Design and synthesis of 3,5-diarylpiperidin-2,6-diones as anticonvulsant agents

Article abstract of DOI:10.1016/j.bmcl.2011.11.035

The present Letter describes a one-pot multi-component method that allows the efficient and mild preparation of 3,5-diphenylpiperidin-2,6-dione and a new series of 3,5-diarylpiperidin-2,6-dione derivatives from ethyl 2-arylacetates, formaldehyde and ammon

Full text of DOI:10.1016/j.bmcl.2011.11.035

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1263–1266
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Bioorganic & Medicinal Chemistry Letters
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Design and synthesis of 3,5-diarylpiperidin-2,6-diones as anticonvulsant agents
⇑
Mariappan Babu, Kasi Pitchumani, Penugonda Ramesh
Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The present Letter describes a one-pot multi-component method that allows the efficient and mild prep-
aration of 3,5-diphenylpiperidin-2,6-dione and a new series of 3,5-diarylpiperidin-2,6-dione derivatives
from ethyl 2-arylacetates, formaldehyde and ammonia/aliphatic/aromatic amines. The structures of the
compounds were elucidated by IR, NMR spectroscopic data and microanalyses. The anticonvulsant activ-
ities of these compounds were evaluated by maximal electroshock seizure test and were also evaluated
for motor impairment. Among the synthesized compounds, 5a, 5b, 5d, and 5e could be considered poten-
tially the most useful and safe therapeutic compound and 5g, 5i, 5j, 5m, and 5o exhibit potent activities.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 19 March 2011
Revised 28 October 2011
Accepted 7 November 2011
Available online 18 November 2011
Keywords:
3,5-Diarylpiperidin-2,6-dione
Maximal electroshock seizure
Anticonvulsant
Motor impairment
Epilepsy is a neurological disorder characterized by unprovoked
seizures, and affects at least 50 million people worldwide. There is
a continuing demand for new anticonvulsant agents as it has not
been possible to control every kind of seizure with the currently
available antiepileptic drugs.1,2 Phenobarbital, mephobarbital3
(barbituric acid derivatives) and phenytoin are used for the
treatment of epilepsy which are very effective in controlling the
seizures but they suffer from major side effects such as sedation,
and hypnosis. Many piperidone derivatives4–6 are also well known
for their pronounced anticonvulsant activity. In continuation of our
program on the pharmacological evaluation of heterocyclic com-
pounds we discuss herein the synthesis and anticonvulsant activity
of highly substituted piperidones, with an in vivo efficacy approach
to furnish drugs which are expected to exert activity atleast
comparable to that of the standard anticonvulsant drug. We have
selected maximal electroshock seizure test (MES Test) to get a first
hint for efficacy and safety. We are therefore interested in synthe-
sizing the highly substituted piperidone derivatives, in which
nitrogen is flanked on both sides by carbonyls and substituted
bulky groups i.e. o-chlorphenyl at positions 3 and 5 to study its
biological and pharmacophoric properties, and another series of
piperidones substituted at amide nitrogen also prepared for exten-
sive studies, to the date only one major synthetic strategy has been
reported to access the core ring 3,5-diarylpiperidindiones (5a) (ap-
proach 1), (Scheme 1), i.e. through the ammoniation of anhydride7
and these approaches are limited in that it involves multisteps and
low yields, therefore it is considered worthwhile to synthesize and
study their activities.
We report here an efficient one-pot, three component synthesis
of 3,5-diphenylpiperidin-2,6-dione (5a) along with a series of
N-substituted-3,5-diarylpiperidin-2,6-diones (5b–p) by condens-
ing ethyl-2-arylacetates (6) with formaldehyde and ammonia/ali-
phatic/aromatic amines (Scheme 2) and the results are tabulated
(Table 1).
The product of the reaction between ethyl 2-phenylacetate,
formaldehyde and ammonia has been characterised as 3,5-diph-
enylpiperidin-2,6-dione8 5a by its IR, 1H NMR, 13C NMR spectro-
scopic data.9 It gave positive test for nitrogen and the presence of
–NH is evident by an IR band (3246 cmÀ1) and a downfield one
proton singlet at d 11.10 that exchanged with D2O. Further, the
possible presence of an amide carbonyls suggested by IR band at
1648 cmÀ1 was confirmed by a downfield carbon signal at d
176.90. The 1H NMR spectrum of 5a displayed only three signals
due to aliphatic protons. A pair of one proton triplets at d 1.79
(J = 9.6 Hz) and 2.04 (J = 1.8 Hz) were assigned to axial Ha and
equatorial He of C-4 which were split by the adjacent enantiotopic
hydrogens of C-3 and C-5 and the coupling interactions between
the geminal protons are negligible. A two proton doublet of dou-
blet at d 3.8 (J = 9.6 and 1.8 Hz) was ascribed to enantiotopic hydro-
gens of C-3 and C-5 which were split by the adjacent axial and
equatorial hydrogens of C-4. The 13C NMR spectrum of (5a) dis-
played only three aliphatic carbon signals (31.8, 44.3 & 176.9)
revealing a high degree of symmetry in the molecule. The magni-
tude of coupling constants between adjacent ring protons (e-H-4/
a-H-4 and H-3&5) and the symmetrical nature of ring system sug-
gests that the heterocyclic ring adopts a deformed chair conforma-
tion10 (Scheme 2). Based on the above data, compound 5a has been
characterised as 3,5-diphenylpiperidin-2,6-dione. Its melting point
and spectral data are in good agreement with the published data
for the natural sample isolated from Derris indica.10 The efficacy
⇑
Corresponding author. Tel.: +91 0452 2458471.
E-mail address: npc_ramesh@yahoo.com (P. Ramesh).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.11.035

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M. Babu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1263–1266
Scheme 1. The available approaches for the synthesis of 2,5-diphenylpiperidin-2,6-diones 5a.
Scheme 2. Synthesis of 3,5-diarylpiperidin-2,6-diones 5a–p from ethyl-2-phenylacetate 6.
Table 1
The compounds 5a–p substituted with substituted phenyl moi-
eties at the 3,5-position of piperidine-2,6-diones, shows varying
degree of anticonvulsant activity. It was observed that compounds
5a, 5b, 5d and 5e exhibited excellent activity compared to stan-
dard, and the compounds 5g, 5i, 5j, 5m and 5o exhibited high
activity, however compounds 5c, 5f, 5h, 5n and 5p exhibited a low-
er degree of anticonvulsant activity (Table 2).
In this study, the MES seizure model was used for preliminary
(phase-I) screening of the compounds and the results were pre-
sented in Table 2. As shown in Table 2, all of the compounds were
active in the MES test, indicative of their ability to prevent seizure
spread.
From general structure/activity relationship observations, it ap-
pears that the existence of a hydrophobic unit (Ar), an electron do-
nor group (D) and hydrogen-bonding domain (HBD) are crucial for
bioactivity, as evidenced by the active drugs, such as carbamaze-
pine or phenytoin, fulfilling these demands. These units that have
critical interactions with the cell receptor constitute the pharma-
cophore and are vital for anticonvulsant activities, in continuation,
compounds with hydrogen at glutarimide nitrogen (5a and 5i)
showed good activity among all the synthesized compounds.
As a result of preliminary screening, compounds were subjected
to phase-II trials for quantification of their anticonvulsant activity
(indicated by ED50) and neurotoxicity (indicated by TD50) in mice.
We found that the ED50 values for all the compounds were, typi-
cally, 10–80 except 5f and only 5f, 5h, 5k and 5n exhibited activ-
ities greater than 50 mg/kg. With an ED50 value of 11.0, 10.0 and
11.2 respectively, compounds 5a, 5e and 5m were nearly equipo-
tent to carbamazepine. Among the tested compounds, 5a and 5b
Synthesis of 3,5-diphenylpiperidin-2,6-diones 5 (a–p) from phenylaceticester 6
S. no.
Substrate
Reaction time (h)
Yield (%)
5a–p
R1
R2
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
3.0
5.0
4.0
3.5
3.5
4.5
5.0
4.5
3.5
5.0
5.5
4.5
3.5
4.0
4.0
4.5
91
72
76
82
80
78
78
82
80
71
75
82
89
73
79
83
CH3
C6H5–
C6H5CH2–
NH2
m-C6H4Cl
o-C6H4CH3
p-C6H4CH3
H
CH3
C6H5 -
C6H5CH2-
NH2
m-C6H4Cl
o-C6H4CH3
p-C6H4CH3
of this synthetic route was assessed by condensing substituted
ethyl-2-arylacetates with various aliphatic and aromatic amines.
In all cases, 3,5-diarylpiperidin-2,6-diones are obtained in excel-
lent yields as sole products without any side products.
All the newly synthesized compounds were tested in vivo in
order to evaluate their anticonvulsant activity, by MES Test11
(Table 2) and the statistically analysed results of motor impair-
ment screening and rotarod test were reported in Table 3.

M. Babu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1263–1266
1265
Table 2
Anticonvulsant and motor impairment screening of the compounds 5 (a–p)
Intraperitoneal injection in mice
MES Test
Motor impairment screena
Compounds 5a–p
Dose (mg/kg)
Duration of extension phase in sec
% Inhibition of extension phase
0.5 h
4 h
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
2.92 0.18
3.42 0.44
7.63 0.33
3.61 0.32
2.65 0.30
9.32 0.20
4.31 0.32
8.63 0.37
4.91 0.34
4.22 0.24
6.48 0.28
5.64 0.25
3.31 0.34
7.22 0.24
4.48 0.28
5.64 0.25
11.68 0.33
2.11 0.25
70. 22
69.11
38.26
64.53
76. 01
32. 24
66.07
43.28
58.32
61.72
40. 56
58.23
73.32
43.72
60.56
58.23
—
—
—
300
—
—
—
—
—
300
—
300
—
—
300
—
—
—
100
300
—
—
300
300
100
—
100
—
—
300
—
—
300
Normal
Phenytoin sodium (standard)
0.1 mL saline
25
80.73
a
Doses of 30, 100 and 300 mg/kg were administered. The animals were examined 0.5 and 4.0 h after injection were made. The dash (—) indicates the absence of activity at
maximum dose administered (300 mg/kg). NOT indicates not calculated.
Table 3
Quantitative anticonvulsant data (ip)
Compounds.
ED50 (mg/kg) (MES)a
TD50 (mg/kg) (rotarod)b
PIc
a
b
c
d
e
f
11.0 (9.9–12.2)
14.8 (13.2–16.5)
43.7 (35.7–52.6)
14.0 (12.9–15.7)
10.0 (8.7–12.1)
>100
193.2 (174.2–212.5)
322.6 (314.0–341.1)
165.0 (152.5–172.9)
218.4 (208.8–234.9)c
123.0 (115.0–139.1)
—
17.5
21.8
3.7
15.6
12.3
—
g
h
i
j
k
l
m
n
21.5 (21.5–25.5)
82.0 (75.2–89.4)
25.5 (23.6–27.5)
23.7(21.3–26.4)
61.4 (53.8–66.9)
38.3 (34.4–42.6)
11.2 (9.6–12.0)
60.2 (57.6–69.7)
27.4 (24.6–30.5)
41.2 (33.7–51.6)
11.8 (9.7–14.1)
9.5 (8.1–10.4)
104.0 (97.5–107.2)
190.0 (183.0–200.4)
175.0 (169.1–183.6)
220.0 (204.7–237.5)
198.0 (192.1–201.6)
105.7 (98.5–111.9)
117.3 (107.5–127.2)
108.0 (102.2–115.9)
227.4 (224.7–237.5)
86.5 (88.1–101.8)
76.1 (69.1–83.7)
4.9
2.3
7.0
9.2
3.2
2.7
10.6
1.8
8.3
2.1
6.4
6.9
o
p
Carbamazepine
Phenytoin
65.5 (52.5–72.9)
a
b
c
Median effective doses of studied compounds against MES in mg/kg.
Median neurotoxic doses determined from rotorod test in mg/kg.
PI = protective index (TD50/ED50).
Scheme 3. Structures of the synthesized compounds 5a–p and phenytoin, showing
the general pharmacophore model for anticonvulsant activity.12–14 The essential
structural requirements are indicated by dotted rectangles (D, electron donor
group; HBD, hydrogen-bonding domain).
with an ED50 values of 11 and 14.8 mg/kg and TD50 values of 193.2
and 322.6 mg/kg resulting in a higher protective index (PI) values
of TD50/ED50 = 17.5 and 21.8 respectively, were the most potent
of all the tested and promising compounds in this work.
(5o) > p-CH3 (5p) > p-CH3 (5h). Derivatives having methyl group
attached to the second position of the phenyl ring were compara-
tively more effective than the derivatives having methyl group at
the fourth position. From the present study, eight compounds
(5a, 5b, 5d, 5e, 5i, 5j, 5m and 5o) have emerged as the lead com-
pounds and compounds 5a and 5b were selected to be the most ac-
tive and promising compounds in this work.
The present study revealed that some of the 3,5-substituted
piperidones and N-substituted piperidones possessed a broad
spectrum of anticonvulsant activity. Eight compounds exhibited
protection in the seizure models, viz MES Test and 5a, 5b, 5d, 5e,
5i, 5j, 5m and 5o have emerged as the most active compounds in
these models. We conclude that further structural modifications
of these molecules might lead to the discovery of potent anticon-
vulsant agents with still lower motor impairment.
As shown in Scheme 3, the replacement of the hydrogen atom
attached to glutarimide nitrogen responsible for hydrogen bond-
ing, lowers the activity, whereas substitution by bulky groups
(5c, 5f, 5h, 5k, 5n and 5p) further decreases the activity, but sub-
stitution by electron donating groups such as methyl (5b, 5j), ben-
zyl (5d) and amino (5e, 5m) groups resulted in an slight decrease
in activity compared to parent compound (5a). The results of anti-
convulsant activity showed that substitution at position 2 on the
aromatic rings by a chloro group lowers the activity (i.e., com-
pounds 5i–p), compared to unsubstituted analogues (5a–h). Com-
parison of ED50 values of the methyl substituted derivatives (5g,
5h, 5o and 5p) indicated that with different substitution positions
on the benzene ring, their activity order was o-CH3 (5g)> o-CH3

1266
M. Babu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1263–1266
6. Archana, S.; Srivastava, V. K.; Kumar, A. Indian J. Pharm. Sci. 2003, 65, 358.
7. Eliel, E. L.; Mcbride, R. T.; Kaufmann, S. T. J. Am. Chem. Soc. 1953, 75, 4291.
8. mixture of ethyl 2-arylacetates (2 mmol), aq formaldehyde (1 mmol),
Acknowledgments
A
The authors thank K. M. College of Pharmacy, Uthankudi,
Madurai, Bose Clinical Laboratory and Madurai for evaluating
samples for Anticonvulsant activity and DST for providing FT-
NMR under UGC-IRHPA programme and one of the authors
(M.B.) is grateful to UGC for UGC-JRF fellowship.
aq.ammonia/aliphaticaromatic amines (2 mmol) and a catalytic amount of
piperidine and pyridine in abs ethanol (250 mL) was refluxed for 4 h. The
course of the reaction was monitored by TLC, and after the disappearance of the
starting materials, excess of alcohol was removed in vacuo and the residue
extracted with benzene and washed with dil.HCl and then with water and
dried. The dried benzene extract was purified by passing through a column of
SiO2. The residue obtained on evaporation of the solvent, on crystallization (aq
EtOH) gave pure 3,5-diarylpiperidin-2,6-diones in appreciable yields (70–90%).
9. Compound 5a: Colourless solid (0.160 g, 91%); mp 172–174 °C; 1H NMR
(300 MHz, CDCl3, 25 °C): d 1.79 (1H, t, J = 9.6 Hz), 2.04 (1H, t, J = 2.4 Hz),
3.55(2H, dd, J = 9.6, 2.4 Hz), 7.30–7.59 (10H, m, Ar-H), 11.10 (1H, s, –NH). 13C
NMR (300 MHz, CDCl3, 25 °C): d 31.95, 48.77, 125.29, 128.70, 129.26, 137.49,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.11.035.
176.95(CO). IR (KBr) (m
max, cmÀ1): 1648 (C@O), 3246 (N–H). UV kmax (MeOH):
259.18, 281.19 nm. MS m/z 266.44 (M+H); Anal. Calcd for C17H15NO2: C, 76.96;
H, 5.70; Found: C, 76.95%; H, 5.71%.
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