Design, synthesis and evaluation of novel 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-2-indenyl-3,4-substituted phenyl methanone analogues

Article abstract of DOI:10.1016/j.bmcl.2009.07.042

In present investigation, a series of substituted phenyl-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-2-indenylmethanone analogues were synthesized and were tested for their potential for treating AD disease. All the newly synthesized compounds were showing moderate to high AChE inhibitory activities, with compound 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-2-indenyl-3,4,5-trimethoxyphenylmethanone (5f) produced significant activities with 2.7 ± 0.01 μmol/L.

Full text of DOI:10.1016/j.bmcl.2009.07.042

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5075–5077
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and evaluation of novel 5,6-dimethoxy-1-oxo-2,3-dihydro-
1H-2-indenyl-3,4-substituted phenyl methanone analogues
b
a
a
Mohamed Ashraf Ali a, , Mohammad Shahar Yar , Mohamed Zaheen Hasan , Mohamed Jawed Ahsan ,
*
Suresh Pandian a
a New Drug Discovery Research, Department of Medicinal Chemistry, Alwar Pharmacy College, Alwar, Rajasthan 301 030, India
b Faculty of Pharmacy, Jamia Hamdard University, Department of Pharmaceutical Chemistry, Hamdard Nagar, New Delhi 110 062, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In present investigation, a series of substituted phenyl-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-2-indenyl-
methanone analogues were synthesized and were tested for their potential for treating AD disease. All
the newly synthesized compounds were showing moderate to high AChE inhibitory activities, with com-
pound 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-2-indenyl-3,4,5-trimethoxyphenylmethanone (5f) pro-
Received 6 April 2009
Revised 5 June 2009
Accepted 7 July 2009
Available online 10 July 2009
duced significant activities with 2.7 0.01 lmol/L.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Diketone
AChE inhibitory activities
Alzheimer’s disease (AD)
The mechanism of Alzheimer’s disease (AD) is till unknown,
three pathological hallmarks have been identified, for example,
amyloid-b plaque, neurofibrillary tagles (NFTs) and synaptic loss.
The neuritic senile plaques consist of afibrillar amyloid core sur-
rounded by dystrophic neuritis and reactive microglia. Acetylcho-
linesterase is present throughout the central and peripheral
nervous systems of mammals, where it catalyses the hydrolysis
of the endogenous ester neurotransmitter acetylcholine (ACh),
allowing the termination of ACh receptor-mediated ion gating at
nerve–nerve and neuromuscular junctions.1
Alzheimer’s disease (AD) is associated with an early and pro-
found loss of central cholinergic function. This is due, in part, to
a reduction in the activity of choline acetyltransferase, the enzyme
primarily responsible for the synthesis of the neurotransmitter
acetylcholine (ACh). Indeed, this cholinergic deficiency correlates
with disease severity.2,3
About 4 million Americans-90 percent of whom are age 65 and
older-have Alzheimer’s disease. The prevalence of Alzheimer’s dis-
ease doubles every five years beyond age 65.4 In the past 25 years
scientists have made great progress in unravelling the mysteries of
Alzheimer’s disease; however, much is still unknown. Unless pre-
vention or a cure is found, the number of Americans with Alzhei-
mer’s disease could reach 14.3 million 50 years from now.
Alzheimer’s disease (AD) is a devastating neurodegenerative
disease with progressive loss in memory destruction of reasoning,
imaginary power and ability to learn. The enzyme, acetylcholines-
terase (AChE), is responsible for the termination of impulse signal-
ling at cholinergic synapses by catalysing the hydrolysis of the
neurotransmitter acetylcholine (ACh). Drugs that are currently
prescribed for AD can have severe side-effects in patients with
FTD.5 Furthermore; FTD itself includes several clinical entities that
require better biochemical characterization. Therefore, it is imper-
ative to develop tools that enable an early, differential diagnosis. In
the recent past, medicinal plants with hetero atom containing mol-
ecules attracted attention due to their potential role in dementia.
Also most heterocyclic systems have been used as a source to dis-
cover new compounds with varied biological potentials. Especially,
indanone derivatives play a vital role in discovering novel candi-
dates having the action of acetyl cholinesterase (AChEI) inhibitors.
Also many literatures reveal that the indanone nucleus acts as pro-
tease inhibitors and acetyl cholinesterase (AChEI) inhibitors, it was
considered to be worth to work on the above mentioned novel
analogues.
5,6-Dimethoxy-1-oxo-2,3-dihydro-1H-2-indenyl-3,4-substituted phe-
nyl methanone analogues 5a–5n described in this study is shown
in Table 1, and a reaction sequence for the preparation is outlined
in Scheme 1. In the initial step, 5,6-dimethoxy-2-[(E)-1-phenylme-
thylidene]-1-indanone were synthesized condensing 5,6-dime-
thoxy-1-indanone with appropriate aromatic aldehydes in dilute
methanolic sodium hydroxide solution at room temperature, then
bromination of 5,6-dimethoxy-2-[(E)-1-phenylmethylidene]-1-
indanone in minimum quantity of chloroform followed by hydro-
lysis with methanolic potassium hydroxide to get titled
* Corresponding author. Tel.: +91 9940531214; fax: +91 11 26059666.
E-mail address: asraf80med@rediffmail.com (M.A. Ali).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.07.042

5076
M. A. Ali et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5075–5077
Magnetic resonance spectra (1H NMR) the signals of the respective
protons of the prepared titled compounds were verified on the ba-
sis of their chemical shifts, multiplicities and coupling constants.
The spectra showed a triple at d 3.20–3.35 ppm corresponding to
CH group; doublet at d 3.41–3.44 ppm corresponding to CH2 group;
singlet at d 3.82, 3.86 ppm corresponding to OCH3 multiplet at d
6.48–7.20 ppm corresponding to aromatic protons. The elemental
analysis results were within 0.4% of the theoretical values.
Among the novel substituted diketone derivatives for treating
AD, their anticholinesterase activities (compounds 5a–n) were as-
sayed according to Ellmann’s method6 against freshly prepared
AChE from electrophorus electricus using donepezil as reference
compound. Inhibition of AChE activities of the synthesized com-
pounds is shown in Table 1.The data listed in Table 1 clearly show
that most of the designed compounds exhibited moderate inhibi-
tory activities toward the cholinesterase. Among the fourteen new-
ly synthesized compounds, compounds 5,6-dimethoxy-1-oxo-2,3-
Table 1
Physical constants and inhibition of AchE activities of the synthesized compounds
O
O
O
H3C
H3C
R
O
5a-5n
Compound
R
Yield
(%)
MP (°C) AChE inhibition
(IC50 SD)a
L)
lmol/
5a
5b
5c
4-Methoxy phenyl-
4-Chloro phenyl-
4-Dimethylamino
phenyl-
74
70
72
164
142
114
6.2 0.02
41.2 0.1
29.4 0.1
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
Donepezil
Phenyl-
80
82
131
118
133
146
125
154
104
98
198
184
202
—
21 0.1
3,4-Dimethoxy phenyl-
3,4,5-Trimethoxy phenyl- 85
4.3 0.01
2.7 0.01
42 0.1
dihydro-1H-2-indenyl-3,4,5-trimethoxyphenylmethanone
(5f)
produced significant activities with 2.7 0.01 mol/L followed by
l
4-Fluoro phenyl-
2-Chloro phenyl-
2,6-Dichloro phenyl-
3-Nitro Phenyl-
Furyl-
92
85
77
82
90
56
81
76
—
64 0.1
(5e) 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-2-indenyl-3,4-dimeth-
oxyphenylmethanone and (5a) 5,6-dimethoxy-1-oxo-2,3-dihy-
102 0.1
In active
9.4 0.1
8.6 0.1
45 0.1
dro-1H-2-indenyl-4-methoxyphenylmethanone
activity with 4.3 0.01 mol/L and 6.2 0.02
inhibitory
mol/L, respectively.
l
l
Thiophenyl
4-Bromo phenyl-
4-Cyano phenyl-
—
The electron stumpy group like methoxy substituted phenyl group
5,6-dimethoxy-1-oxo-2,3-dihydro-1H-2-indenyl-3,4,5-trimeth-
oxyphenylmethanone (5f) showed higher inhibitory activity in
general. However the furyl and thiophenyl substituted analogues
produced moderate AChE inhibitory activity. On the other hand
the electron rich group such as, 4-flurophenyl, 4-bromophenyl, 2-
chlorophenyl, 2,6-dichlorophenyl and 4-nitrophenyl substituted
analogue showed significant decrease in inhibitory activity.
Instead of electron withdrawing groups like 4-flurophenyl, 4-
bromophenyl, 2-chlorophenyl, 2,6-dichlorophenyl and 4-nitro-
phenyl, electron donating group like 4-methoxy phenyl-,3,4-dime-
thoxy phenyl and 3,4,5-trimethoxy phenyl group substituted
53 0.1
0.12 0.01
a
Data are means standard deviation of duplicate independent experiments.
compounds in 56–92% yield after recrystallization with ethanol.
The purity of the compounds was checked by TLC and elemental
analyses. Both analytical and spectral data (1H NMR, IR) of all the
synthesized compounds were in full agreement with the proposed
structures. In general, Infrared spectra (IR) revealed CH, C@O, and
C–F peak at 1640, 1320 and 786 cmÀ1 respectively. In the Nuclear
O
O
O
O
H3C
H3C
CH3OH-NaOH
H3C
H3C
R-CHO
+
R
O
O
2a-n
3a-n
1
CHCl3-Br2.HCl
O
Br
O
O
H3C
H3C
R
4a-n
CH3OH-KOH
O
O
O
H3C
H3C
R
O
5a-n
Scheme 1. Protocol for synthesis.

M. A. Ali et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5075–5077
5077
diketone analogue to worse the AChE inhibitory activity. These re-
References and notes
ports clearly showed the increases the presence of OCH3 group
substituted phenyl ring at diketone derivatives causes remarkable
improvement in AChE inhibitory.
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2. Rossor, M. N. Lancet 1982, 2, 1200.
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 diketone deriv-
atives discovered in this study may provide valuable therapeutic
intervention for the treatment of AD diseases.
3. Bierer, L. M.; Haroutunian, V.; Gabriel, S.; Knott, P. J.; Carlin, L. S.; Purohit, D. P.;
Perl, D. P.; Schmeidler, J.; Kanof, P.; Davis, K. L. J. Neurochem. 1995, 64, 749.
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National Institutes of Health, Bethesda, MD, 1999.
5. Cummings, J. L.; Askin-Edgar, S. CNS Drugs 2000, 13, 385.
6. Ellman, G. L.; Courtney, K. D.; Andres, B.; Feartherstone, R. M. Biochem.
Pharmacol. 1961, 7, 88 (5f): IR: (KBr) cmÀ1: 3042 (CH), 1642 (C@O) 1H NMR
(DMSO-d6) ppm: 3.20–3.35(1H, t, CH), 3.41–3.44 (2H, d, CH2), 3.82, 3.86 (15H, s,
OCH3), 6.48–7.2 (4H, m, aromatic); mass (m/z) 386 (M+); cal/ana [C (65.28)
65.27, H (5.74) 5.73, O (28.96) 28.97].
Acknowledgment
Authors are thankful to the management people of Alwar Phar-
macy College, Alwar, Rajasthan.