Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.02.019

Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated, 1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme

Full text of DOI:10.1016/j.bmcl.2014.02.019

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1815–1819
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and discovery of highly functionalized mono- and
bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors
b,
c
c
Yalda Kia a, Hasnah Osman a, , Raju Suresh Kumar , Alireza Basiri , Vikneswaran Murugaiyah
⇑
⇑
a School of Chemical Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia
b Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh, Saudi Arabia
c School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated,
1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activi-
ties in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed
Received 10 October 2013
Revised 26 January 2014
Accepted 7 February 2014
Available online 15 February 2014
remarkable AChE inhibitory activities with IC50 values ranging from 1.68 to 21.85
compounds 8d and 8j were found to be most active inhibitors against AChE and BChE with IC50 values
of 1.68 and 2.75 M, respectively. Molecular modeling simulation on Torpedo californica AChE and human
lM, wherein
l
Keywords:
Alzheimer’s disease
AChE
BChE receptors, showed good correlation between IC50 values and binding interaction template of the
most active inhibitors docked into the active site of their relevant enzymes.
Ó 2014 Elsevier Ltd. All rights reserved.
BChE
1,3-Dipolar cycloaddition
Spiropyrrolidines
Molecular docking
Alzheimer’s disease (AD) as a neurodegenerative disorder is
manifested by progressive deterioration of intellectual and
cognitive functions, memory loss and personality changes.1,2
Pathogenesis of AD is characterized by two major hallmarks. First,
accumulation of extracellular plaques composed of beta-amyloid
peptides (Ab) due to overexpressed cleavage of amyloid precursor
protein (APP) and second, appearance of intracellular neurofibril-
lary tangles composed of phosphorylated tau proteins, which
together severely damage cholinergic neurons comprising basal
forebrain.3 The loss of cholinergic neurons reduces synaptic
availability of acetylcholine (ACh) neurotransmitter that lead to
the cognitive impairments in AD.4
Two major enzymes hydrolyze and regulate acetylcholine in
vertebrates; acetylcholinesterase (AChE) and butyrylcholinester-
ase. AChE is abundant in brain, muscle and erythrocyte membrane,
whereas BChE has highest activity in liver, intestine, heart, kidney
and lung.5,6 BChE has been supposed to be a naturally developed
protecting enzyme against ChE toxicants.7 According to the
so-called cholinergic hypothesis, the decreased levels of acetylcho-
line in the brain eventuates memory loss and other cognitive
dysfunctions in AD.8 Thus, to increase ACh levels by the aid of
acetylcholinesterase inhibitors (AChEI) is a promising approach
to symptomatic treatment of AD patients.
Presently, there are two classes of drugs being used for the
treatment of AD, namely the cholinesterase inhibitors and gluta-
mate receptor antagonist. These agents are mainly for symptom-
atic treatment of AD and are widely prescribed to ameliorate
cognitive impairments in these patients.9 Despite the tremendous
efforts in search for novel disease modifying agents working via
b-amyloid or tau pathways, none are clinically available due to
their adverse effects.
The overall architecture of the AChE and BChE enzymes is quite
similar. Their active site is located at the bottom of a 20 Å deep
cavity named as ‘aromatic gorge’. Substrate and inhibitor guidance
down the aromatic gorge is facilitated by hydrophobic interactions
with aromatic residues lining the gorge wall such as phenylalanine
(Phe), tryptophan (Trp) and tyrosine (Tyr).10 In the active site of
BChE, aromatic residues such tryptophan and phenylalanine, are
mostly replaced with hydrophobic ones including leucine (Leu)
and valine (Val), making BChE more appropriate to accommodate
bulkier substrates and inhibitors.11
Multi-component reactions offer a wide range of possibilities
for the efficient synthesis of highly complex molecules in a single
operational step. These reactions eliminate the need for several
workups and purification steps, enabling a great saving of both
solvents and reagents.12
⇑
Corresponding authors. Tel.: +60 4 6533558; fax: +60 4 6574854.
E-mail addresses: osman.hasnah2012@yahoo.com (H. Osman), sraju@ksu.edu.sa
(R. Suresh Kumar).
http://dx.doi.org/10.1016/j.bmcl.2014.02.019
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

1816
Y. Kia et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1815–1819
The spiro-oxindoles can be obtained from the cycloaddition
reaction of azomethine ylides generated in situ from isatin and
-amino acids, to dipolarophiles bearing exocyclic double bonds.
good purity, as evident from TLC and 1H NMR spectroscopic
analysis.
The structure of the spiropyrrolidine 8 was in accordance with
its combustion data, 1D and 2D NMR spectroscopic analysis
(vide infra). The 1H NMR spectrum of 8j18 showed a doublet at
a
This heterocyclic system is the core structure of many pharmaco-
logical agents and natural alkaloids.13
In our earlier study,14 we have reported the synthesis and
cholinesterase inhibitory activities of spiropyrrolidines, which
some of them possessed good inhibition against AChE and BChE
enzymes. Herein we wish to report the ionic liquid mediated syn-
thesis and cholinesterase inhibitory activities of another class of
novel mono and bis-cycloadducts comprising spiropyrrolidines,
piperidine and oxindole rings. In addition, molecular docking
analysis was also performed to disclose the binding interaction
template of the most active inhibitors to the amino acid residues
composing active site of the AChE and BChE enzymes and the
findings are represented in this manuscript.
The highly functionalized dipolarophiles viz. 1-acryloyl-3,5-bis-
arylmethylidenepiperidin-4-ones (5) were prepared by the aldol
condensation of 4-piperidone hydrochloride (1) with a series of
aromatic aldehydes, according to the literature procedure15
followed by acylation of the resulting N-unsubstituted 3,5-
bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones (3) with
acryloyl chloride (4). The dipolarophiles (5) are appropriate
synthons for the construction of more complex spiro-heterocycles
as they possess diverse dipolarophilic functions such as three C@C
and two C@O groups. Three-component [3+2]-cycloaddition
reaction of a series of 5 with azomethine ylide generated from isat-
in (6) and phenylglycine (7) was investigated in 1-butyl-3-methyl-
imidazolium bromide ([BMIM]Br), due to its unrivaled catalytic
properties to enhance the rate and the yield of the reactions as well
as its recyclability.16,17 Refluxing equimolar mixture of 5, 6 and 7 in
1 molar equivalent of [BMIM]Br for 0.5 h afforded the mono-spiro-
pyrrolidines 8(a–k) in good yields. The above reaction in 1:2:2
molar ratio of 5, 6 and 7 in 2 molar equivalent of [BMIM]Br for
longer period of time (2 h) also furnished to more complex bis-
spiropyrrolidine 9(a–k) in moderate yields (Scheme 1). In both
the reactions, spiropyrrolidines (8) and (9) were obtained with
4.78 ppm (J = 9.7 Hz) for H-4 and a doublet at 5.56 ppm
(J = 9.7 Hz) for the H-5 of the pyrrolidine ring. HMQC correlations
of H-4 and H-5 assigned the carbon signal at 56.1 and 64.9 ppm
to C-4 and C-5, respectively. Further, H-4 shows HMBCs with (i)
the 400-C@O at 197.2 ppm and (ii) the spiro carbon C-3 at
71.0 ppm. 200-CH2 of piperidone ring appeared as two doublets in
2.61 and 4.34 ppm with J = 14.1. 600-CH2 also showed two doublets
at 3.36 and 4.20 ppm with J = 17.9 Hz. HMQC correlated carbon
signals at 46.2 and 44.0 ppm to C-200 and C-600, respectively. The
protons of acryloyl moiety showed up as two doublets at 5.72
and 6.27 ppm with J = 10.7 and 16.7 Hz for 30-CH2 and a doublet
of doublets at 6.64 ppm with J = 16.7 and 10.7 Hz for 20-CH. From
the HMQC correlation, the carbon signals at 132.6 and 132.9 ppm
were assigned to C-30 and C-20, respectively. The singlets at 7.54,
7.55 and 7.72 ppm were due to the arylmethylidene hydrogens
and NH hydrogen of the oxindole. The aromatic hydrogens
appeared as multiplets around 6.85–7.30 ppm (Fig. 1). The 1H
and 13C NMR chemical shifts of the other spiropyrrolidines were
also assigned by similar straightforward considerations.
A plausible mechanism to rationalize the formation of the spiro-
pyrrolidines 8 is depicted in Scheme 2. The electron-deficient
hydrogen atom of [BMIM]Br, forms hydrogen bonding interaction
with the carbonyl moiety of isatin, facilitating the generation of
reactive azomethine ylide via decarboxylative condensation of
isatin and phenylglycine.17,19 The newly formed ylide, attacks the
C@C bond of piperidone ring of (5) chemo-selectively, furnishing
the mono-spiropyrrolidine (8). Bis-spiropyrrolidines (9) were
obtained due to addition of two moles of azomethine ylide to the
C@C bonds of piperidone ring and acryloyl entity of (5). In both
the reactions, nucleophilic carbon of azomethine ylide adds
regio-selectively to the enone moiety in piperidone ring/acryloyl
entity.
H
N
O
H
N
1
4
2a
2
3
Ph
Ar
1'
NH.HCl
5
N
1"
O
6
O
, 1eq.
3"
1
7, 1eq.
2"
O
O
4"
6"
5"
N
O
0.5 h
2 ArCHO
H
6
HCl, CH3COOH
K2CO3, Acetone
7"
+
Ar
Ar
Ar
O
(+)8
OH
Cl
N
NH
Ar
O
NH2
O
7
4
6
, 1eq.
7, 1eq.
O
O
K2CO3
[BMIM]Br
Reflux
Acetone
Ph
Ar
3
5
5
NH
H
1
O
N
2
4
H
2a
3
N
2a
1
2
3
Ph
N
H
O
5
1'
6
N
, 2eq.
O
4
7, 2eq.
1"
3"
2"
7"
Ar
O
4"
6"
5"
2 h
Ar
(+)9
Scheme 1. Synthesis of spiropyrrolidines 8(a–k) and 9(a–k).

Y. Kia et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1815–1819
1817
6.64, dd, 1H, J=16.70, 10.70 Hz
132.9
5.72, d, 1H, J=10.70 Hz
6.27, d, 1H, J=16.70 Hz
132.6
1.85, s, 1H
H
N
5.56, d, 1H, J=9.7 Hz
O
64.9
H
N
3'
H
1
4
O
2'
N
H
Ph
H
2
1'
71.0
197.2
H
5
N
H
Ph
H
H
3
O
N
1"
N
3"
2"
5"
7"
71.0
O
Ar
O
4.78, d, 1H, J=9.7 Hz
172.7
6"
3.36, d, 1H, J=17.95 Hz
4.20, d,1H, J=17.95 Hz
44.00
4"
56.1
Ar
O
H
Ar
2.61, d, 1H, J=14.15
4.34, d, 1H, J=14.15
46.28
Ar
Figure 1. Selected HMBCs and 1H and 13C chemical shifts of 8j.
Ph
Ar
Ph
Bu
N
H
H
H
COOH
N
N
N
HOOC
Ph
N
O
Br
NH2
O
O
O
-H2O
-CO2
O
N
N
H
H
Ar
H
O
Bu
N
Br
N
H
N
Ph
NH
Ph
H
N
H
O
O
H
N
H
H
H
N
N
N
Ph
Ar
Ph
N
N
Ar
H
O
O
O
H
N
H
O
N
H
H
O
O
Ar
Ar
N
Br
Bu
N
(+)-8
(+)-9
Scheme 2. Plausible mechanism for the formation of 8 and 9.
All the newly synthesized spiropyrrolidines 8/9 were evaluated
in vitro for their AChE and BChE inhibitory activities against AChE
enzyme from electric eel and BChE enzyme from equine serum
(Table 1). In general, mono-spiropyrrolidines 8(a–k) displayed
remarkable AChE inhibitory activities with seven compounds
11.76 to 27.12 lM. However compounds 8b, 8d and 8g showed
better BChE inhibition potencies than galanthamine. Bis-spiropyr-
rolidines in series 9, had lower BChE inhibitory activities than their
mono-analogs with moderate IC50 values of 14.42–35.86 lM.
Compounds 8d and 8j, as the most active inhibitors, were
docked into the active site of their AChE and BChE enzymes, to
disclose their binding interaction profile to the relevant receptors.
This analysis for compound 8d as the most active AChE inhibitor
showed that it has efficiently bound to the peripheral anionic site
of the enzyme, at entrance of the active site channel, through a net-
work of hydrophobic interactions with Trp279, Tyr70 and Tyr334
in addition to strong hydrogen bonding to Ser286 (1.90 Å) and
Arg289 (2.09 Å) (Fig. 2). According to this template, compound
8d can act as a peripheral anionic binding site inhibitor. It is
suggested that deposition of amyloid plaque in AD could be
accelerated or even triggered by interaction of b-amyloid with
the peripheral anionic site of AChE enzyme. Thus, inhibitors
binding at the peripheral anionic site of the enzyme not only symp-
tomatically improve the AD, but also can have disease modifying
effects.20
possessing IC50 values of less than 10
(Ar@2-ClC6H4), 8e (2-FC6H4) and 8k (Ar = 1-naphthyl) with IC50
values of 1.68, 2.27 and 2.07 M displayed comparable or even
lM; therein compounds 8d
l
more AChE inhibition than standard drug. ortho Substituted
derivatives in this series, mostly displayed better activities than
their para-substituted analogs. It is worth to mention that presence
of chloro and fluoro atoms on either ortho or para position of
phenyl ring, showed notable influence on the inhibitory activities.
On the other hand, bis-cycloadducts in series 9, displayed lower
AChE inhibition than mono-cycloadducts with moderate activities
ranging from 7.45 to 30.51 lM. In this series also, ortho-substituted
derivatives displayed better inhibitory activities than para-
substituted ones and the effect of chloro and fluoro atoms was
still obvious on the activities, whereby compound 9e with
(Ar = 2-FC6H4) displayed the highest activity in this series.
Regarding BChE, compounds 8j bearing fluoro substituent at
para position of the aromatic ring remarkably displayed the high-
Docking simulation study for compound 8j, with the highest
BChE inhibitory activity, disclosed its complete accommodation
inside the enzyme active site channel. This compound showed
p,p-stacking interaction with Tyr332 and hydrophobic interactions
with Phe398 at peripheral anionic site along with hydrophobic
est inhibition with IC50 value of 2.75
than standard drug. para-Substituted 8h and 8i also showed good
activities with IC50 <10 M. Rest of the compounds in this series
displayed moderate activities with IC50 values ranging from
lM, almost 7 times stronger
l
interactions with Trp82 and Phe329 at choline binding site of the

1818
Y. Kia et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1815–1819
Table 1
Physical data, AChE and BChE inhibitory activities of 8(a–k) and 9(a–k)
Entry
Compound
Ar
Yield (%)
AChE IC50 SD (
lM)
BChE IC50 SD (lM)
AChE selectivity
BChE selectivity
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
8g
8h
8i
C6H5
75
69
72
67
70
65
74
77
73
75
81
4.57 0.11
10.22 0.17
5.57 0.14
1.68 0.09
2.27 0.12
15.15 0.22
6.16 0.18
14.58 0.21
4.61 0.15
5.98 0.19
2.07 0.11
12.32 0.27
21.78 0.19
17.52 0.17
22.19 0.22
11.76 0.18
10.61 0.13
27.12 0.21
5.87 0.16
8.75 0.21
2.75 0.12
13.77 0.15
2.69
2.13
3.14
13.22
5.18
0.70
4.40
0.40
1.90
0.46
6.65
0.37
0.47
0.32
0.08
0.19
1.43
0.23
2.48
0.53
2.17
0.15
2-CH3C6H4
2-(CH3O)C6H4
2-ClC6H4
2-FC6H4
3-(NO2)C6H4
2,4-Cl2C6H3
4-CH3C6H4
4-ClC6H4
4-FC6H4
1-Naphthyl
10
11
8j
8k
12
13
14
15
16
17
18
19
20
21
22
9a
9b
9c
9d
9e
9f
9g
9h
9i
C6H5
62
59
65
55
57
52
67
71
64
69
74
20.78 0.17
30.5 0.23
9.15 0.16
11.28 0.21
7.45 0.15
16.79 0.22
8.61 0.18
20.19 0.14
12.34 0.16
21.85 0.20
9.24 0.19
26.30 0.21
29.07 0.24
32.12 0.20
17.63 0.18
35.86 0.25
17.63 0.22
26.30 0.17
19.81 0.19
27.81 0.27
14.42 0.18
19.22 0.23
1.27
0.95
3.51
1.56
4.81
1.05
3.06
0.98
2.25
0.66
2.08
0.79
1.05
0.28
0.64
0.21
0.95
0.33
1.02
0.44
1.51
0.48
2-CH3C6H4
2-(CH3O)C6H4
2-ClC6H4
2-FC6H4
3-(NO2)C6H4
2,4-Cl2C6H3
4-CH3C6H4
4-ClC6H4
4-FC6H4
1-Naphthyl
9j
9k
23
—
Galanthamine
—
2.09 0.11
19.34 0.17
3.47
0.28
Figure 2. Orientation and binding interaction of 8d to the active site of AChE
receptor.
BChE enzyme. Mild polar interaction with His438 at catalytic triad
as well as Gly116 and Gly117 at oxyanion hole of the enzyme, were
other major interactions observed for this compound. This
extensive hydrophobic and mild polar interaction pattern
suggested that 8j is effectively bound to the BChE active site, thus
efficiently avoided insertion of substrate into the channel and its
subsequent hydrolysis, which obviously coincides with the
significant in vitro activity observed for this compound (Fig. 3).
In conclusion, a series of piperidone-grafted spiropyrrolidines
has been synthesized by the three-component [3+2]-cycloaddition
reaction of azomethine ylides to highly functionalized dipolarophiles
in search for novel potent AChE and BChE inhibitors. Most of the
synthesized compounds were found to be significantly active with
Figure 3. Orientation and binding interaction of 8j to the active site of BChE
receptor.
showed the maximum inhibitory activity against AChE and BChE with
IC50 values of 1.68 and 2.75 lM, respectively. Molecular docking anal-
ysis for the most active derivative completely coincides with their
in vitro results.
Acknowledgments
The authors thank the Malaysian government and Universiti
Sains Malaysia for short term grant [304/PKIMIA/63/2051] and
FRGS grant [203/PKIMIA/6711179], to conduct this research. Y.K.
IC50 values ranging from 1.68 to 21.85 lM. Compounds, 8d and 8j,

Y. Kia et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1815–1819
1819
12. Strecker, A. Ann. Chem. Pharm. 1850, 75, 27.
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M.; Aimi, N.; Watanabe, H. Eur. J. Pharmacol. 2002, 444, 39.
thanks University Sains Malaysia for financial support by way of a
fellowship.
14. Kia, Y.; Osman, H.; Kumar, R.; Basiri, A.; Murugaiyah, V. Bioorg. Med. Chem.
2014. http://dx.doi.org/10.1016/j.bmc.2014.01.002.
Supplementary data
15. Bhagat, S.; Sharma, R.; Chakraborti, A. K. J. Mol. Catal. A: Chem. 2006, 260, 235.
16. Sarkar, A.; Roy, S. R.; Chakraborti, A. K. Chem. Commun. 2011, 4538.
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18. Synthesis of 4,5-(diphenyl)pyrrolo-(spiro[2.30]oxindole)-spiro[3.300]-500-(phenylme-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.02.
019.
thylidene)-100-N-acrolylpiperidin-400-one 8(a–k):
A mixture of 1-acryloyl-3,
5-diarylidenepiperidin-4-ones (5, 0.364 mmol), isatin (6, 0.364 mmol) and
phenylglycine (7, 0.364 mmol) was refluxed in 1 molar equivalent of [BMIM]Br
for 0.5 h. The reaction progress was monitored by TLC analysis. After
completion of the reaction, the product was obtained through flash column
chromatography and its purity of were checked using TLC and 1H NMR
techniques.
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mp 173–175 °C; 1H NMR (500 MHz, CDCl3) dH 1.85 (s, 1H, NH), 2.61 (d, 1H,
J = 14.15 H-200), 3.36 (d, 1H, J = 17.95, H-600), 4.20 (d, 1H, J = 17.95 Hz, H-600),
4.34 (d, 1H, J = 14.15 Hz, H-200), 4.78 (d, 1H, J = 9.70 Hz, H-4), 5.56 (d, 1H,
J = 9.70 Hz, H-5), 5.72 (d, 1H, J = 10.70 Hz, H-30), 6.27 (d, 1H, J = 16.70 Hz, H-30),
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128.49, 128.87, 129.57, 129.97, 130.21, 131.61, 132.51, 132.67, 132.73, 139.21,
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