Synthesis and anti-acetylcholinesterase activity of N-[(indolyl)ethyl)- coumarin-yloxy)]alkanamides

Article abstract of DOI:10.3184/174751917X14859570937677

Novel coumarin-tryptamine systems attached through a linker were synthesised and evaluated in vitro against acetylcholinesterase by the classical Ellman's test.

Full text of DOI:10.3184/174751917X14859570937677

120 RESEARCH PAPER
VOL. 41 FEBRUARY, 120–123
JOURNAL OF CHEMICAL RESEARCH 2017
Synthesis and anti-acetylcholinesterase activity of N-[(indolyl)ethyl)-
coumarin-yloxy)]alkanamides
Sarah Ghanei-Nasaba, Hamid Nadrib, Alireza Moradib, Azam Marjania, Shabnam Shabanic, Loghman
Firoozpourd, Setareh Moghimid, Mehdi Khoobic,e, Farzin Hadizadehf and Alireza Foroumadic,g*
aDepartment of Chemistry, Arak Branch, Islamic Azad University, Arak, Iran
bDepartment of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
cDepartment of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
dDrug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
eDepartment of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
fBiotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
gDepartment of Medicinal Chemistry, Faculty of Pharmacy and Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical
Sciences, Kerman, Iran
Novel coumarin–tryptamine systems attached through a linker were synthesised and evaluated in vitro against acetylcholinesterase by
the classical Ellman’s test.
Keywords: coumarin, acetylcholinesterase, Alzheimer’s disease, inhibitor
Alzheimer’s disease (AD) is an age-related neurodegenerative
disorder of the central nervous system (CNS) and affects older
people’s skills, knowledge and abilities. Memory loss, cognitive
impairment and language problems are some of the important
symptoms of these people, making them dependent on their
caregivers and relatives.1,2 The reduced levels of acetylcholine
(ACh), aggregation of β-amyloids around the neurons and also
the formation of neurofibrillary tangles within the brain have
been identified as the main causes of this disease.3 Increasing
the low levels of acetylcholine and inhibition of β-amyloid
peptide formation which led to the enhanced cholinergic
neurotransmission, have been regarded as the main treatment
method for this disease.4–6
Targeting the acetylcholinesterase enzyme (AChE) by
the action of effective inhibitors led to increased levels of
acetylcholine in the brain and thus an improvement in AD
symptoms. During the last decades, various AChE inhibitors
have been designed and clinically approved7 such as donepezil,8
galantamine9 and ensaculin.10 Ensaculin is a drug from the
coumarin family, administered for the treatment of dementia.
An efficient binding of ligands to peripheral (non-catalytic)
and central (catalytic) binding sites of AChE is considered the
best way of inhibiting the action of this enzyme.11 In this regard,
medicinal chemists are encouraged to design compounds
involving different moieties to simultaneously interact with
these sites.
The coumarin skeleton is an important fused-ring system
exhibiting various biological activities, therefore, various
synthetic methods have been reported to date to access
different coumarin derivatives.12,13 Due to the ability of this
core in binding to the peripheral anionic site (PAS) of AChE,
coumarins continue to be highly investigated as a main
structural feature of powerful anti-AChE molecules. Various
coumarin derivatives have been known as AChE inhibitors,14
like ensaculin, and AP2238 encompassing substitution at
positions 3- or 4- and regarded as beneficial dual inhibitors.15
Recently, we have synthesised different series of coumarin-
based compounds and evaluated their AChE inhibitory
activities.16–20 Furthermore, indole amine frameworks have been
successfully utilised for the synthesis of new AChE inhibitors
and multi-target agents.21 In this context and in continuation
of our recent work,22,23 it seemed very interesting to develop
coumarin carboxamide derivatives bearing an indole amine
(tryptamine) scaffold to find new AChE inhibitors. Herein, we
report the synthesis and anti-acetylcholinesterases activities of
N-[(indolyl) ethyl)-coumarin-yloxy)]alkanamides 4a–i.
Results and discussions
According to the literature, the reaction of resorcinol and
ethyl acetoacetate in concentrated sulfuric acid was utilised
to prepare 7-hydroxy-4-methylcoumarin.24 Other coumarin
derivatives were purchased and used without purification. The
synthetic sequence was initiated by O-alkylation of coumarins
with bromo ester derivatives and led to the corresponding
alkylated products. Then, hydrolysis of the ester grouping
in 2a–i under basic conditions (aqueous sodium hydroxide
solution) led to acid derivatives 3a–i. Synthesis of these
derivatives were reported previously in the literature.18,25–29 The
conversion of carboxylic acid derivatives to the corresponding
acyl chlorides was carried out in refluxing thionyl chloride.
Subsequent treatment with tryptamine furnished the desired
products in good yields (Scheme 1). The structures of all the
synthesised compounds were confirmed by analytical and
spectroscopic data.
The acetylcholinesterse inhibitory activities of the
synthesised compounds 4a–i were evaluated using Ellman’s
protocol30 and listed in Table 1. The results are reported as IC50
(µM) for active compounds and as a percentage of inhibition
at 50 µM for less active ones. The biological evaluation results
showed that these compounds are weak acetylcholinesterase
inhibitors.
In general, 7-substituted coumarins displayed better
activities compared to 4-hydroxycoumarin derivatives. Among
them, those derivatives bearing a methyl group at position
4 are more active than unsubstituted analogues (4c,d vs
4a,b). The presence of the methyl group as a substituent in a
linker, led to decreased inhibitory activities compared to an
unsubstituted linker. The most potent compound was 4c in
which a 7-hydroxy-4-methylcoumarin moiety was substituted
with an indole through an amide linkage.
* Correspondent. E-mail: aforoumadi@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2016 121
R1
R1
R1
R2
R2
a
b
EtO
HO
O
O
O
n
n
O
O
O
HO
O
O
3a–f
O
2a–f
O
1
1a–b
R1
2
4a
4b
4c
4d
: n =0, R , R = H
1
2
R2
: n =0, R = H, R = Me
1
2
: n =0, R = Me, R = H
c
O
1
2
: n =0, R , R = Me
n
O
O
O
1
2
4e
: n =2, R , R = H
1
2
NH
4f
: n =2, R = Me, R = H
4a–f
HN
R2
R2
OEt
OH
O
O
n
OH
O
O
n
O
O
O
a
b
c
O
O
O
3g–i
1c
2g–i
HN
2
4g
4h
4i
: n =0, R = H
O
2
: n =0, R = Me
: n =2, R = H
2
O
N
n
H
R2
O
4g–i
O
Fig. 1 Reagents and conditions: (a) BrCH2COOEt or BrCH(CH3)COOEt or Br(CH2)3COOEt, K2CO3, DMF, 90 °C, 5 h; (b) NaOH (5%), r.t., 12–24 h; (c) (i)
SOCl2, reflux, 5–6 h, (ii) K2CO3, tryptamine, dry toluene, reflux, 14–16 h.
Table 1 Inhibitory activities of compounds 4a–i against AChE
performed with an Elementar Analysen system GmbH VarioEL CHNS
mode. Mass spectra were determined on an Agilent Technology (HP)
mass spectrometer operating at an ionisation potential of 70 eV. All
reagents and solvents were purchased from Aldrich and Merck, and
used without any purification.
Entry
Compound
AChE inhibitiona
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
4g
4h
74.6 5.2
(11.1 1.3)
27.3 2.7
161.2 9.7
(17.4 2.1)
36.4 3.6
(12.1 0.9)
(5.7 0.6)
Cholinesterase inhibition assay
Acetylcholinesterase (AChE, E.C. 3.1.1.7, Type VeS, lyophilised
powder, from electric eel, 1000 unit) was provided from Sigma-
Aldrich. 5,50-Dithiobis-(2-nitrobenzoic acid) (DTNB), potassium
dihydrogen phosphate, dipotassium hydrogen phosphate, potassium
hydroxide, sodium hydrogen carbonate, and acetylthiocholine iodide
(ATCh) were purchased from Fluka. The stock solutions of the target
compounds were prepared in a mixture of DMSO (1 mL) and ethanol
(9 mL) and diluted with 0.1 MKH2PO4/K2HPO4 buffer (pH ¼ 8.0) to
obtain final concentrations. 20 mL of substrate (acetylthiocholine
iodide 0.075 M) was added to the test solution to obtain the final
concentration of 466 mM. All experiments were performed based on
the previously described method.30 Spectrophotometric measurements
were performed on a UV Unico Double Beam Spectrophotometer.
4i
(6.8 0.8)
0.035 0.002
Donepezil
aIC50 (µM) or inhibition of AChE (%) at 50 µM (in parentheses). The data are expressed as
mean SD from three experiments.
Conclusion
In conclusion, we have reported a multi-step strategy for the
synthesis of a coumarin linked to a tryptamine moiety and
evaluated the acetylcholineasterase inhibitory activities of the
target compounds. The obtained results showed poor activity of
the synthesised compounds against AChE. This finding showed
that these coumarin derivatives require further modification to
achieve promising results.
Synthesis of coumarin esters (2a–i); general procedure
The appropriate hydroxycoumarin derivative (5 mmol) and potassium
carbonate (5.5 mmol) were dissolved in DMF (5 mL). The solution was
stirred at room temperature for 20 min and then ethyl bromoacetate,
or ethyl 2-bromopropionate or ethyl 4-bromobutanoate (5.2 mmol) was
added dropwise to the mixture. The solution was heated at 90 °C for
5 h. Upon completion, determined by thin layer chromatography, the
mixture was cooled and diluted with ice. The resultant precipitate was
filtered, washed and used without further purifications.
Experimental
Melting points were taken on a Kofler hot stage apparatus and are
uncorrected. 1H and 13C NMR spectrum was recorded on Bruker FT-
500, using TMS as an internal standard. The elemental analysis was

122 JOURNAL OF CHEMICAL RESEARCH 2016
Synthesis of coumarin acids (3a–i); general procedure
N-[2- (1H-Indol-3-yl)ethyl]-4- (2-oxo-2H-chromen-7-yloxy)
butanamide (4e): Pale brown solid; yield 84%; m.p. 120–123 ºC; IR
(KBr) νmax/cm–1: 3550, 1715, 1690; 1H NMR (CDCl3, 300 MHz): δ 8.25
(brs, 1H, CONH), 7.65–7.40 (m, 2H), 7.35–7.20 (m, 2H), 7.11 (t, J = 7.5
Hz, 1H), 7.02 (t, J = 6.9 Hz, 1H), 6.93 (s, 1H), 6.80–6.50 (m, 2H), 6.15
(d, J = 9.3 Hz, 1H), 5.63 (brs, 1H, NH), 3.90–3.89 (m, 2H), 3.55–3.53
(m, 2H), 2.89 (t, J = 6.0 Hz, 2H), 2.35–2.15 (m, 2H), 2.10–1.95 (m, 2H).
13C NMR (CDCl3, 75 MHz): δ 170.9, 161.0, 160.3, 154.7, 142.5, 135.4,
127.8, 126.3, 121.2, 121.0, 118.4, 117.6, 112.0, 111.8, 111.6, 111.5, 110.3,
100.5, 66.5, 38.7, 31.6, 28.7, 24.3. Anal. calcd for C23H22N2O4 (390.43):
C, 70.75; H, 5.68; N, 7.17; found: C, 70.55; H, 5.44; N, 6.94%.
An aqueous solution of NaOH (25 mL, 5%) was added to ester
derivatives (2a–i) and stirred at room temperature for 12–24 h.
Upon completion, the mixture was neutralised by the addition of
hydrochloric acid solution (5%). The resultant white precipitate was
isolated by filtration, washed and dried.
Synthesis of coumarin amides (4a–i);general procedure
Compounds (3a–i) (1 mmol) were added to thionyl chloride (5 mL) and
the mixture was refluxed for 5–6 h. Upon completion, thionyl chloride
was removed under reduced pressure to afford the corresponding
coumarin-3-carbonyl chlorides. The crude product was dissolved in
dry toluene (15 mL) followed by the addition of tryptamine (1 mmol)
and potassium carbonate (2 mmol) into the solution and heated at
reflux temperature under nitrogen atmosphere for 14–16 h. After this
time, the solvent was removed under reduced pressure and the product
was filtered and dried under vacuum.
N-[2-(1H-Indol-3-yl)ethyl]-4-(4-methyl-2-oxo-2H-chromen-7-yloxy)
butanamide (4f): Pale brown solid; yield 83%; m.p. 109–111 ºC; IR
(KBr) νmax/cm–1: 3550, 1715, 1690; 1H NMR (CDCl3, 300 MHz): δ 8.41
(s, 1H, CONH), 7.48 (d, J = 6.9 Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H), 7.27
(d, J = 8.1 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.92
(d, J = 1.8 Hz, 1H), 6.68-6.70 (m, 1H), 6.61 (d, J = 2.4 Hz, 1H), 6.01 (d,
J = 0.6 Hz, 1H), 5.76 (t, J = 5.4 Hz, 1H), 3.88 (t, J = 6.0 Hz, 2H), 3.52
(t, J = 6.0 Hz, 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.41 (s, 3H), 2.35–2.15 (m,
2H), 2.02 (m, 2H). 13C NMR (CDCl3, 75 MHz): δ 172.1, 161.9, 161.5,
155.1, 152.8, 136.5, 127.3, 125.6, 122.2, 122.1, 119.4, 118.6, 113.6, 112.7,
112.4, 111.8, 111.4, 101.5, 67.5, 39.8, 32.7, 25.3, 24.9, 18.7. Anal. calcd
for C24H24N2O4 (404.46): C, 71.27; H, 5.98; N, 6.93; found: C, 71.07; H,
5.77; N, 6.74% .
N-[2- (1H-Indol-3-yl)ethyl]-2- (2-oxo-2H-chromen-7-yloxy)
acetamide (4a): Pale brown solid; yield 91%; m.p. 180–184 ºC; IR
(KBr) νmax/cm–1: 3550, 1715, 1690; 1H NMR (DMSO-d6, 300 MHz): δ
10.89 (s, 1H), 8.33 (t, J = 7.8 Hz, 1H, CONH), 8.05 (d, J = 9.3 Hz, 1H),
7.71–7.68 (m, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.21
(d, J = 1.8 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.07–6.99 (m, 3H), 6.37
(d, J = 9.3 Hz, 1H), 4.66 (s, 2H, CH2), 3.48 (t, J = 7.5 Hz, 2H, CH2),
2.92 (t, J = 7.5 Hz, 2H, CH2). 13C NMR (DMSO-d6, 75 MHz): δ 167.3,
161.2, 160.7, 155.6, 144.7, 136.7, 130.0, 127.6, 123.1, 121.4, 118.7 (2C),
113.4, 113.3, 113.1, 112.0, 111.9, 102.2, 67.7, 39.1, 25.6. Anal. calcd for
C21H18N2O4 (362.38): C, 69.60; H, 5.01; N, 7.73; found: C, 69.46; H,
4.89; N, 7.43%.
N-[2- (1H-Indol-3-yl)ethyl]-2- (2-oxo-2H-chromen-4-yloxy)
acetamide (4g): Pale brown solid; yield 85%; m.p. 114–116 ºC; IR
(KBr) νmax/cm–1: 3550, 1715, 1690; 1H NMR (CDCl3, 300 MHz): δ 8.39
(brs, 1H, CONH), 7.80–6.60 (m, 9H), 6.48 (brs, 1H), 5.58 (s, 1H), 4.53
(s, 2H), 3.78–3.76 (m, 2H), 3.08 (t, J = 6.3 Hz, 2H). 13C NMR (CDCl3,
75 MHz): δ 165.5, 163.9, 162.2, 153.2, 136.5, 132.8, 127.1, 124.1, 122.5,
122.4, 122.0, 119.6, 118.5, 116.9, 114.8, 112.1, 111.5, 91.7, 67.4, 39.2,
25.0. Anal. calcd for C21H18N2O4 (362.38): C, 69.60; H, 5.01; N, 7.73;
found: C, 69.82; H, 5.38; N, 7.57.
N-[2- (1H-Indol-3-yl)ethyl]-2- (2-oxo-2H-chromen-7-yloxy)
propanamide (4b): Pale brown solid; yield 86%; m.p. 120–122 ºC; IR
(KBr) νmax/cm–1: 3550, 1715, 1690; 1H NMR (CDCl3, 300 MHz): δ 8.31
(brs, 1H, CONH), 7.50 (d, J = 9.3 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H),
7.26–7.18 (m, 2H), 7.08 (t, J = 7.2 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H),
6.79 (d, J = 1.8 Hz, 1H), 6.65–6.58 (m, 2H), 6.41 (m, 1H), 6.18 (d, J
= 9.3 Hz, 1H), 4.58 (q, J = 6.6 Hz, 1H), 3.65–3.59 (m, 2H), 2.91–2.85
(m, 2H), 1.48 (d, J = 6.9 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 169.9,
160.0, 158.7, 154.4, 142.2, 135.4, 128.0, 126.1, 121.2, 121.1, 118.4, 117.5,
112.8, 112.4, 111.2, 111.2, 110.3, 102.1, 74.3, 38.1, 24.0, 17.6. Anal.
calcd for C22H20N2O4 (376.41): C, 70.20; H, 5.36; N, 7.44; found: C,
69.99; H, 5.06; N, 7.26%.
N-[2- (1H-Indol-2-yl)ethyl]-2- (2-oxo-2H-chromen-4-yloxy)
propanamide (4h): Pale brown solid; yield 81%; m.p. 159–161 ºC;
1
IR (KBr) νmax/ cm–1: 3550, 1715, 1690; H NMR (CDCl3, 300 MHz):
δ 7.99 (brs, 1H, CONH), 7.55–7.42 (m, 2H), 7.37 (d, J = 6.9 Hz, 1H),
7.28–7.16 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H),
6.96 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 1.5 Hz, 1H), 6.13–6.08 (m, 1H),
5.49 (s, 1H), 4.66 (q, J = 6.6 Hz, 1H), 3.68–3.53 (m, 2H), 2.94–2.89
(m, 2H), 1.56 (d, J = 6.6 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 169.3,
163.7, 162.4, 153.3, 136.4, 132.7, 127.0, 124.1, 122.7, 122.4, 122.2, 119.5,
118.4, 116.8, 115.1, 112.0, 111.4, 91.9, 65.5, 39.3, 24.9, 18.3. Anal. calcd
for C22H20N2O4 (376.41): C, 70.20; H, 5.36; N, 7.44; found: C, 70.08; H,
5.17; N, 7.23%.
N-[2-(1H-Indol-3-yl)ethyl]-2-(4-methyl-2-oxo-2H-chromen-7-yloxy)
acetamide (4c): Pale brown solid; yield 80%; m.p. 166–168 ºC; IR
(KBr) νmax/cm–1: 3550, 1715, 1690; 1H NMR (CDCl3, 300 MHz): δ 8.10
(brs, 1H, CONH), 7.52 (d, J =7.8 Hz, 1H), 7.39 (d, J =8.4 Hz, 1H), 7.31
(d, J = 8.1 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H),
6.98–6.95 (m, 1H), 6.69–6.65 (m, 1H), 6.63 (s, 1H), 6.58–6.47 (m, 1H),
6.11–6.10 (m, 1H), 4.43 (s, 2H), 3.65–3.63 (m, 2H), 2.96 (t, J = 6.6 Hz,
2H), 2.32 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 166.0, 159.9, 158.7,
153.9, 151.3, 135.4, 126.2, 124.9, 121.3, 121.1, 118.5, 117.5, 113.7,
111.8, 111.5, 110.4, 110.3, 101.6, 66.5, 38.3, 29.9, 21.7. Anal. calcd for
C22H20N2O4 (376.41): C, 70.20; H, 5.36; N, 7.44; found: C, 69.98; H,
5.09; N, 7.25%.
N-[2- (1H-Indol-3-yl)ethyl]-4- (2-oxo-2H-chromen-4-yloxy)
butanamide (4i): Pale brown solid; yield 87%; m.p. 252–254 ºC; IR
1
(KBr) νmax/cm–1: 3550, 1715, 1690; H NMR (CDCl3, 300 MHz): δ
8.28 (brs, 1H, CONH), 7.68 (d, J = 7.8 Hz, 2H), 7.55–7.40 (m, 2H), 7.29
(d, J = 7.8 Hz, 1H), 7.25–6.96 (m, 3H), 6.93 (s, 1H), 5.60 (brs, 1H),
5.51 (s, 1H), 4.05–3.90 (m, 2H), 3.65–3.40 (m, 2H), 2.90 (t, J = 6.0 Hz,
2H), 2.35–2.05 (m, 4H). 13C NMR (CDCl3, 75 MHz): δ 170.6, 164.5,
162.1, 152.2, 135.4, 131.4, 126.3, 122.9 (2C), 122.0, 121.1, 118.4, 117.5,
115.7, 114.6, 111.7, 110.4, 89.4, 67.5, 38.8, 31.6, 28.7, 24.2. Anal. calcd
for C23H22N2O4 (390.43): C, 70.75; H, 5.68; N, 7.17; found: C, 70.89; H,
5.87; N, 6.95%.
N-[2-(1H-Indol-3-yl)ethyl]-2-(4-methyl-2-oxo-2H-chromen-7-yloxy)
propanamide (4d): Pale brown solid; yield 86%; m.p. 103–105 ºC;
IR (KBr) νmax/cm–1: 3550, 1715, 1690; 1H NMR (CDCl3, 300 MHz): δ
8.41 (brs, 1H, CONH), 7.43 (d, J = 7.8 Hz, 1H), 7.33–7.18 (m, 2H), 7.05
(t, J = 7.2 Hz, 1H), 6.95 (t, J = 6.9 Hz, 1H), 6.79 (d, J = 1.8 Hz, 1H),
6.63–6.58 (m, 2H), 6.45 (t, J = 5.1 Hz, 1H), 6.06–6.04 (m, 1H), 4.58
(q, J = 6.6 Hz, 1H), 3.61–3.45 (m, 2H), 2.94–2.89 (m, 2H), 2.26 (s, 3H),
1.47 (d, J = 6.9 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 170.1, 160.1,
158.6, 153.8, 151.5, 135.4, 126.1, 124.8, 121.2, 121.0, 118.3, 117.4, 113.5,
111.5, 111.1, 110.8, 110.3, 102.1, 66.8, 38.1, 29.2, 24.0, 17.6. Anal. calcd
for C23H22N2O4 (390.43): C, 70.75; H, 5.68; N, 7.17; found: C, 70.57; H,
5.47; N, 6.97%.
Acknowledgment
This work was supported and funded by Iran National Science
Foundation (INSF).
Received 13 August 2016; accepted 15 January 2017
Paper 1604257 DOI: 10.3184/174751917X14859570937677
Published online: 10 February 2017

JOURNAL OF CHEMICAL RESEARCH 2016 123
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