Nitrogen-containing flavonoid and their analogs with diverse B-ring in acetylcholinesterase and butyrylcholinesterase inhibition

Article abstract of DOI:10.1002/ddr.21726

In this study, a series of new flavones (2-phenyl-chromone), 2-naphthyl chromone, 2-anthryl-chromone, or 2-biphenyl-chromone derivatives containing 6 or 7-substituted tertiary amine side chain were designed, synthesized, and evaluated in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The results indicated that the alteration of aromatic ring connecting to chromone scaffold brings about a significant impact on biological activity. Compared with flavones, the inhibitory activity of 2-naphthyl chromone, 2-anthryl-chromone derivatives against AChE significantly decreased, while that of 2-biphenyl chromone derivatives with 7-substituted tertiary amine side chain is better than relative flavones derivatives. For all new synthesized compounds, the position of tertiary amine side chain obviously influenced the activity of inhibiting AChE. The results above provide great worthy information for the further development of new AChE inhibitors. Among the newly synthesized compounds, compound 5a is potent in AChE inhibition (IC₅₀ = 1.29 ± 0.10 μmol/L) with high selectivity for AChE over BChE (selectivity ratio: 27.96). An enzyme kinetic study of compound 5a suggests that it produces a mixed-type inhibitory effect against AChE.

Full text of DOI:10.1002/ddr.21726

Received: 25 December 2019
DOI: 10.1002/ddr.21726
Revised: 1 June 2020
Accepted: 6 July 2020
R E S E A R C H A R T I C L E
Nitrogen-containing flavonoid and their analogs with diverse
B-ring in acetylcholinesterase and butyrylcholinesterase
inhibition
Qiao-Qiao Lu1 | Ya-Ming Chen1 | Hao-Ran Liu1
| Jian-Ye Yan2
|
Pei-Wu Cui2 | Qian-Fan Zhang1 | Xiao-Hui Gao3 | Xing Feng4 | Ying-Zi Liu4
1Department of Chemical Biology, College of
Abstract
Chemistry and Chemical Engineering, Hu'nan
University, Changsha, China
In this study, a series of new flavones (2-phenyl-chromone), 2-naphthyl chromone,
2Department of Pharmacy, College of
2-anthryl-chromone, or 2-biphenyl-chromone derivatives containing
6
or
Pharmacy, Hu'nan University of Chinese
Medicine, Changsha, China
7-substituted tertiary amine side chain were designed, synthesized, and evaluated in
acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The results
indicated that the alteration of aromatic ring connecting to chromone scaffold brings
about a significant impact on biological activity. Compared with flavones, the inhibi-
tory activity of 2-naphthyl chromone, 2-anthryl-chromone derivatives against AChE
significantly decreased, while that of 2-biphenyl chromone derivatives with
7-substituted tertiary amine side chain is better than relative flavones derivatives.
For all new synthesized compounds, the position of tertiary amine side chain obvi-
ously influenced the activity of inhibiting AChE. The results above provide great wor-
thy information for the further development of new AChE inhibitors. Among the
newly synthesized compounds, compound 5a is potent in AChE inhibition
(IC50 = 1.29 0.10 μmol/L) with high selectivity for AChE over BChE (selectivity
ratio: 27.96). An enzyme kinetic study of compound 5a suggests that it produces a
mixed-type inhibitory effect against AChE.
3Department of Pharmacy, College of
Pharmacy, Changsha Medical University,
Changsha, China
4Department of Pharmacy, College of
Medicine, Hu'nan Normal University,
Changsha, China
Correspondence
Hao-Ran Liu, College of Chemistry and
Chemical Engineering, Hu'nan University,
Changsha 410082, China.
Email: pharmaliu@126.com
Ying-Zi Liu, College of medicine, Hu'nan
Normal University, Changsha; 410013, China.
Email: liuyingzi111@sina.com
Funding information
the Grant of Department of Education of
Hu'nan Province, Grant/Award Number:
18B543; the grant of Key Laboratory Breeding
Base of Hu'nan Oriented Fundamental and
Applied Research of Innovative Pharmaceutics,
Grant/Award Number: 2016TP1029
K E Y W O R D S
cholinesterase inhibitors, flavonoid analog, structure–activity relationship
1
|
INTRODUCTION
et al., 2017). Structural modification of natural products is beneficial
to improve drug-likeness and enrich this molecular library (Hati
Natural products and their analogs have a long history as valuable
starting points in drug discovery (Rodrigues, Reker, Schneider, &
Schneider, 2016). In past several decades, statistically, more than one-
third of new drugs on the market are directly or indirectly originated
from natural products (Calixto, 2019). Natural product-based mole-
cules library with diverse architectures have evolved as one of the
most useful tools for discovering lead compounds (Kumar
et al., 2016). Screening enzyme inhibitors in vitro is one of efficient
approaches to find new drugs quickly from natural products or their
derivatives (Majumdar et al., 2015).
Flavonoids are a class of natural products widely existing in plants. Up
to now, over 10,000 flavonoids have been identified (Kozlowska &
Szostak-Węgierek, 2014) and their bioactivities such as antioxidant, anti-
tumor, antiinflammatory，antivirus, and antimultidrug resistance have
been reported (Rana & Gulliya, 2019; Bian et al., 2018). There are also
some studies on the effects of flavones in nervous system diseases partic-
ularly Alzheimer's disease (AD) (Wang, Cao, Wu, Wang, & Xiao, 2016;
Qiao-Qiao Lu and Ya-Ming Chen contributed equally to this work and should be regarded as
co-first authors.
Drug Dev Res. 2020;1–11.
wileyonlinelibrary.com/journal/ddr
© 2020 Wiley Periodicals LLC
1

2
LU ET AL.
Sevindik, Güvenalp, Erdelen, Yuca, & Demirezer, 2015). Among them some
of flavonoid derivatives show better inhibition on AChE than their parent
flavonoids (Luo, Chen, Wang, Hong, & Wang, 2015; Khan et al., 2009).
At present, the drugs for AD in clinic mainly are cholinesterase
inhibitors such as Tacrine, Rivastigmine, Galantamine, Donepezil
(Starner
& Gleason, 2008; Lane, Kivipelto, & Greig, 2004; Fox,
Maidment, Boustani, & Katona, 2006). But most of them have various
adverse reactions. Earlier, Tacrine was withdrawn from the market due
to severe liver injury (Giacobini, 2004). Both Rivastigmine and
Galantamine have a greater number of gastrointesinal side effects
reports (Thompson, Lanctôt, & Herrmann, 2004). In addition, there is a
report that three cases of new-onset bradycardia presenting as syncope
is believed to be related to Donepezil dosed at 5 mg (Bordier
et al., 2003). Huperzine A, a cholinesterase inhibitor discovered from
Chinese medicinal herb, is found having some side effects such as diar-
rhea, insomnia, anxiety, and dizziness (Yang, Wang, Tian, & Liu, 2013).
So, there is an increasing demand to develop new cholinesterase inhibi-
tors. In our laboratory, flavokawain B Mannich base derivatives with
chalcone scaffold were found have an inhibitory effect on AChE in the
screening bioactive compounds from natural products (Liu et al., 2014;
Liu et al., 2016). Subsequently, a number of chalcone derivatives with
tertiary amine side chains were confirmed having inhibitory effect on
AChE (Liu et al., 2014; Liu et al., 2015). Considering that flavonoids are
cyclized derivatives of chalcone; in the present study, a series of flavo-
noids (2-phenyl chromone) were synthesized and evaluated in AChE or
BChE inhibition. According to International Union of Pure and Applied
Chemistry (IUPAC) nomenclature, three rings in the flavonoid are named
A-ring, B-ring, and C-ring (Siasos et al., 2013) (Figure 1). In this study,
the influence of B-ring in flavonoid scaffold was taken into consider-
ation. So, 2-napohthyl-chromone, 2-anthryl-chromone, or 2-biphenyl-
chromone derivatives that similar to flavonoids were synthesized and
compared the bioactivity in AChE and BChE inhibition (Figure 1).
FIGURE 1 Design pathway of nitro-containing flavonoid
derivatives. (a) Chalcone; (b) chalcone derivatives with tertiary amine
moiety; (c) flavonoids; (d) aromatic ring-substituted flavonoid
derivatives with tertiary amine moiety
are added into the flask at room temperature, followed by the addi-
tion of pyridinium toluene-4-sulphonate (1.4 mmol). After stirring for
10 min, 3,4-dihydro-2H-pyran (DHP, 2.65 ml, 28 mmol) was added
into the mixture and stirred overnight (Won et al., 2005). The reaction
was monitored by thin layer chromatography (TLC) until the reaction
is completed. Then 5% sodium hydroxide solution (30 ml × 3) was
added into the solution. The organic layer was dried over anhydrous
sodium sulfate and filtered. Then the residual solvent was removed by
the evaporation under reduced pressure, and the yellowish solid crys-
tals (Compounds 2a, 2b) were gained. Yield:Compound 2a, 90.6%;
Compound 2b, 82.2%. These compounds were used as the intermedi-
ates to synthesize compounds 3a–3h without further purification.
Compound 2a or 2b (2.24 g, 7 mmol) and benzaldehyde
(or 1-naphthalene formaldehyde, 9-anthracene formaldehyde,
4-phenylbenzaldehyde， 7.7 mmol)were placed in the flask with
50 ml of polyethylene glycol 400 (PEG 400) as the solution
(Tanemura, Suzuki, Nishida, & Horaguchi, 2005).. After stirring at
40ꢀC for 15 min, 20% NaOH (30 ml) was added into the mixture. The
reaction was monitored by TLC. After the reaction was completed, ice
water was poured into the flask, and a large amount of precipitate
was produced. Then ethyl acetate (20 mL × 3) was added into the
mixture, and the organic layer was got and dried over anhydrous
sodium sulfate, filtered, and followed by the removal of the solvent.
The products (Compounds 3a–3h) are diastereomeric mixtures
because of the two THP groups, so these intermediates were not
characterized and applied for the next step without further purifica-
tion. Yield:Compound 3a, 78.5%; Compound 3b, 80.4%； Compound
3c, 77.3%; Compound 3d, 75.7%; Compound 3e, 72.8%; Compound
3f, 77.1%; Compound 3g, 81.8%; Compound 3h, 83.6%.
2
|
MATERIALS AND METHODS
| Chemistry
2.1
All chemicals or reagents are of analytical grade and used without fur-
ther purification. 1H NMR and 13C NMR spectra were recorded on a
Bruker 400 MHz nuclear magnetic instrument in CDCl3 with tetra-
methylsilane (TMS) as the internal reference. Mass spectra were
obtained on Waters XEVO G2-XS QTOF by electrospray ionization
(ESI-MS). Infrared spectrum was obtained on Shimadzu Infinity-1
infrared spectrometer. The purity of compounds was checked by
Agilent 1,100 high-performance liquid chromatography.
2.2
|
General procedure for the synthesis of
compounds 3a–3h
Compound 1a (2,4-dihydroxyacetophenone, 10 mmol) or 1b
(2,5-dihydroxyacetophenone, 10 mmol) and dichloromethane (30 ml)

LU ET AL.
3
2.3
|
General procedure for the synthesis of
13C NMR (101 MHz, DMSO-d6) δ 181.74, 168.65, 167.31, 148.92,
133.82, 131.92, 130.56, 129.96, 129.36, 128.33, 127.76, 126.82,
126.64, 126.24, 123.74, 113.70, 113.22, 106.05, 99.20. ESI-HRMS
(m/z): Calcd for C19H11O3 [M − H]−: 287.0708; found, 287.0717.
compounds 4a–4h
Compounds 3a–3h (5 mmol) dissolving in DMSO (20 ml) was added into
the flask, then concentrated hydrochloric acid (3 ml) was added drop by
drop at room temperature. After stirring for 30 min, a catalytic amount
of iodine was added (Milanea, Ferreirab, & Pizzutia, 2012). The reaction
temperature is raised to 110ꢀC, monitoring the reaction progression by
TLC until the reaction was completed. The saturated sodium hydrogen
sulfite solution was added into the flask, and then there was a large
amount of solid produced. The solid was dissolved in NaOH solution
and filtered. The pH of the filtrate was adjusted to 3–4 with dilute
hydrochloric acid and then a lot of solids precipitated. The solids
(Compounds 4a–4h) were recrystallized by ethanol. These intermediates
are characterized by 1H NMR and ESI-MS except known compounds.
2.3.4
|
Hydroxy-2-(naphthalen-2-yl)-4H-chromen-
4-one (4d)
Brown solid，yield: 78.5%； Rf = 0.44, MeOH:CH2Cl2 = 1:10. 1H
NMR (400 MHz, DMSO-d6) δ (ppm):10.127 (s, 1H, OH), 8.194 (d,
J = 8.4 Hz, 1H, Ar H), 8.118–8.076 m, 2H, Ar H), 7.897 (d,
J = 6.8 Hz, 1H, Ar H), 7.708–7.639 (m, 3H, Ar H), 7.601 (d,
J = 9.0 Hz, 1H, Ar H), 7.430 (d, J = 3.0 Hz, 1H, Ar H), 7.301 (dd,
J = 9.0, 3.0 Hz, 1H, Ar H), 6.618 (s, 1H, CH
C
O). 13C NMR
(101 MHz, DMSO-d6) δ 177.29, 165.03, 155.50, 150.39, 133.70,
131.76, 130.73, 130.29, 129.14, 128.71, 128.09, 127.10, 125.84,
125.12, 124.77, 123.70, 120.41, 111.76, 108.06. ESI-MS (m/z): Calcd
for C19H11O3 [M − H]−: 287.0708; found, 287.0707.
2.3.1
4-one (4a)
|
7-Hydroxy-2-phenyl-4H-chromen-
White solid, yield: 85.3%； Rf = 0.52, MeOH:CH2Cl2 = 1:10. It is a
known compound (Ibrahim & Abul-Hajj, 1990; Zhu, Li, Shu, Zhou, &
Su, 2009). 1H NMR (600 MHz, DMSO-d6) δ (ppm):10.842 (s, 1H, OH),
8.077–8.061 (m, 2H, Ar H), 7.894 (d, J = 8.7 Hz, 1H, Ar H),
7.610–7.560 (m, 3H, Ar H), 7.013 (d, J = 2.2 Hz, 1H, Ar H), 6.937 (dd,
2.3.5
4-one (4e)
|
2-(Anthracen-9-yl)-7-hydroxy-4H-chromen-
Yellow powder, yield: 68.8%； Rf = 0.56, MeOH:CH2Cl2 = 1:15. 1H
NMR (600 MHz, DMSO-d6) (ppm): 8.745 (s, 1H, Ar H),
J = 8.7, 2.2 Hz, 1H, Ar H), 6.907 (s, 1H, CH
C
O). 13C NMR
δ
(101 MHz, DMSO-d6) δ 177.25, 163.34, 162.74, 158.04, 132.17,
131.60, 129.65, 127.07, 126.64, 116.47, 115.73, 106.94, 103.03. ESI-
HRMS (m/z): Calcd for C15H9O3 [M − H]−: 237.0552; found, 237.0543.
8.1064–8.068 (m, 4H, Ar H), 7.720 (d, J = 8.5 Hz, 1H, Ar H),
7.658–7.586 (m, 5H, Ar H), 6.745 (d, J = 8.5 Hz, 1H, Ar H), 6.475 (s,
1H, CH
C
O).13C NMR (101 MHz, DMSO-d6) δ 180.92, 168.70,
168.11, 150.41, 131.29, 129.69, 129.25, 128.65, 127.03, 126.69,
126.18, 126.11, 126.06, 113.83, 113.18, 107.30, 98.95. ESI-MS (m/z):
Calcd for C23H13O3 [M − H]−: 337.0865; found, 337.0876.
2.3.2
|
6-Hydroxy-2-phenyl-4H-chromen-
4-one (4b)
White solid, yield: 82.5%； Rf = 0.55, MeOH:CH2Cl2 = 1:10. It is a
known compound (Ibrahim & Abul-Hajj, 1990; Tang, Zhang, Yang,
Gao, & Cui, 2004). 1H NMR (400 MHz, DMSO-d6) δ (ppm):10.076 (s,
1H, OH), 8.119–8.094 (m, 2H, Ar H), 7.687 (d, J = 9.0 Hz, 1H, Ar H),
7.615–7.575 (m, 3H, Ar H), 7.357 (d, J = 3.0 Hz, 1H, Ar H), 7.291 (dd,
2.3.6
4-one (4f)
|
(Anthracen-9-yl)-6-hydroxy-4H-chromen-
Yellow solid, yield: 74.7%； Rf = 0.55, MeOH:CH2Cl2 = 1:15. 1H
NMR (400 MHz, DMSO-d6) δ (ppm):10.162 (s, 1H, OH), 8.914 (s,
1H, Ar H), 8.305–8.238 (m, 2H, Ar H), 7.967–7.943 (m, 2H, Ar H),
7.650–7.599 (m, 4H, Ar H), 7.560 (d, J = 9.0 Hz, 1H, Ar H), 7.515 (d,
J = 3.0 Hz, 1H, Ar H), 7.306 (dd, J = 8.9, 3.0 Hz, 1H, Ar H), 6.656 (s,
J = 9.0, 3.0 Hz, 1H, Ar H), 6.988 (s, 1H, CH
C
O). 13C NMR
(101 MHz, DMSO-d6) δ 177.54, 162.72, 155.37, 149.88, 132.13,
131.82, 129.59, 126.71, 124.69, 123.63, 120.36, 107.95, 106.38. ESI-
HRMS (m/z): Calcd for C15H9O3 [M − H]−: 237.0552; found, 237.0563.
1H, CH
C
O). 13C NMR (101 MHz, DMSO-d6) δ 177.12, 162.80,
155.62, 151.03, 131.01, 130.42, 129.72, 129.18, 128.10, 126.67,
126.30, 125.16, 125.01, 123.77, 120.48, 114.82, 108.20. ESI-MS
(m/z): Calcd for C23H13O3 [M − H]−: 337.0865; found, 337.0879.
2.3.3
|
7-Hydroxy-2-(naphthalen-2-yl)-4H-
chromen-4-one (4c)
Yellow powder, yield: 77.8% ； Rf = 0.42, MeOH:CH2Cl2 = 1:10. It is
a known compound (Hu et al., 2013).1H NMR (400 MHz, DMSO-d6) δ
(ppm):11.23 (s, 1H, OH), 8.372–8.294 (m, 2H, Ar H), 8.063–8.025
2.3.7
|
2-([1,10-Biphenyl]-4-yl)-7-hydroxy-4H-
chromen-4-one (4g)
(m, 2H, Ar H), 7.713–7.609 (m, 4H, Ar H), 7.469 (s, 1H, CH
C
O),
Yellow powder, yield: 75.6%； Rf = 0.51, MeOH:CH2Cl2 = 1:15. It is a
known compound (Hu et al., 2013).1H NMR (400 MHz, DMSO-d6) δ
6.818 (d, J = 2.0 Hz, 1H, Ar H), 6.762 (dd, J = 8.5, 2.0 Hz, 1H, Ar H).

4
LU ET AL.
(ppm):8.072–7.426 (m, 10H, Ar H), 6.866 (s, 2H, CH
C
O and Ar H),
J = 7.7, 2.0 Hz, 2H, Ar H), 7.965 (d, J = 8.8 Hz, 1H, Ar H),
7.638–7.609 (m, 3H, Ar H), 7.385 (d, J = 2.4 Hz, 1H, Ar H), 7.094
6.775–6.755 (m, 1H, Ar H). 13C NMR (101 MHz, DMSO-d6) δ 181.87,
168.41, 167.14, 147.97, 141.51, 139.66, 132.15, 131.71, 129.52, 128.48,
127.59, 127.19, 126.49, 113.62, 113.24, 110.49, 99.14. ESI-HRMS (m/z):
Calcd for C21H13O3 [M − H]−: 313.0865; found, 313.0872.
(dd, J = 8.9, 2.4 Hz, 1H, Ar H), 6.998 (s, 1H, CH O), 4.250 (t,
C
J
=
5.7 Hz, 2H, CH2 CH2 ), 2.709 (t, J = 5.7 Hz, 2H,
O
CH2 CH2 N), 2.263 (s, 6H, 2 × NCH3). 13C NMR (101 MHz,
CDCl3) δ (ppm) 178.27, 163.28, 155.99, 151.24, 131.89, 131.53,
129.05, 126.27, 124.54, 124.21, 119.60, 106.88, 105.76, 65.94,
57.89, 45.45. IR (KBr, cm−1): 3041, 2937, 1635, 1575, 1452, 1352,
1174, 972, 771. ESI-MS (m/z): Calcd for C19H20NO3 [M + H]+:
310.1443: found, 310.1440.
2.3.8
|
2-([1,10-Biphenyl]-4-yl)-6-hydroxy-4H-
chromen-4-one (4h)
Yellow solid, yield: 81.5%； Rf = 0.53, MeOH:CH2Cl2 = 1:15.1H NMR
(600 MHz, DMSO-d6) δ (ppm):10.041 (s, 1H, OH), 8.194–8.180 (m,
2H, Ar H), 7.894–7.884 (m, 2H, Ar H), 7.797–7.782 (m, 2H, Ar H),
7.695 (d, J = 8.9 Hz, 1H, Ar H), 7.537–7.511 (m, 2H, Ar H),
7.454–7.425 (m, 1H, Ar H), 7.341 (d, J = 3.0 Hz, 1H, Ar H), 7.278
2.4.3
|
2-Phenyl-7-(2-(pyrrolidin-1-yl)ethoxy)-4H-
chromen-4-one (5c)
(dd, J = 9.0, 3.0 Hz, 1H, Ar H), 7.029 (s, 1H, CH
C
O). 13C NMR
Gray solid， yield: 74.6%； mp: 168.4–169.1ꢀC， Rf = 0.39, MeOH:
(101 MHz, DMSO-d6) δ 177.47, 162.39, 155.39, 149.88, 143.54,
139.31, 130.74, 129.58, 128.76, 127.71, 127.36, 127.33, 124.76,
123.60, 120.36, 107.98, 106.31. ESI-MS (m/z): Calcd for C21H13O3
[M − H]−: 313.0865; found, 313.0863.
CH2Cl2 = δ (ppm):8.166 (d,
1:15. 1H NMR (400 MHz, CDCl3)
J = 8.7 Hz, 1H, Ar H), 7.957–7.933 (m, 2H, Ar H), 7.517–7.553 (m,
3H, Ar H), 7.053 (dd, J = 8.8, 2.4 Hz, 1H, Ar H), 7.026 (d, J = 2.3 Hz,
1H, Ar H)., 6.804 (s, 1H, CH O), 4.268 (t, J = 5.8 Hz, 2H,
C
O
CH2 CH2 ), 3.007 (t, J = 5.8 Hz, 2H, CH2 CH2 N),
2.711–2.677 (m, 4H, Pyrrolidine-H), 1.887–1.853 (m, 4H, Pyrrolidine-
H). 13C NMR (101 MHz, CDCl3) δ (ppm) 177.87, 163.42, 163.03,
157.93, 131.40, 128.98, 126.98, 126.14, 117.80, 114.83, 107.45,
101.04, 67.81, 54.73, 23.51. IR (KBr, cm−1): 3059, 2949, 1627, 1577,
1452, 1363, 1182, 908, 777. ESI-MS (m/z): Calcd for C21H22NO3 [M
+ H]+:336.1600; found, 336.1595.
2.4
|
General procedure for the synthesis of
compounds 5a–8f
Refer to previous report, Compounds 5a–8f were synthesized from com-
pounds 4a–4h and aminoethyl chlorides hydrochloride, then purified
using silica-gel column chromatography with methanol / dichloromethane
(1:55–80, v/v) as the elution (Gao, Tang, Liu, Liu, & Liu, 2019).
2.4.4
|
2-Phenyl-6-(2-(piperidin-1-yl)ethoxy)-4H-
chromen-4-one (5d)
2.4.1
|
2-Phenyl-7-(2-(piperidin-1-yl)ethoxy)-4H-
chromen-4-one (5a)
White solid， yield:72.2%； mp: 188.1–189.8ꢀC， Rf = 0.43, MeOH:
CH2Cl2 = 1:15. 1H NMR (400 MHz, CDCl3) δ (ppm):7.982–7.958 (m,
2H, Ar H), 7.647 (d, J = 3.1 Hz, 1H, Ar H), 7.595–7.546 (m, 4H,
Ar H), 7.371 (dd, J = 9.2, 3.1 Hz, 1H, Ar H), 6.863 (s, 1H,
Gray solid， yield: 70.2%， mp: 179.3–181.2ꢀC, Rf = 0.42, MeOH:
CH2Cl2 = 1:15. 1H NMR (400 MHz, DMSO-d6): 1H NMR (400 MHz,
DMSO-d6) δ (ppm):8.130 (dd, J = 7.7, 2.0 Hz, 2H, Ar H), 7.959 (d,
J = 8.8 Hz, 1H, Ar H), 7.642–7.587 (m, 3H, Ar H), 7.395 (d,
J = 2.4 Hz, 1H, Ar H), 7.093 (dd, J = 8.8, 2.4 Hz, 1H, Ar H), 6.998 (s,
1H, CH C- O), 4.263 (t, J = 5.9 Hz, 2H, O CH2 CH2 ), 2.736 (t,
J = 5.9 Hz, 2H, CH2 CH2 N), 2.489–2.463 (m, 4H, Piperidine-H)),
1.560–1.504 (m, 4H, Piperidine-H), 1.437–1.392 (m, 2H, Piperidine-
H). 13C NMR (101 MHz, CDCl3) δ (ppm):177.87, 163.42, 163.03,
157.95, 131.89, 131.40, 129.00, 127.02, 126.16, 117.85, 114.83,
107.54, 101.09, 66.76, 57.60, 55.10, 25.91, 24.12. IR (KBr, cm−1):
3059, 2920, 1628, 1595, 1441, 1364, 1240, 997, 764. ESI-MS(m/z):
Calcd for C22H24NO3 [M + H]+: 350.1756; found, 350.1741.
CH
C O), 4.293 (t, J = 5.7 Hz, 2H, O CH2 CH2 ), 2.916 (t,
J = 5.7 Hz, 2H, CH2 CH2 N), 2.635–2.606 (m, 4H, Piperidine-H),
1.735–1.678 (m, 4H, Piperidine-H), 1.548–1.501 (m, 2H, Piperidine-
H). 13C NMR (101 MHz, CDCl3) δ (ppm) 178.25, 163.19, 156.13,
151.10, 131.86, 131.50, 129.02, 126.24, 124.05, 119.48, 106.81,
105.95, 66.27, 57.64, 54.89, 25.62, 23.98. IR (KBr, cm−1): 3061, 2929,
1625, 1570, 1456, 1361, 1294, 906, 769. ESI-MS (m/z): Calcd for
C
22H24NO3 [M + H]+: 350.1756; found, 350.1747.
2.4.5
|
6-(2-(Dimethylamino)ethoxy)-2-phenyl-4H-
chromen-4-one (5e)
2.4.2
|
7-(2-(Dimethylamino)ethoxy)-2-phenyl-4H-
Light brown solid， yield: 50.4%， mp:189.3–190.5ꢀC， Rf = 0.40,
chromen-4-one (5b)
MeOH:CH2Cl2
=
1:15. 1H NMR (400 MHz, CDCl3)
δ
(ppm):7.979–7.955 (m, 2H, Ar H), 7.642 (d, J = 3.1 Hz, 1H, Ar H),
7.594–7.546 (m, 4H, Ar H), 7.408 (dd, J = 9.1, 3.1 Hz, 1H, Ar H),
Gray solid，yield: 80.3%； mp: 172.2–172.8ꢀC，Rf = 0.45, MeOH:
CH2Cl2 = 1:15. 1H NMR (400 MHz, DMSO-d6) δ (ppm):8.128 (dd,
6.865 (s, 1H, CH
C O), 4.249 (t, J = 5.3 Hz, 2H, O CH2 CH2 ),

LU ET AL.
5
2.874 (t, J = 5.4 Hz, 2H, CH2 CH2 N), 2.439 (s, 6H, 2 × NCH3). 13
C
J
=
5.4 Hz, 2H,
O
CH2 CH2), 2.950 (t,
J
=
5.4 Hz, 2H,
NMR (101 MHz, CDCl3) δ (ppm) 178.27, 163.22, 156.13, 151.16,
131.86, 131.50, 129.02, 126.24, 124.49, 124.28, 119.54, 106.82,
105.62, 66.20, 58.02, 45.62. IR (KBr, cm−1): 2970, 2927, 1616, 1571,
1452, 1359, 1190, 910, 771. ESI-MS (m/z): Calcd for C19H20NO3 [M
+ H]+: 310.1443; found, 310.1452.
CH2 CH2 N), 2.498 (s, 6H, 2 × NCH3). 13C NMR (101 MHz,
DMSO-d6) δ (ppm) 181.42, 169.72, 168.08, 163.14, 138.43, 136.55,
135.25, 135.02, 133.89, 133.46, 132.84, 131.83, 130.54, 129.88,
122.51, 120.41, 117.49, 106.84, 70.84, 61.82, 49.82. IR (KBr, cm−1):
3059, 2924, 1627, 1597, 1506, 1440, 1363, 908, 777. ESI-MS (m/z):
Calcd. for C23H22NO3 [M + H]+: 360.1600; found, 360.1602.
2.4.6
|
2-Phenyl-6-(2-(pyrrolidin-1-yl)ethoxy)-4H-
chromen-4-one (5f)
2.4.9
|
2-(Naphthalen-1-yl)-7-(2-(pyrrolidin-1-yl)
ethoxy)-4H-chromen-4-one (6c)
Light brown viscous liquid， yield: 50.1%， Rf = 0.47, MeOH:
CH2Cl2 = 1:15. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.997–7.953 (m,
2H, Ar H), 7.644 (d, J = 3.1 Hz, 1H, Ar H), 7.579–7.539 (m, 4H,
Yellow viscous liquid， yield: 65.6%， Rf = 0.43, MeOH:CH2Cl2 = 1:15.
1H NMR (400 MHz, CDCl3) δ (ppm):8.246 (d, J = 9.0 Hz, 1H, Ar H),
8.188–8.164 (m, 1H, Ar H), 8.068 (d, J = 8.2 Hz, 1H, Ar H),
8.007–7.983 (m, 1H, Ar H), 7.799 (dd, J = 7.2, 1.2 Hz, 1H, Ar H),
7.644–7.606 (m, 3H, Ar H), 7.104 (dd, J = 8.9, 2.4 Hz, 1H, Ar H),
Ar H), 7.389 (dd, J = 9.2, 3.1 Hz, 1H, Ar H), 6.861 (s, 1H, CH
C O),
4.268 (t, J = 5.7 Hz, 2H, O CH2 CH2 ), 3.000 (t, J = 5.7 Hz, 2H,
CH2 CH2 N), 2.715–2.684 (m, 4H, pyrrolidine-H), 1.890–1.856 (m,
4H, pyrrolidine-H). 13C NMR (101 MHz, CDCl3) δ (ppm) 178.24,
163.14, 156.26, 151.08, 131.89, 131.46, 129.00, 126.22, 124.53,
124.16, 119.44, 106.82, 105.78, 67.65, 54.97, 54.67, 23.51. IR (KBr,
cm−1): 3059, 2926, 1614, 1583, 1454, 1361, 1203, 970, 721. ESI-MS
(m/z): Calcd for C21H22NO3 [M + H]+: 336.1600; found, 336.1592.
6.983 (d, J = 2.4 Hz, 1H, Ar H), 6.667 (s, 1H, CH
C O), 4.260 (t,
J = 5.8 Hz, 2H, O CH2 CH2), 3.017 (t, J = 5.8 Hz, 2H, CH2 CH2 N),
2.725–2.694 (m, 4H, Pyrrolidine-H), 1.890–1.857 (m, 4H, Pyrrolidine-
H). 13C NMR (101 MHz, CDCl3) δ (ppm):177.68, 165.01, 163.29,
158.40, 133.74, 131.40, 130.68, 130.42, 128.71, 127.88, 127.41,
127.24, 126.55, 125.07, 124.91, 117.99, 114.99, 113.00, 101.17,
65.42, 54.74, 54.61, 23.49. IR (KBr, cm−1): 3057, 2927, 1624, 1577,
1440, 1361, 1240, 1089, 777. ESI-MS (m/z): Calcd for C25H24NO3
[M + H]+: 386.1756; found, 386.1750.
2.4.7
|
2-(Naphthalen-1-yl)-7-(2-(piperidin-1-yl)
ethoxy)-4H-chromen-4-one (6a)
Yellow viscous liquid， yield: 58.2%， Rf
=
0.38, MeOH:
(ppm):8.248 (d,
CH2Cl2
=
1:15. 1H NMR (400 MHz, CDCl3)
δ
2.4.10
|
2-(Naphthalen-1-yl)-6-(2-(piperidin-1-yl)
J = 8.9 Hz, 1H, Ar-H), 8.193–8.169 (m, 1H, Ar H), 8.070 (d,
J = 8.3 Hz, 1H, Ar H), 8.010–7.966 (m, 1H, Ar H), 7.800 (dd, J = 7.1,
1.2 Hz, 1H, Ar H), 7.647–7.608 (m, 3H, Ar H), 7.093 (dd, J = 8.9,
2.4 Hz, 1H, Ar H), 6.981 (d, J = 2.3 Hz, 1H, Ar H), 6.670 (s,
ethoxy)-4H-chromen-4-one (6d)
Light brown viscous liquid， yield: 44.6%， Rf = 0.45, MeOH:
CH2Cl2 = 1:10. 1H NMR (400 MHz, CDCl3) δ (ppm):8.186–8.153 (m,
1H, Ar H), 8.072 (d, J = 8.0 Hz, 1H, Ar H), 8.014–7.982 (m, 1H,
Ar H), 7.807 (d, J = 7.2 Hz, 1H, Ar H), 7.717 (d, J = 3.0 Hz, 1H,
Ar H), 7.646–7.605 (m, 3H, Ar H), 7.520 (d, J = 9.2, 1H, Ar H),
1H, CH
C O), 4.250 (t, J = 5.9 Hz, 2H, O CH2 CH2), 2.873 (t,
J = 5.9 Hz, 2H, CH2 CH2 N), 2.586–2.559 (m, 4H, Piperidine-H),
1.690–1.633 (m, 4H, Piperidine-H), 1.527–1.483 (m, 2H, Piperidine-
H). 13C NMR (101 MHz, CDCl3) δ (ppm) 177.73, 165.01, 163.47,
158.43, 133.75, 131.39, 130.69, 130.42, 128.71, 127.88, 127.39,
127.18, 126.55, 125.06, 124.91, 117.87, 115.05, 112.96, 101.15,
66.69, 57.55, 55.05, 25.81, 24.06. IR (KBr, cm−1): 3095, 2941, 1629,
1579, 1506, 1444, 1361, 1093, 777. ESI-MS (m/z): Calcd for
7.334 (dd, J = 9.1, 2.9 Hz, 1H, Ar H), 6.718 (s, 1H, CH
C O),
4.361 (t, J = 5.6 Hz, 2H, O CH2 CH2 ), 2.987 (t, J = 5.6 Hz, 2H,
CH2 CH2 N), 2.719–2.687 (m, 4H, Piperidine-H), 1.781–1.731 (m,
4H, Piperidine-H), 1.561–1.532 (m, 2H, Piperidine-H). 13C NMR
(101 MHz, CDCl3) δ (ppm) 178.10, 165.19, 156.29, 151.59, 133.75,
131.43, 130.74, 130.41, 128.72, 127.92, 127.41, 126.56, 125.06,
124.90, 124.60, 124.19, 119.64, 112.27, 106.05, 66.40, 57.67, 54.93,
25.68, 24.04. IR (KBr, cm−1): 3246, 3064, 2929, 1627, 1593, 1570,
1458, 1450, 1361. ESI-MS (m/z): Calcd for C26H26NO3 [M + H]+:
400.1913; found, 400.1914.
C
26H26NO3 [M + H]+: 400.1913; found, 400.1900.
2.4.8
|
7-(2-(Dimethylamino)ethoxy)-
2-(naphthalen-1-yl)-4H-chromen-4-one (6b)
Yellow viscous liquid， yield: 64.8%， Rf = 0.36, MeOH:CH2Cl2 = 1:15.
1H NMR (400 MHz, CDCl3) δ (ppm):8.251 (d, J = 8.9 Hz, 1H, Ar-H),
8.184–8.160 (m, 1H, Ar H), 8.067 (d, J = 8.3 Hz, 1H, Ar H),
8.005–7.981 (m, 1H, Ar H), 7.796 (d, J = 7.1 Hz, 1H, Ar H),
7.642–7.604 (m, 3H, Ar H), 7.104 (dd, J = 9.0, 1.8 Hz, 1H, Ar H),
2.4.11
|
6-(2-(Dimethylamino)ethoxy)-
2-(naphthalen-1-yl)-4H-chromen-4-one (6e)
Light brown viscous liquid， yield: 56.7%， Rf = 0.42, MeOH:
CH2Cl2 = 1:10. 1H NMR (400 MHz, CDCl3) δ (ppm):8.183–8.158 (m,
6.992 (d, J = 1.7 Hz, 1H, Ar H), 6.670 (s, 1H, CH
C O), 4.286 (t,

6
LU ET AL.
1H, Ar H), 8.074 (d, J = 8.3 Hz, 1H, Ar H), 8.013–7.984 (m, 1H,
Ar H), 7.808 (d, J = 7.2 Hz, 1H, Ar H), 7.716 (d, J = 2.6 Hz, 1H,
Ar H), 7.647–7.607 (m, 3H, Ar H), 7.520 (d, J = 9.1, 1H, Ar H),
2.4.14
|
2-(Anthracen-9-yl)-7-(2-(dimethylamino)
ethoxy)-4H-chromen-4-one (7b)
7.418 (dd, J = 9.2, 2.6 Hz, 1H, Ar H), 6.721 (s, 1H, CH
C
O),
Yellow viscous liquid， yield: 58.7%， Rf
=
0.32, MeOH:
4.290 (t, J = 5.6 Hz, 2H, O CH2 CH2 ), 2.905 (t, J = 5.6 Hz, 2H,
CH2 CH2 N), 2.467 (s, 6H, 2 × NCH3). 13C NMR (101 MHz,
CDCl3) δ (ppm):178.07, 165.28, 156.02, 151.71, 133.74, 131.47,
130.67, 130.40, 128.72, 127.95, 127.43, 126.57, 125.05, 124.88,
124.55, 124.27, 119.77, 112.26, 105.91, 65.83, 57.76, 45.34. IR
(KBr, cm−1): 3446, 3385, 1629, 1570, 156, 1456, 1361, 804, 777.
ESI-MS (m/z): Calcd for C23H22NO3 [M + H]+: 360.1600; found,
360.1606.
CH2Cl2 = 1:15.1H NMR (400 MHz, CDCl3) δ (ppm):8.686 (s, 1H, Ar-
H), 8.330 (d, J = 8.9 Hz, 1H, Ar H), 8.146–8.121 (m, 2H, Ar H),
8.0134–8.008 (m, 2H, Ar H), 7.599–7.536 (m, 4H, Ar H), 7.160 (dd,
J = 9.0, 2.4 Hz, 1H, Ar-H), 6.925 (d, J = 2.4 Hz, 1H, Ar H), 6.680 (s,
1H, CH
J = 5.6 Hz, 2H, CH2 CH2 N), 2.378 (s, 6H, 2 × NCH3). 13C NMR
(101 MHz, DMSO-d6) (ppm):177.39, 163.52, 163.09, 158.97,
C O), 4.168 (t, J = 5.6 Hz, 2H, O CH2 CH2 ), 2.807 (t,
δ
131.05, 130.06, 129.91, 128.71, 127.29, 126.43, 127.20, 125.63,
125.00, 118.10, 116.10, 115.35, 101.14, 66.72, 57.93, 45.85. IR (KBr,
cm−1): 3051, 2927, 1647, 1591, 1427, 1321, 1244, 952, 734. ESI-MS
(m/z): Calcd for C27H24NO3 [M + H]+: 410.1756; found, 410.1762.
2.4.12
|
2-(Naphthalen-1-yl)-6-(2-(pyrrolidin-1-yl)
ethoxy)-4H-chromen-4-one (6f)
Light brown viscous liquid， yield: 82.6%， Rf = 0.48, MeOH:
CH2Cl2 = 1:10. 1H NMR (400 MHz, CDCl3) δ (ppm):8.181–8.157
(m, 1H, Ar H), 8.074 (d, J = 8.2 Hz, 1H, Ar H), 8.010–7.986 (m,
1H, Ar H), 7.810 (d, J = 7.1 Hz, 1H, Ar H), 7.723 (d, J = 3.0 Hz,
1H, Ar H), 7.649–7.610 (m, 3H, Ar H), 7.523 (d, J = 9.1 Hz, 1H,
Ar H), 7.418 (dd, J = 9.2, 3.0 Hz, 1H, Ar H), 6.720 (s, 1H,
2.4.15
|
2-(Anthracen-9-yl)-7-(2-(pyrrolidin-1-yl)
ethoxy)-4H-chromen-4-one (7c)
Yellow viscous liquid， yield: 83.6%， Rf
= 0.35, MeOH:
CH2Cl2 = 1:15.1H NMR (400 MHz, CDCl3) δ (ppm):8.680 (s, 1H,
Ar H), 8.333 (d, J = 8.9 Hz, 1H, Ar H), 8.137–8.113 (m, 2H, Ar H),
8.020–7.996 (m, 2H, Ar H), 7.585–7.533 (m, 4H, Ar H), 7.143 (dd,
J = 8.9, 2.4 Hz, 1H, Ar H), 6.917 (d, J = 2.4 Hz, 1H, Ar H), 6.672 (s,
CH
C O), 4.391 (t, J = 5.5 Hz, 2H, O CH2 CH2 ), 3.151 (t,
J = 5.5 Hz, 2H, CH2 CH2 N), 2.907–2.876 (m, 4H, pyrrolidine-
H), 1.983–1.949 (m, 4H, pyrrolidine-H). 13C NMR (101 MHz,
CDCl3) δ (ppm):178.04, 165.27, 155.96, 151.70, 133.74, 131.47,
130.67, 130.40, 128.72, 127.94, 127.43, 126.57, 125.05, 124.87,
124.59, 124.02, 119.77, 112.26, 106.28, 66.75, 54.63 (d,
J = 3.5 Hz), 23.46. IR (KBr, cm−1): 3080, 2926, 1618, 1575, 1448,
1354, 1197, 910, 781. ESI-MS (m/z): Calcd for C25H24NO3 [M
+ H]+: 386.1756; found, 386.1759.
1H, CH
C O), 4.255 (t, J = 5.6 Hz, 2H, O CH2 CH2 ), 3.032 (t,
J = 5.6 Hz, 2H, CH2 CH2 N), 2.757–2.727 (m, 4H, Pyrrolidine-H),
1.895–1.862 (m, 4H, Pyrrolidine-H). 13C NMR (150 MHz, CDCl3) δ
(ppm): 177.45, 163.50, 163.13, 158.99, 131.05, 130.08, 129.91,
128.73, 127.30, 127.22, 125.65, 125.01, 116.10, 115.35, 101.18,
67.69, 54.74, 54.67, 23.48. IR (KBr, cm−1): 3421, 2926, 1647, 1591,
1558, 1425, 1359, 1172, 734. ESI-MS (m/z): Calcd for C29H26NO3
[M + H]+:436.1913; found, 436.1918.
2.4.13
|
2-(Anthracen-9-yl)-7-(2-(piperidin-1-yl)
ethoxy)-4H-chromen-4-one (7a)
2.4.16
|
2-(Anthracen-9-yl)-6-(2-(piperidin-1-yl)
ethoxy)-4H-chromen-4-one (7d)
Yellow viscous liquid， yield: 69.7%， Rf
= 0.36, MeOH:
CH2Cl2 = 1:15. 1H NMR (400 MHz, CDCl3) δ (ppm):8.682 (s, 1H,
Ar H), 8.326 (d, J = 8.8 Hz, 1H, Ar H), 8.144–8.133 (m, 2H, Ar H),
8.029–7.997 (m, 2H, Ar H), 7.580–7.542 (m, 4H, Ar H), 7.134 (dd,
J = 9.0, 2.4 Hz, 1H, Ar H), 6.916 (d, J = 2.4 Hz, 1H, Ar H), 6.676 (s,
Light yellow solid， yield: 72.8%， mp: 187.6–188.5ꢀC ，Rf = 0.33,
MeOH:CH2Cl2 = 1:15. 1H NMR (400 MHz, CDCl3) δ (ppm):8.690 (s, 1H,
Ar H), 8.145–8.120 (m, 2H, Ar H), 7.992–7.968 (m, 2H, Ar H), 7.796 (d,
J = 3.0 Hz, 1H, Ar H), 7.590–7.532 (m, 4H, Ar H), 7.462 (d, J = 9.1 Hz,
1H, Ar H), 7.390 (dd, J = 9.1, 3.0 Hz, 1H, Ar H), 6.721 (s, 1H,
1H, CH
C O), 4.223 (t, J = 5.6 Hz, 2H, O CH2 CH2 ), 2.863 (t,
J = 5.6 Hz, 2H, CH2 CH2 N), 2.578–2.547 (m, 4H, Piperidine-H),
1.675–1.617 (m, 4H, Piperidine-H), 1.489–1.468 (m, 2H, Piperidine-
H). 13C NMR (150 MHz, CDCl3) δ (ppm):177.47, 163.34, 163.21,
158.98, 131.04, 130.10, 129.90, 128.73, 127.33, 127.23, 126.37,
125.64, 124.98, 118.10, 116.06, 115.29, 101.26, 66.31, 57.36, 54.92,
25.47, 23.81. IR (KBr, cm−1): 3327, 2929, 1645, 1591, 1456, 1425,
1321, 1170, 734. ESI-MS (m/z): Calcd for C30H28NO3 [M + H]+:
450.2069; found, 450.2082.
CH C O), 4.357 (t, J = 5.8 Hz, 2H, O CH2 CH2 ), 2.952 (t,
J = 5.9 Hz, 2H, CH2 CH2 N), 2.666–2.636 (m, 4H, Piperidine-H),
1.752–1.698 (m, 4H, Piperidine-H), 1.564–1.519 (m, 2H, Piperidine-H).
13C NMR (151 MHz, CDCl3) δ (ppm):177.85, 163.45, 156.48, 152.14,
131.03, 130.09, 129.91, 128.72, 127.21, 126.49, 125.63, 124.98, 124.79,
124.37, 119.84, 115.34, 106.01, 66.60, 57.76, 55.00, 25.83, 24.14. IR
(KBr, cm−1): 3421, 3385, 3367, 1637, 1558, 1541, 1448, 1361, 1338. ESI-
MS (m/z): Calcd for C30H28NO3 [M + H]+: 450.2069; found, 450.2056.

LU ET AL.
7
2.4.17
|
2-(Anthracen-9-yl)-6-(2-(dimethylamino)
2.4.20
|
2-([1,10-Biphenyl]-4-yl)-
ethoxy)-4H-chromen-4-one (7e)
7-(2-(dimethylamino)ethoxy)-4H-chromen-4-one (8b)
Light yellow solid， yield: 70.7%， mp:194.2–195.8ꢀC， Rf = 0.32,
MeOH:CH2Cl2 = 1:15. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.690 (s,
1H, Ar H), 8.144–8.121(m, 2H, Ar H), 7.990–7.967 (m, 2H, Ar H),
7.793 (d, J = 2.9 Hz, 1H, Ar H), 7.589–7.532 (m, 4H, Ar H),
Light yellow solid， yield: 38.2%， mp: 111.1–111.6ꢀC， Rf = 0.52,
MeOH:CH2Cl2 = 1:10. 1H NMR (600 MHz, CDCl3) δ (ppm):8.148 (d,
J = 8.8 Hz, 1H), 7.995–7.981 (m, 2H, Ar H), 7.761–7.747 (m, 2H,
Ar H), 7.671–7.659 (m, 2H, Ar H), 7.505–7.448 (m, 2H, Ar H),
7.438–7.413 (m, 1H, Ar H), 7.043–7.021 (m, 2H, Ar H), 6.819 (s,
7.477–7.408 (m, 2H, Ar H), 6.723 (s, 1H, CH
C
O), 4.318 (t,
J
=
5.4 Hz, 2H, CH2 CH2 ), 2.916 (t,
O
J
=
5.4 Hz, 2H,
1H, CH C O ), 4.244 (t, J = 5.6 Hz, 2H, O CH2 CH2 ), 2.876
CH2 CH2 N), 2.473 (s, 6H, 2 × NCH3). 13C NMR (151 MHz,
(t, J = 5.6 Hz, 2H, CH2 CH2 N), 2.434 (s, 6H, 2 × NCH3). 13C
NMR (101 MHz, CDCl3) δ (ppm): 177.86, 163.30, 162.82, 157.93,
144.22, 139.77, 130.57, 129.01, 128.18, 127.63, 127.15, 127.08,
126.63, 117.99, 114.81, 107.38, 101.11, 66.53, 57.90, 45.80, 29.71.
IR (KBr, cm−1): 3392, 2920, 1608, 1487, 1373, 1284, 1091,
977, 766. ESI-MS (m/z): Calcd for C25H24NO3 [M + H]+: 386.1756;
found, 386.1765.
CDCl3) δ (ppm):177.87, 163.50, 156.47, 152.20, 131.02, 130.10,
129.90, 128.72, 127.22, 126.46, 125.63, 124.96, 124.75, 124.56,
119.90, 115.34, 105.70, 66.49, 58.11, 45.74. IR (KBr, cm−1): 3055,
2926, 1639, 1581, 1448, 1330, 1193, 896, 734. ESI-MS (m/z): Calcd
for C27H24NO3 [M + H]+: 410.1756; found, 410.1771.
2.4.18
|
2-(Anthracen-9-yl)-6-(2-(pyrrolidin-1-yl)
ethoxy)-4H-chromen-4-one (7f)
2.4.21
|
2-([1,10-Biphenyl]-4-yl)-7-(2-(pyrrolidin-
1-yl)ethoxy)-4H-chromen-4-one (8c)
Yellow solid， yield: 74.3%， mp: 198.4–199.1ꢀC， Rf = 0.35,
MeOH:CH2Cl2 = 1:15. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.688 (s,
1H, Ar H), 8.144–8.0121 (m, 2H, Ar H), 7.994–7.970 (m, 2H, Ar H),
7.799 (d, J = 2.9 Hz, 1H, Ar H), 7.590–7.531 (m, 4H, Ar H),
Light yellow solid， yield: 41.6%， mp: 185.3–186.7ꢀC， Rf = 0.56,
MeOH:CH2Cl2 = 1:10. 1H NMR (600 MHz, CDCl3) δ (ppm): 8.129 (d,
J = 8.8 Hz, 1H, Ar H), 7.988–7.973 (m, 2H, Ar H), 7.751–7.737 (m,
2H, Ar H), 7.662–7.651 (m, 2H, Ar H), 7.508–7.483 (m, 2H, Ar H),
7.434–7.409 (m, 1H, Ar H), 7.039 (d, J = 2.4 Hz, 1H, Ar H), 7.015
7.474–7.400 (m, 2H, Ar H), 6.723 (s, 1H, CH
5.6 Hz, 2H, CH2 CH2 ), 3.037 (t,
C
=
O), 4.333 (t,
5.6 Hz, 2H,
J
=
O
J
CH2 CH2 N), 2.738–2.707 (m, 4H, Pyrrolidine-H), 1.911–1.876
(dd, J = 8.8, 2.4 Hz, 1H, Ar H), 6.813 (s, 1H, CH
C O ), 4.404 (t,
(m, 4H, Pyrrolidine-H). 13C NMR (101 MHz, CDCl3) δ (ppm):177.86,
163.46, 156.54, 152.16, 131.03, 130.08, 129.91, 128.71, 127.21,
126.49, 125.62, 124.97, 124.79, 124.45, 119.84, 115.34, 105.94,
67.83, 55.00, 54.72, 23.55. IR (KBr, cm−1): 3053, 2933, 1643, 1558,
1446, 1330, 1193, 983, 732. ESI-MS (m/z): Calcd for C29H26NO3 [M
+ H]+: 436.1913; found, 436.1904.
J = 5.5 Hz, 2H, CH2 CH2 ), 3.206 (t, J = 5.5 Hz, 2H,
O
CH2 CH2 N), 2.959–2.939 (m, 4H, Pyrrolidine-H), 1.986–1.964
(m, 4H, Pyrrolidine-H). 13C NMR (101 MHz, CDCl3) δ (ppm):177.81,
162.89, 162.85, 157.90, 144.26, 139.74, 130.44, 129.01, 128.19,
127.62, 127.15, 126.65, 118.15, 114.76, 107.33, 101.22, 66.59,
54.77, 54.47, 23.45. IR (KBr, cm−1): 3030, 2964, 1616, 1444, 1359,
1240, 1177, 910, 771. ESI-MS (m/z): Calcd for C27H26NO3 [M + H]+:
412.1913; found, 412.1924.
2.4.19
|
2-([1,10-Biphenyl]-4-yl)-7-(2-(piperidin-
1-yl)ethoxy)-4H-chromen-4-one (8a)
2.4.22
|
2-([1,10-Biphenyl]-4-yl)-6-(2-(piperidin-
Light yellow viscous liquid， yield: 40.3%， Rf = 0.53, MeOH:
CH2Cl2 = 1:10. 1H NMR (600 MHz, CDCl3) δ (ppm):8.159 (d, J = 8.8 Hz,
1H, Ar H), 8.013–7.999 (m, 2H, Ar H), 7.777–7.763 (m, 2H, Ar H),
7.684–7.672 (m, 2H, Ar H), 7.524–7.498 (m, 2H, Ar H),
7.446–7.422 (m, 1H, Ar H), 7.041 (d, J = 2.3 Hz, 1H, Ar H), 7.020
1-yl)ethoxy)-4H-chromen-4-one (8d)
Light yellow solid， yield: 70.3%， mp: 133.5–134.2ꢀC， Rf = 0.52,
MeOH:CH2Cl2
=
1:10. 1H NMR (400 MHz, CDCl3)
δ
(ppm):8.047–8.024 (m, 2H, Ar H), 7.800–7.776 (m, 2H, Ar H),
7.705–7.685 (m, 2H, Ar H), 7.651 (d, J = 1.8 Hz, 1H, Ar H),
7.576–7.511 (m, 3H, Ar H), 7.468–7.432 (m, 1H, Ar H), 7.367 (dd,
(dd, J = 8.8, 2.3 Hz, 1H, Ar H), 6.835 (s, 1H, CH
C O ), 4.346 (t,
J = 5.7 Hz, 2H, CH2 CH2 ), 2.978 (t, J = 5.7 Hz, 2H,
O
CH2 CH2 N), 2.706–2.683 (m, 4H, Piperidine-H), 1.757–1.719 (m,
4H, Piperidine-H), 1.555–1.516 (m, 2H, Piperidine-H). 13C NMR
(101 MHz, CDCl3) δ (ppm): 177.81, 163.16, 162.83, 157.95, 144.24,
139.79, 130.57, 128.99, 128.17, 127.63, 127.15, 127.09, 126.03,
118.03, 114.80, 107.39, 101.18, 65.49, 57.40, 54.91, 25.45, 23.79. IR
(KBr, cm−1): 3031, 2922, 1602, 1440, 1374, 1248, 1174, 908, 766.
ESI-MS (m/z): Calcd for C28H28NO3 [M + H]+: 426.2069; found,
426.2084.
J = 9.1, 1.8 Hz, 1H, Ar -H), 6.898 (s, 1H, CH
5.8 Hz, 2H, CH2 CH2 ), 2.864 ((t,
C
=
O), 4.258 (t,
5.8 Hz, 2H,
J
=
O
J
CH2 CH2 N), 2.578–2.557 (m, 4H, Piperidine-H), 1.693–1.638 (m,
4H, Piperidine-H), 1.552–1.467 (m, 2H, Piperidine-H). 13C NMR
(101 MHz, CDCl3) δ (ppm):178.22, 162.85, 156.32, 151.05, 144.24,
139.76, 130.63, 128.99, 128.17, 127.61, 127.13, 126.68, 124.60,
124.14, 119.42, 106.69, 105.84, 66.63, 57.83, 55.01, 25.96, 24.23. IR
(KBr, cm−1): 3030, 2927, 1624, 1573, 1452, 1363, 1190, 908, 727.

8
LU ET AL.
ESI-MS (m/z): Calcd For C28H28NO3 [M + H]+: 426.2069; found,
426.2070.
2.6
|
Kinetic studies
Compound 5a was selected for kinetic study. Kinetic characterization
of AChE was performed with the method reported in our previous
investigation (Gao et al., 2017)
2.4.23
|
2-([1,10-Biphenyl]-4-yl)-
6-(2-(dimethylamino)ethoxy)-4H-chromen-4-one (8e)
Light yellow solid， yield: 83.6%， mp: 149.1–149.9ꢀC， Rf = 0.51,
3
|
RESULTS AND DISCUSSION
| Chemistry
MeOH:CH2Cl2
=
1:10. 1H NMR (400 MHz, CDCl3)
δ
(ppm):8.059–8.039 (m, 2H, Ar H), 7.811–7.791 (m, 2H, Ar H),
7.713–7.694 (m, 2H, Ar H), 7.658 (d, J = 3.1 Hz, 1H, Ar H),
7.589–7.518 (m, 3H, Ar H), 7.478–7.441 (m, 1H, Ar H), 7.409
3.1
In the beginning, we tried to synthesize compounds 4a–4h using
Baker–Venkatarama method (Sun et al., 2016). Although this method
is very effective for the synthesis of compounds 4a–4b, the reaction
is difficult to occur for other compounds. So, another synthesize path-
way was applied with dihydroxychalone as the intermediates to syn-
thesize compounds 4a–4h as shown in Scheme 1.
(dd, J = 9.1, 3.0 Hz, 1H, Ar H), 6.910 (s, 1H, CH
C O), 4.235 (t,
J = 5.4 Hz, 2H, CH2 CH2 ), 2.835 (t, J = 5.4 Hz, 2H,
O
CH2 CH2 N), 2.412 (s, 6H, 2 × NCH3). 13C NMR (101 MHz,
CDCl3) δ (ppm):178.21, 162.87, 156.29, 151.10, 144.24, 139.74,
130.61, 128.99, 128.17, 127.61, 127.12, 126.67, 124.55, 124.32,
119.47, 106.69, 105.53, 66.53, 58.22, 45.83. IR (KBr, cm−1):
2991, 2926, 1608, 1575, 1450, 1348, 1253, 1016, 700. ESI-MS
Due to the presence of two phenolic hydroxyl groups on phenyl
ring, it is difficult for the ketone carbonyl to form carbanions. Refer-
ring to the relevant literature, 3,4-dihydro-2H-pyran protection
method was applied, since the protective group is easily removed in
the presence of strong acid.
(m/z): Calcd for
386.1756.
C
25H24NO3 [M + H]+: 386.1756; found,
In the process of synthesizing chalcone, anhydrous methanol or
anhydrous ethanol was used as solvents, but no satisfactory results
were got. Subsequently, PEG 400 was selected as the solvent and
phase transfer catalyst (Gaikwad et al., 2015), the reaction was com-
pleted in 4–5 hr with fewer by-products.
2.4.24
|
2-([1,10-Biphenyl]-4-yl)-6-(2-(pyrrolidin-
1-yl)ethoxy)-4H-chromen-4-one (8f)
Light yellow solid， yield: 70.2%， mp: 166.4–168.1ꢀC，Rf = 0.54,
MeOH:CH2Cl2
=
1:10. 1H NMR (400 MHz, CDCl3)
δ
(ppm):
In the process of the synthesis of flavone from chalcone, ethanol
was used as the solvent to remove the protect group bearing in
hydroxyl group in the presence of HCl, but there were many by-
products in result. After many attempts, DMSO was selected as the
solvent in this process for that intermediate product could be conve-
niently reacted in the next step without separation from the mixture.
Hydrochloric acid or sulfuric acid can promote the reaction with I2 as
the catalyzer. This reaction is usually completed in 1 hr, and the yield
is about 80%.
8.052–8.032 (m, 2H, Ar H), 7.805–7.785 (m, 2H, Ar H),
7.710–7.690 (m, 2H, Ar H), 7.658 (d, J = 3.0 Hz, 1H, Ar H),
7.582–7.516 (m, 3H, Ar H), 7.476–7.437 (m, 1H, Ar H), 7.397 (dd,
J = 9.2, 3.0 Hz, 1H, Ar H), 6.906 (s, 1H, CH
5.7 Hz, 2H, CH2 CH2 ), 3.003 (t,
C
=
O), 4.273 (t,
5.7 Hz, 2H,
J
=
O
J
CH2 CH2 N), 2.716–2.686 (m, 4H, Pyrrolidine-H), 1.893–1.861
(m, 4H, Pyrrolidine-H). 13C NMR (101 MHz, CDCl3) δ (ppm):178.23,
162.87, 156.30, 151.07, 144.24, 139.74, 130.60, 128.99, 128.17,
127.60, 127.12, 126.67, 124.57, 124.19, 119.44, 106.67, 105.76,
67.69, 55.00, 54.69, 23.53. IR (KBr, cm−1): 3030, 2922, 1616, 1575,
1452, 1363, 1290, 912, 729. ESI-MS (m/z): Calcd for C27H26NO3[M
+ H]+: 412.1913; found, 412.1903.
Then compounds 4a–4h in acetone were applied to generate com-
pounds 5a–8f in the presence of K2CO3 and NaI (Kumar et al., 2012).
The final products were purified by silica gel chromatography and char-
acterized by 1H NMR and 13C NMR. The raw characterization data of
new synthesized compounds are shown in Supporting Information.
2.5
|
AChE and BChE inhibition assay
3.2
|
Bioactivity evaluation
AChE or BChE activity assays were conducted using Ellman Method
(Ellman, Courtney, Andres, & Featherstone, 1961). The resource of
AChE and BChE originated from the brain and serum of Sprague–
Dawley rats, respectively. All the new synthesized compounds was
dissolved in water with Tween 80 as a solubilizer and then diluted
with water to various concentrations immediately before use. AChE
or BChE activity assays are based on the method previously reported
in our laboratory (Liu et al., 2017), each sample are tested for three
duplicates.
The biological activity of all new synthesized compounds was evaluated
as shown in Table 1. All compounds but not compounds 7a–7f exhibit
moderate or potent inhibitory effects on AChE and BChE. Compounds
5d (IC50 = 0.80 0.04 μmol/L), 8a (IC50 = 0.65 0.03 μmol/L), and 8c
(IC50 = 0.80 0.07 μmol/L) have excellent inhibitory effects on AChE
but have no good selectivity to AChE over BChE (Table 1). Interestingly,
compound 5a showed potent inhibitory activity (1.29 0.10 μmol/L)
and high selectivity against AChE over BChE (ratio: 27.96).

LU ET AL.
9
SCHEME 1 Reagents and conditions: (I) DCM, 3,4-dihydro-H-pyran(DHP), pyridinium p-toluenesulfonate (PPTS), room temperature; (II) PEG
400, 20%NaOH, 40ꢀC; (III) DMSO, iodine, concentrated hydrochloric acid, 110ꢀC; (IV) Cl(CH2)2R1, K2CO3, NaI, acetone, reflux
TABLE 1 Effect of Compounds 5a–8f on inhibitory activity against AChE and BChE
IC50a (μmol/L)
Compound
Ar
R1
AChE
BChE
Selectivity for AChEb
5a
7-Piperidine
1.29 0.10
17.39 1.90
1.27 0.03
0.80 0.04
10.83 0.63
3.42 0.30
10.86 0.24
17.98 1.24
9.86 0.63
4.44 0.40
13.82 0.82
4.28 0.17
286.37 14.55
>500
36.07 0.56
14.21 0.45
12.28 0.45
4.84 0.50
11.07 0.81
22.11 1.05
8.07 0.74
38.28 3.64
7.55 0.54
18.16 0.65
21.80 0.59
18.55 0.42
26.87 2.34
247.67 22.23
88.32 2.39
>500
27.96
0.81
9.66
6.05
1.02
6.46
0.74
2.12
0.76
4.09
1.57
4.33
0.10
0.50
<0.18
—
5b
7-Dimethylamino
7-Pyrrolidine
6-Piperidine
5c
5d
5e
6-Dimethylamino
6-Pyrrolidine
7-Piperidine
5f
6a
6b
7-Dimethylamino
7-Pyrrolidine
6-Piperidine
6c
6d
6e
6-Dimethylamino
6-Pyrrolidine
7-Piperidine
6f
7a
7b
7-Dimethylamino
7-Pyrrolidine
6-Piperidine
7c
>500
7d
>500
7e
6-Dimethylamino
6-Pyrrolidine
7-Piperidine
417.69 10.24
>500
146.55 5.36
>500
0.35
—
7f
8a
0.65 0.03
5.18 0.30
0.80 0.07
5.61 0.25
19.68 1.94
4.01 0.35
10.54 0.86
3.63 0.24
1.12 0.06
1.53 0.10
5.91 0.07
6.56 0.08
3.15 0.07
0.26 0.08
5.58
0.21
1.91
1.05
0.33
0.76
0.02
8b
7-Dimethylamino
7-Pyrrolidine
6-Piperidine
8c
8d
8e
6-Dimethylamino
6-Pyrrolidine
8f
Rivastigminec
aIC50 values of compounds represent the concentration that caused 50% enzyme activity loss.
bThe selectivity is defined as the ratio of IC50 of compounds inhibiting BChE/AChE.
cUsed for positive control for IC50
.

10
LU ET AL.
TABLE 2 Kinetics parameters assay
of compound 5a inhibiting AChE
C/μM
Michaelis–Menten equation
1/v = 164.28/[S] + 33.70
1/v = 216.36/[S] + 39.83
1/v = 319.60/[S] + 48.17
1/v = 469.24/[S] + 60.87
Km/mM
4.88
Vmax/ΔAmin−1
0.016
Ki/μM
Ki'/μM
0
0.891
2.161
0.34
0.85
1.71
6.63
0.021
5.43
0.025
4.88
0.030
were evaluated in AChE and BChE inhibition. The results revealed
that the alteration of B-ring of chromone brings about a significant
effect on biological activity. The substituted position of tertiary amine
side chain also appeared important impact on bioactivity. It is note-
worthy that 2-biphenyl chromone derivatives with 7-substituted ter-
tiary amine side chain (Compounds 8a-8c) are better than that of
flavones derivatives in AChE and BChE inhibition. This result may pro-
vide valuable information for further research on new cholinesterase
inhibitors.
ACKNOWLEDGMENT
The present investigation was supported by the grant of Key Labora-
tory Breeding Base of Hu'nan Oriented Fundamental and Applied
Research of Innovative Pharmaceutics (No. 2016TP1029) and the
Grant of Department of Education of Hu'nan Province (18B543).
FIGURE 2 Lineweaver–Burk plot based on Michaelis–Menten
equation of compound 5a inhibiting AChE
CONFLICT OF INTEREST
The authors have declared no conflict of interest.
According to the results, the alteration of tertiary amine side
chain markedly influence the activity and selectivity in inhibiting AChE
over BChE, generally the compounds bearing pyrrolidine or piperidine
side chain possess more potent bioactivity than that of compounds
with dimethylamino side chain. In addition, the alteration of aromatic
ring connecting to chromone scaffold can lead to the variations of bio-
activity. For the compounds with the same tertiary amine group, the
order of AChE inhibitory activity is Phenyl, Biphenyl > Naphthyl >
Anthracene. While for the order of BChE inhibitory activity is:
Naphthyl、Biphenyl > Phenyl > Anthracene. It seemed that too big
aromatic ring in chromone compounds would lead to a decrease in
bioactivity, such as 2-naphthyl chromone, 2-anthracene chromone.
But interestingly， the bioactivity of 2-biphenyl chromone is compa-
rable or higher than that of flavones (2-phenyl chromone).
ORCID
Hao-Ran Liu
https://orcid.org/0000-0002-0622-5310
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