Synthesis of Novel 1,2,3-Triazole-dihydro[3,2-c[chromenones as Acetylcholinesterase Inhibitors

Article abstract of DOI:10.1080/00397911.2015.1077971

A novel series of 1,2,3-triazole-dihydro[3,2-c]chromenone derivatives were synthesized through an efficient three-step reaction starting from 4-hydroxybenzaldehyde. All the newly synthesized compounds were characterized by infrared and NMR spectroscopy as

Full text of DOI:10.1080/00397911.2015.1077971

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Synthesis of Novel 1,2,3-Triazole-dihydro[3,2-
c]chromenones as Acetylcholinesterase Inhibitors
Mina Saeediab, Shirin Ansaric, Mohammad Mahdavic, Reyhaneh Sabourianb, Tahmineh
Akbarzadehcb, Alireza Foroumadic & Abbas Shafieec
a Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical
Sciences, Tehran, Iran
b Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences,
Tehran, Iran
c Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences
Research Center, Tehran University of Medical Sciences, Tehran, Iran
Accepted author version posted online: 17 Aug 2015.
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To cite this article: Mina Saeedi, Shirin Ansari, Mohammad Mahdavi, Reyhaneh Sabourian, Tahmineh Akbarzadeh, Alireza
Foroumadi & Abbas Shafiee (2015): Synthesis of Novel 1,2,3-Triazole-dihydro[3,2-c]chromenones as Acetylcholinesterase
Inhibitors, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2015.1077971
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Synthesis of Novel 1,2,3-Triazole-Dihydro[3,2-c]Chromenones as
Acetylcholinesterase Inhibitors
Mina Saeedi1,2, Shirin Ansari3, Mohammad Mahdavi3, Reyhaneh Sabourian2, Tahmineh
Akbarzadeh3,2, Alireza Foroumadi3, Abbas Shafiee3
1Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical
Sciences, Tehran, Iran 2Persian Medicine and Pharmacy Research Center, Tehran
University of Medical Sciences, Tehran, Iran 3Department of Medicinal Chemistry,
Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences, Tehran, Iran
Corresponding author Abbas Shafiee , E-mail: ashafiee@ams.ac.ir
Abstract
A novel series of 1,2,3-triazole-dihydro[3,2-c]chromenone derivatives were synthesized
through an efficient three-step reaction starting from 4-hydroxybenzaldehyde. All the
newly synthesized compounds were characterized by IR and NMR spectroscopy as well
as elemental analysis and evaluated for their acetylcholinesterase inhibitory (AChEI)
activity.
KEYWORDS: 1,2,3-Triazole-dihydro[3,2-c]chromenones; acetylcholinesterase;
heterocycles
INTRODUCTION
1

1,2,3-Triazole and chromenone derivatives are important classes of heterocyclic
compounds possessing valuable medicinal properties. 1,2,3-Triazoles have exhibited
cytotoxic,[1], anti-HIV-1,[2] anti-influenza,[3] anti-platelet,[4] and anti-tuberculosis[5]
activities. Also, AChEI,[6] IRE-1 RNase,[7] human steroid sulfatase,[8] anticoagulation and
cardiovascular,[9] antimicrobial,[10] anticancer,[11] anti-inflammatory and antioxidant,[12]
antiviral (inhibitor of HIV-1 protease and integrase),[13] and enzyme-inhibition effects[14]
of chromenones have been well documented in the literature. It seems that the
combination of 1,2,3-triazoles and chromenones presents versatile biological activities.
The main method for the synthesis of 1,2,3-triazole follows the click reaction
described by Sharpless et al.[15] and modified procedures.[16-18] Preparation of chromenone
derivatives usually is achieved by the classic methods such as Perkin,[19] Pechmann,[20]
Knoevenagel,[21] Wittig,[22] and Kostanecki-Robinson[23] reactions. However, literature
lacks efficient and versatile procedures for the construction of 1,2,3-triazole-chromenone
scaffolds.[24]
As part of our activities on the synthesis of novel heterocycles as well as bioactive
compounds,[25-28] we have specially focused on the anti-Alzheimer agents acting via
inhibition of AChE enzyme. Alzheimer’s disease (AD) is known as the main origin of
dementia among older people.[29] The most common factors causing AD include
cholinergic system disorders, accelerated aggregation of β-amyloid peptides, and the
dyshomeostasis of biometals.[30-34] As the most of AD symptoms are arose from
acetylcholine-producing system dysfunction specially hydrolysis of ACh by AChE,[35]
2

lots of efforts is belonged to the inhibition of acetylcholinesterase (AChE). Here, we
described synthesis and characterization of novel 1,2,3-triazole-dihydro[3,2-
c]chromenones 10 (Scheme 1) which were evaluated for their AChEI activity.
RESULTS AND DISCUSSION
Chemistry
At first, 4-(prop-2-yn-1-yloxy)benzaldehyde 3 was prepared by the reaction of 4-
hydroxybenzaldehyde 1 and propargyl bromide 2 in the presence of potassium carbonate
in DMF at 80 °C. Next, reaction of 4-(prop-2-yn-1-yloxy)benzaldehyde 3, 4-
hydroxycoumarin 4, and malononitrile 5 was achieved in the presence of 1,8-
diazabicycloundec-7-ene (DBU) in EtOH at room temperature to obtain 2-amino-5-oxo-
4-(4-(prop-2-yn-1-yloxy)phenyl)-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile 6 in
good yield. Presence of triple bond in compound 6 led us to conduct click reaction using
various organic azide derivatives 9. In this respect, the corresponding azides 9 were
synthesized from the reaction of different benzyl bromides/chlorides 7 and sodium azide
8 in DMF at 80 °C. In the next step, reaction of compounds 6 and 9 in the presence of
CuI in DMF at 80 °C led to the formation of the tile compounds 10. In this way, different
1,2,3-triazole-dihydro[3,2-c]chromenones were prepared using various azide derivatives
9 (Table 1).
The structure of all products was confirmed using IR, 1H NMR, and 13C NMR
spectroscopy and elemental analysis. For example, 1 HNMR spectrum of compound 2-
amino-4-(4-((1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-5-oxo-4H,5H-
3

pyrano[3,2-c]chromene-3-carbonitrile 10a confirmed the presence of 23 protons based on
the expected chemical shifts and coupling patterns. The methyl group protons were
observed at 2.26 ppm as a singlet. H4 and two methylene groups’ protons were appeared
at 4.40, 5.11, and 5.71 ppm, respectively. Aromatic and amino group protons were
observed in the range of 6.95-7.89 and 7.39 ppm, respectively. Also, 1,2,3-triazole singlet
signal was distinguished at 8.25 ppm. 13C NMR spectrum showed 26 expected signals. 5
signals at 20.7, 36.2, 52.7, 58.2, and 61.1 ppm in aliphatic range confirmed methyl,
methylene groups, methyne, and C4 carbons. Also, 21 signals in the range of 104.3-159.6
ppm demonstrated aromatic carbons.
Pharmacology
All the synthesized 1,2,3-triazole-dihydro[3,2-c]chromenones 10 were evaluated for their
AChE inhibitory activity using modified colorimetric Ellman’s method[27,33,36] and
compared with rivastigmine as the reference drug (Table 1). It was found that most of the
synthesized compounds showed mild to weak inhibitory activity. Among them,
compound 10g having 4-bromobenzyl group connected to 1,2,3-triazole ring exhibited
more potent activity (55% inhibition) comparing with rivastigmine (80% inhibition). As
can be seen in Table 1, compounds 10a-f were found less active than compound 10g. It
seems that introduction of methyl and chlorine groups into the pendant benzyl group led
to the reduction of activity. Also, presence of methoxy group on the aryloxy moiety did
not improve anti-AChE activity.
EXPERIMENTAL
4

All reagents and solvents were obtained from Merck and Aldrich. Melting points were
determined with a Kofler hot-stage apparatus (Reichert, Vienna, Austria). 1H and 13C
NMR spectra were measured using 500-Brucker spectrometer. IR spectra were recorded
on a Nicolet Magna FTIR 550 spectrophotometer (potassium bromide disks). The
elemental analysis was carried out using Elementar Analysensysteme (Vario EL).
Synthesis Of 1,2,3-Triazole-Dihydro[3,2-C]Chromenone Derivatives 10: General
Procedure
A solution of 2-amino-5-oxo-4-(4-(prop-2-yn-1-yloxy)phenyl)-4,5-dihydropyrano[3,2-
c]chromene-3-carbonitrile 6 (1 mmol), azide derivative 9 (1 mmol), and CuI (5 mol%) in
DMF (8 mL) was stirred at 80 °C for 4-5 h. After completion of reaction, the mixture was
cooled down to room temperature. Then, water (25 mL) was added to the mixture and the
organic phase was extracted using ethyl acetate (3 × 25). It was dried over Na2SO4 and
the solvent was evaporated under vacuum. Crude product was recrystallized from ethanol
to give pure product 10.
Selected Data
2-Amino-4-(4-((1-(4-Methylbenzyl)-1H-1,2,3-Triazol-4-Yl)Methoxy)Phenyl)-5-Oxo-
4H,5H-Pyrano[3,2-C]Chromene-3-Carbonitrile (10a).
Yield: 80%, white crystals, mp 230-232 oC. IR (KBr): 3351, 3320, 3079, 29551, 2197,
1715, 1673, 1606, 1507 cm-1. 1H NMR (500 MHz: DMSO-d6): 2.26 (s, 3H, CH3), 4.40 (s,
1H, H4), 5.11 (s, 2H, CH2), 5.71 (s, 2H, CH2), 6.95 (d, J = 8.8 Hz, 2H, H3', H5'), 7.11-
7.22 (m, 6H, H2', H6', H2", H3", H5", H6"), 7.39 (s, 2H, NH2), 7.45 (d, J = 8.0 Hz, 1H,
5

H7), 7.48 (t, J = 8.0 Hz, 1H, H9), 7.70 (td, J = 8.0, 1.5 Hz, 1H, H8), 7.89 (d, J = 8.0 Hz,
1H, H10), 8.25 (s, 1H, triazole). 13C NMR (125 MHz: DMSO-d6): 20.7 (Me), 36.2 (C4),
52.7 (benzyl CH2), 58.2 (C3), 61.1 (OCH2), 104.3 (4H-pyran), 113.0 (C3' and 5'), 114.6
(coumarin), 116.6 (coumarin), 119.4 (CN), 122.5 (triazole), 124.6 (Ar), 124.7 (Ar), 128.1
(Ar), 128.8 (Ar), 129.4 (Ar), 132.9 (Ar), 133.0 (Ar), 135.8 (Ar), 137.6 (Ar), 143.0
(triazole), 152.1 (C4'), 153.2 (coumarin, C-O), 157.2 (C2), 158.0 (4H-pyran, C-O), 159.6
(C=O (C5)). Anal. calcd. for C30H23N5O4: C, 69.62; H, 4.48; N, 13.53. Found: C, 69.80;
H, 4.32; N, 13.71.
FUNDING
This work was supported by the Research Council of Tehran University of Medical
Sciences and Iran National Science Foundation (INSF).
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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13

Table 1. Synthesis and AChE inhibitory activity of 1,2,3-triazole-dihydro[3,2-
c]chromenone 10
Entry X
Y
Product 10 AChEI Inhibition (%) (40 µg/mL) Yield (%)a
1
2
3
4
5
6
7
8
9
H
4-Me
2-Me
2-Cl
15
22
10
27
10
7
80
75
82
77
70
70
80
75
10a
10b
10c
10d
10e
10f
H
H
H
2,3-di-Cl
2,4-di-Cl
2,6-di-Cl
4-Br
H
H
H
55
20
80
10g
10h
OMe
4-Br
Rivastigmine
aIsolated yields.
14

Scheme 1. Synthesis of 1,2,3-triazole-dihydro[3,2-c]chromenones 10.
15