Substituted spiro [2.3′] oxindolespiro [3.2″]-5,6-dimethoxy- indane-1″-one-pyrrolidine analogue as inhibitors of acetylcholinesterase

Article abstract of DOI:10.1016/j.bmcl.2010.09.108

Series of pyrolidine analogues were synthesized and examined as acetylcholinesterase (AChE) inhibitors. Among the compounds, compounds 4k and 6k were the most potent inhibitors of the series. Compound 4k, showed potent inhibitory activity against acetyl c

Full text of DOI:10.1016/j.bmcl.2010.09.108

Bioorganic & Medicinal Chemistry Letters 20 (2010) 7064–7066
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Substituted spiro [2.30] oxindolespiro
[3.200]-5,6-dimethoxy-indane-100-one-pyrrolidine analogue as inhibitors of
acetylcholinesterase
Mohamed Ashraf Ali a, , Rusli Ismail a, Tan Soo Choon a, Yeong Keng Yoon a, Ang Chee Wei a,
⇑
Suresh Pandian b, Raju Suresh Kumar c, Hasnah Osman c, Elumalai Manogaran d
a Pharmacogenetic and Novel Therapeutics Research, Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Pennag 11800, Malaysia
b New Drug Discovery Research, Department of Medicinal Chemistry, Alwar Pharmacy College, Alwar 301030, Rajasthan, India
c School of Chemical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia
d Karpagam College of Pharmacy, Department of Pharmacology, Karpakam University, Coimbatore 641032, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 April 2010
Revised 17 September 2010
Accepted 21 September 2010
Available online 26 September 2010
Series of pyrolidine analogues were synthesized and examined as acetylcholinesterase (AChE) inhibitors.
Among the compounds, compounds 4k and 6k were the most potent inhibitors of the series. Compound
4k, showed potent inhibitory activity against acetyl cholinesterase enzyme with IC50 0.10 lmol/L. Pyroli-
dine analogues might be potential acetyl cholinesterase agents for AD.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Alzheimer diseases
Acetyl cholinesterase
AChE inhibitor
1,3-Dipolar cycloaddition
Azomethine ylide
Alzheimer’s disease (AD) is a neurodegenerative disorder that is
the most common cause of dementia among the elderly. In the last
decade, treatment for AD has been based on the ‘cholinergic
hypothesis’.1 This hypothesis suggested that patients with AD suf-
fer from a deficit of cholinergic function in the brain such as de-
crease in hippocampal and cortical levels of acetylcholine (ACh)
and associated enzyme choline transferase. Many AChE inhibitors
used clinically for the treatment of AD are natural products or nat-
ural product analogues, such as rivastigmine (a physostigmine
derivative), galantamine and huperzine A (available in China; in
phase II trials in the USA).2,3 The only approved natural agents
for the treatment of AD are alkaloids, which along with many of
the synthetic AChE inhibitors (e.g., donepezil and tacrine) possess
side-effects including nausea, vomiting, diarrhoea and loss of appe-
tite. In fact, tacrine was discontinued due to its significant side ef-
fect profile.4 there is considerable interest therefore in the
discovery of more centrally selective non-alkaloidal inhibitors
which may avoid the side-effects that have been recorded with
alkaloids. These natural products could also provide templates
for the development of other compounds.5
For a quarter of a century, the pathogenesis of Alzheimer’s dis-
ease (AD) has been linked to a deficiency in the brain neurotrans-
mitter acetylcholine. This was based on observations that
correlated cholinergic system abnormalities with intellectual
impairment.6 The pathogenesis of Alzheimer’s disease (AD) has
been linked to a deficiency in the brain neurotransmitter acetyl-
choline. Subsequently, acetylcholinesterase inhibitors (AChEIs)
were introduced for the symptomatic treatment of AD. The prevail-
ing view has been that the efficacy of AChEIs is attained through
their augmentation of acetylcholine-medicated neuron to neuron
transmission.7
In the search for new molecules with the potential effect of
inhibiting the enzyme acetyl cholinesterase it is important to note
that many heterocycles have shown significant inhibitory activity
on this enzyme, including three of the four AD drugs currently
on the market. In the recent past, medicinal plants with hetero
atom containing molecules attracted attention due to their poten-
tial role in dementia. Also most heterocyclic systems have been
used as a source to discover new compounds with varied biological
potentials. Especially, pyrolidine derivatives play a vital role in dis-
covering novel candidates having the action of acetyl cholinester-
ase (AChEI) inhibitors.
⇑
In the scope of a research program aiming at the design, synthe-
sis and evaluation of new neuroactive lead-compound candidates
Corresponding author.
E-mail address: asraf80med@rediffmail.com (M.A. Ali).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.09.108

M. A. Ali et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7064–7066
7065
O
O
O
MeOH
H
O
R
H3CO
H3CO
N
COOH
O
+
O
+ H3C
Reflux 4-6 h
N
R1
R
H
N
CH3
2
3
1
O
N
H
4a-o
Scheme 1. Protocol for synthesis.
Table 1
Physical constants and inhibition of AchE activities of the synthesized compounds
Compound
R
R1
Rf value
Yield (%)
Mp (°C)
AchE inhibitiona (IC50 SD)
lmol/L
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
Pyridyl-
H
H
H
H
H
Cl
Cl
Cl
0.67
0.64
0.69
0.62
0.78
0.73
0.76
0.74
0.66
0.70
0.78
0.82
0.85
0.59
0.83
74
65
72
80
82
85
92
85
77
82
90
56
81
76
72
204
183
194
161
138
113
126
105
154
162
126
178
194
172
182
0.46 0.02
2.12 0.02
4.2 0.02
3.12 0.1
4.3 0.01
0.37 0.01
3.7 0.1
4.2 0.1
11.2 0.1
6.6 0.1
0.10 0.1
8.6 0.1
6.10 0.1
13.2 0.1
7.6 0.1
4-Flurophenyl-
3,4-Dimethoxy phenyl-
Phenyl-
2-Chloro phenyl-
Pyridyl-
4-Flurophenyl-
3,4-Dimethoxy phenyl-
Phenyl-
2-Chloro phenyl-
Pyridyl-
Cl
Cl
NO2
NO2
NO2
NO2
NO2
4-Flurophenyl-
3,4-Dimethoxy phenyl-
Phenyl-
2-Chloro phenyl-
a
Data are means standard deviation of duplicate independent experiments.
O
O
O
COOH
NH2
O
R
H3CO
MeOH
Reflux 4-6 h
+
O
O
+
Ph
N
H
R
H3CO
R1
H
NH
2
5
1
O
N
H
6a-o
Scheme 2. Protocol for synthesis.
with beneficial effects in treatment of AD as AChE inhibitors, we
became interested in developing new pyrolidine analogues. It
was considered to be worth to work on the above mentioned novel
analogues substituted spiro [2.30] oxindolespiro [3.200]-5, 6-dime-
thoxy-indane-100-one-pyrrolidine analogue 4a–o and 6a–o de-
scribed in this study is shown in Tables 1 and 2, and a reaction
sequence for the preparation is outlined in Scheme 1.
In the present investigation, the 1,3-dipolar cycloaddition of
azomethine ylides, generated in situ via decarboxylative condensa-
tion of sarcosine 3 and substituted isatins 2 (R = H, Cl, NO2) to 2-
2,3-dihydro-1H-inden-1-ones
1
in methanol afforded novel
spiro[2.30]oxindolespiro[3.200]-5,6-dimethoxy-100-indanone-4-(aryl
substituted)-5-phenyl pyrrolidine 6a–o (Scheme 2, Table 2). The
reaction was performed by heating an equimolar mixture of 2-
(arylmethylene)-5,6-dimethoxy2,3-dihydro-1H-inden-1-ones
1,
substituted isatins 2 and sarcosine or phenylglycine 3 or 5 in meth-
anol under reflux for 4–6 h. After completion of the reaction (TLC),
the reaction mixture was poured into ice-water, the resulting
crude solid was filtered off and purified by column chromatogra-
phy to obtain pure pyrrolidine derivatives 4a–o and 6a–o in 56–
92% yields after recrystallization with pet ether/ethyl acetate
(4:1). The purity of the compounds was checked by TLC and ele-
mental analyses. Both analytical and spectral data (1H NMR, IR)
of all the synthesized compounds were in full agreement with
the proposed structures. In general, Infra red spectra (IR) 1525,
(arylmethylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-ones
1
in methanol afforded novel N-methyl-spiro[2.30]oxindolespi-
ro[3.200]-5,6-dimethoxy-100-indanone-4-(aryl substituted) pyrroli-
dine 4a–o (Scheme 1, Table 1), 5 phenylglycine and substituted
isatins 2 (R = H, Cl, NO2) to 2-(arylmethylene)-5,6-dimethoxy-

7066
M. A. Ali et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7064–7066
Table 2
Physical constants and inhibition of AchE activities of the synthesized compounds
Compound
R
R1
Rf value
Yield (%)
Mp (°C)
AchE inhibitiona (IC50 SD)
lmol/L
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
Pyridyl-
H
H
H
H
H
Cl
Cl
Cl
0.90
0.71
0.78
0.89
0.85
0.83
0.81
0.83
0.79
0.84
0.88
0.75
0.63
0.82
0.80
78
82
72
80
82
85
92
85
77
92
85
77
82
90
56
—
164
175
134
171
148
183
146
125
154
146
145
184
204
118
168
—
0.30 0.02
6.86 0.02
5.2 0.02
5.12 0.1
7.3 0.01
0.42 0.01
9.86 0.02
8.26 0.02
7.26 0.02
12.2 0.02
0.24 0.1
14.3 0.01
15.37 0.01
3.7 0.1
4-Flurophenyl-
3,4-Dimethoxy phenyl-
Phenyl-
2-Chloro phenyl-
Pyridyl-
4-Flurophenyl-
3,4-Dimethoxy phenyl-
Phenyl-
2-Chloro phenyl-
Pyridyl-
4-Flurophenyl-
3,4-Dimethoxy phenyl-
Phenyl-
2-Chloro phenyl-
—
Cl
Cl
NO2
NO2
NO2
NO2
NO2
4.2 0.1
0.12 0.01
Donepezil
a
Data are means standard deviation of duplicate independent experiments.
1690, 1724 and 3290 cmꢀ1, respectively. In the nuclear magnetic
resonance spectra (1H NMR) the signals of the respective protons
of the prepared titled compounds were verified on the basis of
their chemical shifts, multiplicities and coupling constants. The
spectra showed a singlet at d 2.32 ppm corresponding to CH3
group; doublet at d 2.43–2.60 ppm corresponding to CH2 group;
These reports clearly showed pyrolidine substituted derivatives
causes’ remarkable improvement in AChE inhibitory activity.
Among the newer derivatives, it is conceivable that derivatives
showing AChE inhibitory activity can be further modified to exhibit
better potency than the standard drugs. Further studies to acquire
more information about quantitative structure–activity relation-
ships (QSAR) are in progress in our laboratory. The indanone con-
taining pyrolidine derivatives discovered in this study may provide
valuable therapeutic intervention for the treatment of AD diseases.
singlet at
d 3.82 ppm corresponding to OCH3, triplet at d
3.43–3.46 ppm to CH proton; multiplet at d 6.84–7.20 ppm corre-
sponding to aromatic protons, multiplet at d 7.42–8.27 ppm corre-
sponding to pyridine ring proton, singlet at d 8.46 corresponding to
NH proton. The elemental analysis results were within 0.4% of the
theoretical values.
Acknowledgements
All the newly synthesized (4a–4o and 6a–6o) pyrolidine deriv-
atives were tested for their inhibitory activities toward AChE
in vitro according to Ellmann’s method8 against freshly prepared
human AChE, in comparison to the donepezil as reference com-
pound. Inhibition of AChE activities of the synthesized compounds
is shown in Tables 1 and 2 the data listed in Table 1 and 2 clearly
showed that most of the designed compounds exhibited good to
moderate inhibitory activities toward the acetylcholinesterase.
Among the thirty newly synthesized compounds, compounds
spiro[2.30]oxindolespiro[3.200]-5,6-dimethoxy-100-indanone-4-(pyr-
idyl)-1-N-methyl pyrolidine (4k) produced significant activities
The authors wish to express their thanks to Pharmacogenetic
and Novel Therapeutics Research, Institute for Research in Molec-
ular Medicine, Universiti Sains Malaysia, Pennag, Malaysia and Al-
war Pharmacy College, Alwar, Rajasthan, India for providing
research facilities.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.09.108.
with 0.10 0.1
0.24 0.1 mol/L,
0.42 0.02 mol/L and 0.46 0.02
l
mol/L followed by (6k), (4f), (4a),(6f) and (6a)
0.30 0.02 mol/L, 0.37 0.01 mol/L,
mol/L, respectively.
References and notes
l
l
l
l
l
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The compound containing group like nitro with pyridine substi-
tuted (4k) showed higher inhibitory activity in general. However
the pyridine substituted (4f), (4a), (6f) and (6a) analogues also pro-
duced good AChE inhibitory activity. Among the two series of com-
pounds, (4a–4o and 6a–6o) the compounds belonging to both
series (4a–4o and 6a–6o) with nitro group on the isatin nucleus
and pyridine ring at 4th position of pyrolidine ring display higher
potency than other substitution on either series (4a–4o and 6a–6o).
8. Ellman, G. L.; Courtney, K. D.; Andres, B.; Featherstone, R. M. Biochem. Pharmacol.
1961, 7, 88.