Substituted 2-[2-(pyridin-3-yl) phenyl] acetamides and ureas: Design, synthesis, and anticonvulsant screening in mice

Article abstract of DOI:10.1007/s00044-011-9717-y

Five novel 2-[2[(pyridin-3-yl) phenyl] acetamides and ureas were designed based on a two-point pharmacophore, synthesized by improved methods, and screened for anticonvulsant activity in maximal electroshock seizure (MES) and ScPTZ-induced seizure models in Swiss mice at doses of 30, 100, and 300 mg/kg body weight. Compound 15 displayed potent anticonvulsant activity in MES test with ED₅₀ value of 8.28 mg/kg and higher protective index (TD ₅₀/ED₅₀ = 26) compared with Phenytoin, which can be considered as a promising lead.

Full text of DOI:10.1007/s00044-011-9717-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1929–1934
DOI 10.1007/s00044-011-9717-y
ORIGINAL RESEARCH
Substituted 2-[2-(pyridin-3-yl) phenyl] acetamides and ureas:
design, synthesis, and anticonvulsant screening in mice
•
A. V. Shindikar C. L. Viswanathan
Received: 28 March 2010 / Accepted: 16 June 2011 / Published online: 7 July 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Five novel 2-[2[(pyridin-3-yl) phenyl] aceta-
mides and ureas were designed based on a two-point
pharmacophore, synthesized by improved methods, and
screened for anticonvulsant activity in maximal electro-
shock seizure (MES) and ScPTZ-induced seizure models in
Swiss mice at doses of 30, 100, and 300 mg/kg body
weight. Compound 15 displayed potent anticonvulsant
activity in MES test with ED50 value of 8.28 mg/kg and
higher protective index (TD50/ED50 = 26) compared with
Phenytoin, which can be considered as a promising lead.
Inhibition of neuronal cation conductance is a proven
mechanism wherein drugs like Phenytoin and Carbamaz-
epine act to control seizures (Taylor, 1996). In our previous
study, a series of derivatives of anilinophenylacetamides
were found to have anticonvulsant activities among which
1-{[2-(Phenylamino) phenyl] acetyl}-2-pyrrolidinone (14)
showed the strongest activity with a median effective dose
(ED50) value of 8.0 mg/kg in maximal electroshock seizure
(MES) test and protective index (PI) (ED50/TD50) value of
87.5, which was much greater than the PI value of the
prototype drug Phenytoin (Shindikar et al., 2006). These
findings prompted us to find more molecules possessing
better therapeutic action.
Keywords Phenylacetamides ꢀ Phenylacetylureas ꢀ
Pyridinylphenylacetamides ꢀ MES test ꢀ ScPTZ test
Introduction
Epilepsy is one of the most frequent neurological afflic-
tions in man characterized by excessive temporal neuronal
discharges resulting in uncontrolled convulsions. It is
estimated that there are *50 million people with epilepsy
worldwide (Duron et al., 2005; Loscher, 1998). Marketed
anticonvulsants suffer from a broad range of adverse
effects such as ataxia, gingival hyperplasia (Phenytoin),
vertigo, rash (Carbamazepine), and Stevens–Johnson syn-
drome (Lamotrigine) (Linn and Kadaba, 1997; Perucca,
1996). A significant group of patients (20–30%) are resis-
tant to the currently used therapeutic agents (Kwan et al.,
2000). Thus, the need for more efficacious drugs is
imperative.
Phenylacetamides and related compounds are known to
possess wide range of biological activities (Almasirad
et al., 2006; Afantitis et al., 2006; Ertan et al., 2007; Lee
et al., 1994; Rineh et al., 2007). In order to search for more
active compounds which would fit the derived pharmaco-
phore, we designed and prepared a series of 2-[2-(pyridin-
3-yl) phenyl] acetamides. The new compounds were
evaluated as anticonvulsant agents in experimental epi-
lepsy models, i.e., MES test and pentylenetetrazole-
induced seizure (ScPTZ) test. The rotarod test was
performed to evaluate neurotoxicity.
A. V. Shindikar (&) ꢀ C. L. Viswanathan
Department of Pharmaceutical Chemistry, The Bombay College
of Pharmacy, Kalina, Santacruz (East), Mumbai 400098, India
e-mail: anandshindikar@gmail.com
123

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Med Chem Res (2012) 21:1929–1934
Results and discussion
Synthesis of compounds 18 and 19 has also been
achieved by a novel method i.e., lead-tetraacetate-cata-
lyzed oxidative rearrangement of amides to ureas
(Scheme 2). It involves formation of a complex with lead
tetraacetate to give isocyanate, which on treatment with
amine offers the substituted urea. This method offered
many advantages such as (i) one pot synthesis and (ii) cost
effectiveness.
Design
Molecular Operating Environment software version 2003
on a Pentium IV 1.6 GHz workstation was utilized for
designing test compounds. The training set comprised
anticonvulsants-Phenytoin, Carbamazepine, Lamotrigine,
Remacemide, Rufinamide, and Zonisamide. Superposition
of the minimum energy conformers of each of the mole-
cules of the training set led to identification of common
structural features like presence of at least one aromatic
ring (Aro.) and a hydrogen bond acceptor/donor (H.A/D)
unit (Fig. 1). This query was subjected to 3D database
search wherein molecules obeying the distance constraints
were retrieved. Among these were 2-aryl-substituted
phenylacetamides. Out of these, 2-heteroaryl substituent
was chosen based on lipophilicity. Modifications in the
amide functionality led to the generation of the novel set of
molecules.
Pharmacology
Results of anticonvulsant screening (Table 1) showed that
Compound 15 had potent anticonvulsant activity in MES
test. It was, therefore, further tested at doses ranging from
23 to 2.0 mg/kg, and an ED50 value determined was
8.28 mg/kg (Table 2). Compounds 16 and 17 were, how-
ever, not effective. Compounds 18 and 19 reduced the
duration of seizure ( to 8.0–10.0 s) and prevented death. In
chemically induced seizures, test compounds did not
completely abolish seizures.
Compound 15 was subjected to neurotoxicity testing so
as to determine its protective index.
Chemistry
In conclusion, we were able to obtain in this study a new
lead compound 15 with anticonvulsant activity comparable
with standard drugs like Phenytoin and/or Carbamazepine.
15 also exhibited higher protective index compared to
Phenytoin. The present study indicates that derivatization
of the parent amide (15) into more substituted amides or
into ureas has led to loss of activity. In biphenyl systems,
there is restricted rotation between the two aromatic rings.
When either of the rings is substituted with a side chain, the
molecule cannot reach the desired minimum energy con-
formation essential for binding to the receptor. This results
in higher energy of the system. Another factor responsible
for unfavorable binding to the receptor may have some
bearing on the steric effect of large amide functionality or
on the size of the Na channel pores.
Synthesis of test compounds was accomplished using 2-[2-
(pyridin-3-yl) phenyl] acetamide (15)as shownin Scheme 1.
Condensation of compound 15 with semicarbazide hydro-
chloride/thiosemicarbazide at higher temperatures (180°C)
led to synthesis of 16 and 17, respectively. Similarly,
reaction of 15 with cyclohexylamine/tert-butyl amine in
the presence of lead tetra-acetate at room temperature gave
high yields of compounds 18 and 19, respectively.
In the present study, synthesis of substituted amides (16
and 17) was achieved more efficiently by a novel process,
which involved condensation of compound 15 with various
amines in acidic environment. Under these conditions the
amide i.e., 15 was converted into a good acylating agent
which caused the reaction taking place in a short period of
time. The above reaction when carried out without the
addition of acid required longer period of time (Sowa and
Nieuwland, 1937). The conventional method of synthe-
sizing amides involves converting the corresponding acid
to the acid chloride followed by treatment with amine,
which is accompanied by the formation of side products. It
is also difficult to handle acid chlorides because of their
unstable nature. The present method has overcome all these
difficulties.
Experimental
Synthesis
Progress of all the reactions was monitored by thin-layer
chromatography using Merck precoated silica gel GF 254.
Melting points were recorded on an electrically heated
melting point apparatus. Infrared (IR) spectra were
recorded on JASCO FT-IR 5300. Nuclear magnetic res-
onance (1H-NMR) spectra were recorded on VARIAN-
VXR-300 S at 300 MHz instrument and chemical shifts
were expressed in ppm relative to tetramethylsilane as an
internal standard.
° A
3.43-4.70
Aro.
H.A/D
Fig. 1 Pharmacophore for anticonvulsant activity
123

Med Chem Res (2012) 21:1929–1934
1931
Scheme 1 Synthesis route of
compounds 15–19
Synthesis of 2-[2-(pyridin-3-yl) phenyl] acetamide (15)
was stirred for 2 h and the solid precipitated out was fil-
tered off. The solid was then washed with water, dried, and
recrystallized from aqueous ethanol.
2-[2-(pyridin-3-yl) phenyl] acetic acid (a) (35 g, 0.16 mol)
was reacted with redistilled thionyl chloride (24.4 g,
0.20 mol) for an hour. The 2-[2-(pyridin-3-yl) phenyl]
acetyl chloride thus obtained was cooled to 10°C. To this
was added ammonia solution in a dropwise manner with
stirring. After addition was complete, the reaction mixture
Table 1 Anticonvulsant screening data of test compounds 15–19
Compound
administered
Protection against
maximal electroshock
induced seizures
Protection against
subcutaneous
Pentylenetetrazole
induced seizures
O
O
O
0.5 h
???
–
4.0 h
???
–
0.5 h
4.0 h
H
H
O
O
15
–
–
–
–
–
–
–
–
–
–
O
R
N
H
. .
16
R
N
Pb(OAc)3
. .
Pb(OAc)3
17
–
–
18
–
–
19
–
–
Phenytoin
Carbamazepine
Diazepam
Phenobarbitone
Vehicle treated
???
???
???
???
. .
N
O
O
R' NH2
???
???
–
???
???
–
R
:
N
R
rearrangement
. .
N
N
–
–
R'
R
Statistical analysis was conducted by the method of Litchfield and
Wilcoxon (1949), P \ 0.025 compared to vehicle treated control
groups
O
substituted urea
??? activity at 30 mg/kg, ?? activity at 100 mg/kg, ? activity at
300 mg/kg, – no activity even at 300 mg/kg
Scheme 2 Mechanism of lead-tetraacetate-catalyzed synthesis of
substituted ureas
123

1932
Med Chem Res (2012) 21:1929–1934
Yield ¼ 60 %; Melting point ¼ 180ꢁ181ꢂC:
Table 2 Effective dose and protective index of Compound 15
Compound
MES EDa50
TDa50
Protective
index (PI)b
1H-NMR (DMSO-d6): 8.5 (m, 1H, Ar); 7.8 (m, 2H, Ar);
7.4–7.1 (m, 5H, Ar); 5.2 (s, 2H, NH2); 3.4 (s, 2H, –CH2–).
IR (KBr) cm-1: 3240 (N–H), 1682 (C=O). MS: m/z 287
(M ? 1); Anal. Calcd. for C14H14N4OS: C 58.72; H 4.93;
N 19.57; O 5.59; S 11.20. Found: C 58.0; H 4.95; N 19.49;
O 5.63; S 11.11.
15
8.28 [0.5]
9.5 [2.0]
215 [0.5]
66 [2.0]
26
Phenytoin
6.9
a
ED50 and TD50 values are in mg/kg. Numbers in parentheses are
95% confidence intervals. The dose data was obtained at the ‘time of
peak effect’ (indicated in hours in square brackets)
b
Synthesis of 1-cyclohexyl-3-{[2-(pyridin-3-yl) phenyl]
methyl}-urea (18)
PI calculated as (TD50/ED50
)
A 250-ml round-bottomed flask was charged with (15)
(12.0 g, 0.057 mol) in 40 ml of dry N,N-dimethylform-
amide. To this was added lead tetraacetate (25.2 g,
0.057 mol), and the reaction mixture stirred for 20 min
after which the corresponding isocyanate was formed.
Cyclohexylamine (10 g, 0.1 mol) was added dropwise and
the reaction mixture stirred for 1 h. The reaction mixture
was then quenched in cold water, and the precipitate
obtained was filtered off. The solid was washed with dilute
HCl followed by washing with water and then dried. The
product was purified by column chromatography (petro-
leum ether 70: chloroform 30).
Yield ¼ 81%: Melting point ¼ 124ꢁ125ꢂC
1H-NMR (DMSO-d6): 8.5 (m, 1H, Ar); 7.8 (m, 2H, Ar);
7.4–7.1 (m, 5H, Ar); 5.2 (s, 2H, NH2); 3.4 (s, 2H, –CH2–).
IR (KBr) cm-1: 3393 (N–H), 1685 (C=O); MS: m/z 213
(M ? 1); Anal. Calcd. for C13H12N2O: C 73.57; H 5.70; N
13.20; O 7.54. Found: C 73.52; H 5.60; N 13.25; O 7.49.
Synthesis of N-(carbamoylamino)-2-[2-(pyridin-3-yl)
phenyl] acetamide (16)
A mixture of (15) (0.057 mol, 12.0 g) and semicarbazide
hydrochloride (0.05 mol, 5.5 g) was stirred in a 250-ml
round-bottomed flask equipped with a reflux condensor.
The reaction mixture was heated to 180°C for 20 min.
After cooling to room temperature, 100 ml of water was
added and the mixture stirred for 20 min. The solid
obtained was filtered off, washed with sodium bicarbonate
solution followed by washing with water, and dried. The
product was recrystallized from aqueous ethanol.
Yield ¼ 84%: Melting point ¼ 245ꢁ246ꢂC:
1H-NMR (DMSO-d6): 8.5 (m, 1H, Ar); 7.8 (m, 2H, Ar);
7.4–7.1 (m, 5H, Ar); 5.4 (s, 2H, NH2); 3.8 (s, 2H, –CH2–);
3.5 (m, 1H, –CH–); 2.5–2.4 (m, 5H, cyclohexyl). IR (KBr)
cm-1: 3389 (N–H), 1653 (C=O). MS: m/z 310 (M ? 1);
Anal. Calcd. for C19H23N3O: C 73.78; H 7.44; N 13.58; O
5.17. Found: C 73.69; H 7.42; N 13.62; O 5.12.
Yield ¼ 78%; Melting point ¼ 248ꢁ250ꢂC:
Synthesis of 3-tert-butyl-1-{[2-(pyridin-3-yl) phenyl]
1H-NMR (DMSO-d6): 8.5 (m, 1H, Ar); 7.8 (m, 2H, Ar);
7.4–7.1 (m, 5H, Ar); 5.2 (s, 2H, NH2); 3.4 (s, 2H, –CH2–).
IR (KBr) cm-1: 3240 (N–H), 1682 (C=O). MS: m/z 271
(M ? 1); Anal. Calcd. for C14H14N4O2: C 62.21; H 5.22;
N 20.73; O 11.84. Found: C 62.29; H 5.15; N 20.68; O
11.79.
methyl}-urea (19)
A 250-ml round-bottomed flask was charged with (15)
(12.0 g, 0.057 mol) in 40 ml of dry N,N-dimethylform-
amide. To this was added lead tetraacetate (25.2 g,
0.057 mol) and the reaction mixture stirred for 20 min after
which the corresponding isocyanate was formed. tert-
butylamine (7.3 g, 0.1 mol) was added dropwise, and the
reaction mixture was stirred for 1 h. The reaction mixture
was then quenched in cold water, and the precipitate
obtained was filtered off. The solid was washed with dilute
HCl followed by washing with water, and then dried. The
product was purified by column chromatography (petro-
leum ether 70: chloroform 30).
Synthesis of N-(carbamothioylamino)-2-[2-(pyridin-3-
yl) phenyl] acetamide (17)
A mixture of (15) (0.057 mol, 12.0 g) and thiosemicarba-
zide (0.05 mol, 4.5 g) was taken in a 250-ml round-bot-
tomed flask equipped with a reflux condensor. To the above
mixture boron trifluoride etherate was added, and the
reaction mixture was heated to 180°C for 20 min. After
cooling to room temperature, 100-ml of ice-water was
added and the mixture stirred for 20 min. The solid
obtained was filtered off, washed with dilute HCl followed
by washing with water, and dried. The product was
recrystallized from absolute ethanol.
Yield ¼ 81%: Melting point ¼ 232ꢁ233ꢂC:
1H-NMR (DMSO-d6): 8.5 (m, 1H, Ar); 7.8 (m, 2H, Ar);
7.4–7.1 (m, 5H, Ar); 5.4 (s, 2H, NH2); 3.8 (m, 2H, –CH2–);
2.0 (m, 9H, t-butyl). IR (KBr) cm-1: 3389 (N–H), 1653
(C=O). MS: m/z 284 (M ? 1); Anal. Calcd. for C17H21N3O:
123

Med Chem Res (2012) 21:1929–1934
1933
ꢀ
ꢁ
C 72.08; H 7.42; N 14.84; O5.65. Found: C 71.98; H 7.37; N
14.91; O 5.61.
log Dk ꢁ log Di
n ꢁ 1
r ¼ logꢁ1
where r is the ratio of dosage of adjacent group, Dk is the
maximum dosage, Di is the minimum dosage, and n is the
number of groups
Pharmacology
Experimental protocol was approved by Institutional Ethics
Committee (Regd.No. 242/CPCSEA). Swiss albino male
mice in the weight range of 25–30 g were used. Mice were
fed on standard laboratory diet and supplied with drinking
water. Acute toxicity studies were carried out according to
OECD guidelines (1998, 2001) to ascertain the safety of
the compounds (15–19) before performing anticonvulsant
activity testing. Test compounds (15–19) were suspended
in 0.5% tween80 and administered intraperitoneally at
three dose levels (30, 100, and 300 mg kg-1) and were
screened for anticonvulsant activity using MES and
ScPTZ-induced seizure models (OECD, 1998, 2001; Clark
et al., 1984; Krall et al., 1978).
ꢀ
ꢁ
log 23 ꢁ log 2
9 ꢁ 1
r ¼ logꢁ1
r ¼ 1:355
ED50 value was then determined by the following
formula:
"
#
ED50 ¼ logꢁ1 Xk ꢁ kꢁ1 ðPn þ Pnþ1
Þ
X
i
2 n¼1
where Xk is the logarithm of maximum dosage, and i is the
logarithm of ratio of adjacent groups, i.e., log(r)
kꢁ1 ðPn þ Pnþ1Þ ¼ 80
X
n¼1
MES test
Cumulative total of number of mice showing positive
The mice were subjected to electrical current delivered
through corneal electrodes (40 mA, 50 Hz for 0.2 s) at 0.5
and 4.0 h after administration of test/standard compounds.
Failure to extend the hind limbs to an angle with the trunk
greater than 908 was defined as protection.
response in each group was 80.
ꢂ
ꢃ
logð1:355Þ
ED50 ¼ logꢁ1 logð23Þ ꢁ
ꢃ ð80Þ
2
ED50 ¼ logꢁ1ð1:3617 ꢁ 5:280Þ
ꢄ
ꢅ
ED50 ¼ logꢁ1 3:9183
ScPTZ test
ED50 ¼ 8:285
Pentylenetetrazole at a dose of 85 mg/kg was administered
subcutaneously at 0.5 and 4.0 h after administration of test/
standard compounds. Protection was defined as a failure to
observe a single episode of clonic spasms of at least 5 s
duration during a 30-min period following administration
of test/standard compound.
Determination of Median Neurotoxic dose (TD50)
of Compound 15
Rotarod Test
The median minimal neurotoxic dose (TD50) in mice was
determined by the rotarod procedure. Suspension of com-
pound 15 in 0.5% tween80 in saline was administered
intraperitoneally with dose levels in increasing order
(100–600 mg/kg). The mice were placed on a 1-inch-
diameter knurled plastic rod rotating at 6 rpm. Unimpaired
mice can easily remain on a rod rotating at this speed. The
inability of the mice to maintain their balance for at least
1 min in three successive trials was interpreted as dem-
onstration of motor impairment or toxicity. Results are
shown in Table 2.
Determination of ED50 of compound 15
ED50 is a the dosage that makes half of the animals react
positively to dugs. Karber’s method is commonly used to
determine ED50. In this method, the drug dosage is arran-
ged by geometric progression growth. First, the dose range
of 100 and 0% positive responses to drug is determined
according to experience or the literature data. As per our
observations during anticonvulsant screening, the mice
responded positively till 30 mg/kg for compound 15
(Table 1). Hence, the dose was further lowered, wherein
23.0 and 2.0 mg/kg were found as doses having 100 and
0% positive responses, respectively. Nine groups of mice
were administered the dosage which was calculated from
the following formula
TD50 is a the dosage that produces neurotoxicity in 50%
of animal population. The drug dosage is arranged by
geometric progression growth. First the dose range pro-
ducing 0 and 100% negative response i.e., inability of the
mouse to easily remain on a rod 1-inch diameter knurled
123

1934
Med Chem Res (2012) 21:1929–1934
1-(3, 3-diphenyl propyl)-piperidinyl phenyl acetamides on CCR5
binding affinity using QSAR and virtual screening techniques.
J Comp-Aided Mol Des 20:93–95
plastic rod rotating at 6 rpm for at least 1 min on admin-
istration of drug is determined. As per our observations, the
mice responded positively i.e., remained on rod till
100 mg/kg. Hence, the dose was progressively increased
till 600 mg/kg, when all the mice fell off the rod. Eight
groups of mice were administered the dosage that was
calculated from the following formula:
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ꢀ
ꢁ
log Dk ꢁ log Di
n ꢁ 1
r ¼ logꢁ1
where r is the ratio of dosage of adjacent group, Dk is the
maximum dosage, Di is the minimum dosage, and n is the
number of groups
ꢀ
ꢁ
logð600Þ ꢁ logð100Þ
8 ꢁ 1
r ¼ logꢁ1
r ¼ 1:29
TD50 value was determined by the following formula:
"
#
TD50 ¼ logꢁ1 Xk ꢁ kꢁ1 ðPn þ Pnþ1
Þ
X
i
2 n¼1
where Xk is the logarithm of maximum dosage, and i is the
logarithm of ratio of adjacent groups, i.e., log (r)
kꢁ1 ðPn þ Pnþ1Þ ¼ 74
X
n¼1
Cumulative total of number of mice falling off the rod in
OECD (Organization for Economic Cooperation and Development,
1998, 2001 USA) guidelines
each group was 74.
ꢂ
ꢃ
logð1:290Þ
Perucca E (1996) The new generation of antiepileptic drugs:
advantages and disadvantages. Br J Clin Pharmacol 42:531–543
Rineh A, Mahmoodi N, Abdollahi M, Fouramadi A, Sorkhi M,
Shafiee A (2007) Synthesis, analgesic and anti-inflammatory
activity of 4-(2-phenoxyphenyl) semicarbazones. Arch Pharm
Chem Life Sci 340(8):409–415
Shindikar AV, Khan F, Viswanathan CL (2006) Design, synthesis and
invivo anticonvulsant screening in mice of novel phenylaceta-
mides. Eur J Med Chem 41(6):786–792
TD50 ¼ logꢁ1 logð600Þ ꢁ
ꢃ ð74Þ
2
TD50 ¼ logꢁ1ð2:7782 ꢁ 4:1107Þ
ꢄ
ꢅ
TD50 ¼ logꢁ1 1:3325
TD50 ¼ 215:0
Acknowledgments The authors are grateful to the Council of Sci-
entific and Industrial Research (C.S.I.R.), Govt. of India for funding
the project.
Sowa FJ, Nieuwland JA (1937) Organic reactions with boron fluoride.
XIV. the reaction of amides with acids and amines. J Am Chem
Soc 59:1202–1203
Taylor CP (1996) Voltage gated Na? channels as targets for
anticonvulsant, analgesic and neuroprotective drugs. Curr Pharm
Des 2:375–381
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123