that presence of 4-fluorophenyl group at 2nd
position of imidazo[1,2-a]pyridine ring is responsible for enhanced
anticonvulsant activity. Additionally, the in vivo results also indi-
cate that the presence of heterocyclic systems at 3rd position im-
proves their efficacy. Further, significant influence on the activity
is observed when different substituents are present on these
heterocyclic ring systems. The presence of electron rich aryl and
halophenyl substituents on these heterocyclic systems has resulted
Acknowledgments
The authors are thankful to National Institute of Technology
Karnataka, India for financial support, Indian Institute of Science,
Bangalore, India for NMR facilities and SAIF, Punjab, SAIF, Shillong
for mass spectral facilities.

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