Synthesis and biological evaluation of 2,5-disubstituted furan derivatives as P-glycoprotein inhibitors for Doxorubicin resistance in MCF-7/ADR cell

Article abstract of DOI:10.1016/j.ejmech.2018.04.012

Multidrug resistance (MDR) is a tendency in which cells become resistant to structurally and mechanistically unrelated drugs, which is mediated by P-glycoprotein (P-gp). It is one of the noteworthy problems in cancer therapy. As one of the most important

Full text of DOI:10.1016/j.ejmech.2018.04.012

Accepted Manuscript
Synthesis and biological evaluation of 2,5-disubstituted furan derivatives as P-
glycoprotein inhibitors for Doxorubicin resistance in MCF-7/ADR cell
Ya-Sheng Li, Dong-Sheng Zhao, Xing-Yu Liu, Yi-Xian Liao, Hong-Wei Jin, Gao-Peng
Song, Zi-Ning Cui
PII:
S0223-5234(18)30346-5
10.1016/j.ejmech.2018.04.012
EJMECH 10361
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 26 January 2018
Revised Date: 4 April 2018
Accepted Date: 4 April 2018
Please cite this article as: Y.-S. Li, D.-S. Zhao, X.-Y. Liu, Y.-X. Liao, H.-W. Jin, G.-P. Song, Z.-N. Cui,
Synthesis and biological evaluation of 2,5-disubstituted furan derivatives as P-glycoprotein inhibitors
for Doxorubicin resistance in MCF-7/ADR cell, European Journal of Medicinal Chemistry (2018), doi:
10.1016/j.ejmech.2018.04.012.
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Graphical Abstract
Synthesis and biological evaluation of 2,5-disubstituted furan
derivatives as P-glycoprotein inhibitors for Doxorubicin
resistance in MCF-7/ADR cell
a,#
b,#
a
a
c
Ya-Sheng Li , Dong-Sheng Zhao , Xing-Yu Liu , Yi-Xian Liao , Hong-Wei Jin ,
d,*
a,*
Gao-Peng Song , Zi-Ning Cui
R1
R1
R
N
N
O
R
O
O
O
4
: R = H
1
3
Title compounds in present work
5: R = OCH3
1
5
m: R = 4-OCH3
P-gp inhibitory activity: EC50 = 0.89 ± 0.11 µ M
Papp = 5.3
Antiproliferative effect: 97.8 ± 1.9%
Folds of Doxorubicin: 9.2 ± 0.9

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Synthesis and biological evaluation of 2,5-disubstituted furan
derivatives as P-glycoprotein inhibitors for Doxorubicin
resistance in MCF-7/ADR cell
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b, #
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Ya-Sheng Li , Dong-Sheng Zhao , Xing-Yu Liu , Yi-Xian Liao , Hong-Wei Jin ,
d,*
a,*
Gao-Peng Song , Zi-Ning Cui
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a
State Key Laboratory for Conservation and Utilization of Subtropical
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Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province
Key Laboratory of Microbial Signals and Disease Control, South China Agricultural
University, Guangzhou 510642, China
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Department of Pharmacy, Quanzhou Medical College, Quanzhou 362100, China
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State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking University, Beijing 100191, China
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College of Materials and Energy, South China Agricultural University, Guangzhou
510642, China
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Both authors contributed equally to this paper.
*Corresponding author. Tel.: +86-20-85288229; Fax: +86-20-85288229
E-mail address: ziningcui@scau.edu.cn (Z. C.), vinsin1021@126.com (G. S.)

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Abstract
Multidrug resistance (MDR) is a tendency in which cells become resistant to
structurally and mechanistically unrelated drugs, which is mediated by P-glycoprotein
(P-gp). It is one of the noteworthy problems in cancer therapy. As one of the most
important drugs in cancer therapy, doxorubicin has not good effectiveness if used
independently. So targeting the P-gp protein is one of the key points to solve the MDR.
Three series of furan derivatives containing tetrahydroquinoline or
tetrahydroisoquinoline were designed and synthesized as P-gp inhibitors in this paper.
Compound 5m containing 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline possessed
good potency against P-gp (EC = 0.89±0.11 µM). The preliminary structure–activity
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relationship and docking studies demonstrated that compound 5m would be great
promise as a lead compound for further study. Most worthy of mention is drug
combination of doxorubicin and 5m displayed antiproliferative effect of about 97.8%.
This study provides highlighted P-gp inhibitor for withstanding malignant tumor cell
with multidrug resistance especially doxorubicin resistance setting the basis for
further studies.
Keywords: tetrahydroquinoline; inhibitors; P-glycoprotein; multidrug resistance;
structure-activity relationship

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1. Introduction
The overexpression of some transmembrane proteins, belonging to the ABC (ATP
Binding Cassette) transporter family, led to Multidrug resistance (MDR) [1]. ABC
transporters consumed the energy from the ATP hydrolysis to efflux xenobiotics out
of cells. The overexpression of ABC transporter proteins in tumor cells caused MDR
that is the main reason for the failure of antineoplastic treatment, because ABC
transporters efflux chemotherapeutic agents out of tumor cells [2.3]. P-glycoprotein
(P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance
protein (BCRP) are the key ABC transporter proteins, which are mostly involved in
MDR [4,5]. The development of P-gp modulators is one of the considerable strategies
approached to overcome MDR in cancer therapy [6-13]. The P-gp inhibitors could be
applied in co-administration with the antineoplastic drugs to restore drug sensitivity to
tumor cells [14.15].
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The most potent P-gp modulators, tariquidar and elacridar (Figure 1), subjected to
clinical trials, showed high P-gp inhibition but poor selectivity due to their interaction
with other ABC transporters such as MRP1 and BCRP [5]. Recently PET (positron
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emission tomography) studies using the corresponding C-radiolabelled ligand
showed that both inhibitors demonstrated high activity towards P-gp, as well as
moderate activity towards BCRP [16-18].
Based on these lead compounds, some other P-gp potent modulators [19-26] such
as MC18 [19,20], MC70 [21,22], MC113 [21,23], and MC266 [19,20] (Figure 1)
bearing a tetrahydroisoquinoline fragment, were developed for improving the P-gp

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selectivity. Among them, MC18 and MC70 were found to be P-gp inhibitors, whereas
MC113 and MC266 were P-gp substrates.
Considering these findings, new P-gp ligands with better binding affinities and
higher selectivity with respect to that of the lead compound are needed to be
developed and discovered. In continuation of our research on the synthesis of
biological heterocyclic compounds [27-33], a series of tetrahydroquinoline derivatives
containing 5-phenyl-2-furan moiety were synthesized, and their P-gp potency and
selectivity were evaluated. The SAR (structure-activity relationship) study and the
docking research were discussed in this paper, and the choice of substituents such as
fluorine atoms or methoxy groups was made for the additional purpose of developing
useful tools with easy radiolabeling points for in vivo PET (Positron Emission
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Computed Tomography, C or F) analysis to check P-gp activity and expression.
2. Results and discussion
2.1. Chemical synthesis
The
synthetic
route
of
title
compounds
3a-3o
(containing
1,2,3,4-tetrahydroquinoline), 4a-4o (containing 1,2,3,4-tetrahydroisoquinoline) and
5a-5o (containing 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) was described in
Scheme 1. The key intermediates 2 (the different carboxylic acids 2) were synthesized
from substituted aniline by Meerwein arylation reaction according to the reported
procedure [31.33]. Then a mixture of 5-substitutedphenyl-2-furancarboxylic acid 2
and thionyl chloride was refluxed in anhydrous toluene for 3.5 h to afford the various
5-phenyl-2-furancarbonyl chloride, which was added into tetrahydroquinoline in

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anhydrous dichloromethane to react and obtain the title compounds 3 (3a-3o). With
the different carboxylic acids
2
and 1,2,3,4-tetrahydroisoquinoline or
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, their coupling reaction was then
performed in the presence of EDCI and HOBt to provide the different title compounds
4 (4a-4o) or 5 (5a-5o), respectively.
2.2. X-ray diffraction
X-ray single crystals of compounds 3b and 4d were obtained as described below in
this section. In the case, well-shaped crystals were obtained by interfacial
crystallization of n-hexane and dichloromethane. A summary of the experimental and
crystallography data for compounds 3b and 4d were given in Table S1 to S3 (see
Supplementary materials) and molecular structure of compounds 3b and 4d are
depicted in Figure 2. Crystallographic data were collected at 113(2) K on a Rigaku
XtaLAB P200 using a X-ray source Mo/Kα radiation (λ=0.71073 Å). The structure
was solved by the direct method with SHELXS-97 [34,35] and refined by the
full-matrix least-squares method on F2 data using SHELXL-97 [34,35]. All
non-hydrogen atoms were refined with anisotropic displacement parameters. H atoms
were finally included in their calculated positions. Crystallographic data (excluding
structure factors) for the structures in this paper have been deposited at the Cambridge
Crystallographic Data Centre with CCDC numbers 1505007 (3b) and 1505009 (4d),
respectively. Copies of the data can be obtained, free of charge, on application to
CDC, 12 Union Road, Cambridge CB2 1EZ, UK.
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2.3. Biological evaluation and SAR studies.

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In this paper, three series of benzene substituted furyl derivatives were studied, and
all the derivatives displayed good bioactive potency. In vitro data for the inhibition of
P-gp and Papp (apparent permeability) was reported in Table 1. Cyclosporin A and
verapamil were chosen as the positive controls. As depicted in Table 1, compounds
with substituent at para-position of benzene ring exerted better bioactivity against
P-gp (EC < 10 µM) than the other two substituents in benzene ring , suggesting the
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position of benzene ring played a key role in bioactivity. As shown in Table 1,
compound 5m containing 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and methoxyl
group at para-position of benzene ring showed the best bioactivity against P-gp (EC50
= 0.89 µM) among all the title compounds, which displayed better activity than both
cyclosporin A and verapamil (EC50 = 83.68 µM and 20.54 µM against P-gp,
respectively) and the similar to the MC113 [21,23]. Analysis of three series of
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potential inhibitors revealed that
5
(containing 6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline) displayed stronger bioactivity than both 3 (containing 1,2,3,4-
tetrahydroquinoline) and 4 (containing 1,2,3,4-tetrahydroisoquinoline). For instance,
compound 5m showed better bioactivity (EC = 0.89 µM against P-gp) than 4m
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(EC = 5.48 µM against P-gp) and 3m (EC = 6.82 µM against P-gp). Similarly,
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compound 5j displayed better bioactivity (EC = 9.23 µM against P-gp) than 4j (EC
50
5
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= 12.45 µM against P-gp) and 3j (EC = 15.46 µM against P-gp). These results
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indicated that the moiety of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline has a
crucial influence on the inhibitory activity against P-gp. Like the best inhibitor 5m,
compounds 5l and 5d also exhibited strong inhibition against P-gp (EC = 4.34 µM
5
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and 3.27 µM, respectively). What is more, all the compounds 5m, 5l and 5d showed
greater Papp values more than 2, which displayed better selectivity compared to
verapamil, suggesting that they could be potential P-gp inhibitors. In addition, it was
observed that electron-donating group (methoxyl group) and the halogen substituents
(bromine atom and chlorine atom) at para-position of benzene ring are excellent
options for future designs of P-gp inhibitor.
Doxorubicin resistance is one of the thorniest problems in tumor therapy. As shown
in Table 2, the simultaneous treatment with Doxorubicin and the title compounds
increased Doxorubicin accumulation in overexpressing P-gp MCF-7/ADR cells.
Compound 5m displayed an increased Doxorubicin cell accumulation of 9.2- fold at
20 µM in the cells (Table 2). Compounds 5d and 5l increased Doxorubicin
accumulation 6.8- and 5.0- fold, respectively (Table 2). At 20 µM the positive
references Cyclosporin A and Verapamil showed an increase of Doxorubicin cell
accumulation of 5.4- and 3.6- fold, respectively. The antiproliferative effect indicated
that Doxorubicin cell accumulation induced by the title compounds improved that of
the chemotherapeutic. At 5 µM, Doxorubicin itself demonstrated a low
antiproliferative effect (5.3%) as listed in Table 2. In the presence of 20 µM
compound 5m, Doxorubicin inhibited cell growth of about 97.8%. Moreover, high
antiproliferative effect was induced by Doxorubicin compounds 5d and 5l (89.6% and
79.8%). Mixed Cyclosporin A or Verapamil with Doxorubicin displayed good to
moderate increase of antiproliferative effect (84.2% and 52.5%). The results of
Doxorubicin antiproliferative effect as drugs combination with the title compounds
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are well correlate with the increased Doxorubicin accumulation. These findings
suggested that the drugs combination of Doxorubicin with the title compounds could
improve Doxorubicin antiproliferative effect in MCF-7/ADR tumor cells.
Moreover, title compounds 5d, 5l and 5m were evaluated in the absence of
Doxorubicin for the cytotoxicity effects at 24 and 48 h, respectively. The cytotoxicity
of tested compounds at 100 µM, checked in cell medium after treatment, was
negligible (< 15% for each tested compound). Further study will be undergoing to
evaluate in vivo bioactivity using some suitable animal models, such as the
established patient-derived orthotopic xenograft (PDOX) nude mouse models where
both efficacy and toxicity of the title compounds could be detected [36-39].
2.4. Docking study
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Considering the inhibitory activity of title compounds, it was of interest to explore
the binding to the active site of P-gp. Docking results revealed that compound 5m was
well located within P-gp. Binding models of compound 5m and Cyclosporin A were
depicted in Figure 3. Generally, a key hydrogen bond interaction could be observed
between O of the furan ring and the H at amine of Gln721 (distance: 2.59Å). At the
active site, the docking showed molecular skeleton shape from X-ray single crystal
diffraction is folded. 2-Phenyl-furane moiety and 1,2,3,4-tetrahydroisoquinoline
moiety have good site in this dock (Figure 3). The bending angle of amide bond
revealed vital linking effect for those crucial pharmacophores. The hydrophobic effect
of
three
para-methoxy
groups
(-OMe)
at
benzene
ring
and
1,2,3,4-tetrahydroisoquinoline to enhance the binding affinity with the enzyme. Such

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orientations and interactions would form the foundation for inhibition of
P-glycoprotein and increase Doxorubicin intracellular accumulation in MCF-7/ADR
cells.
3. Conclusion
In this study, three series of 2,5-disubstituted furan derivatives were synthesized
and evaluated as P-glycoprotein inhibitors in Doxorubicin resistance MCF-7/ADR
cells. Their in vitro activities for the inhibition of P-gp and Papp (apparent permeability)
were evaluated, and the results showed that compounds containing 6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (series 5) exhibited the best bioactivity among these
three series of compounds. The primary structure-activity relationship (SAR) study
showed that substituents at para-position of benzene ring in the molecule were
favored to the bioactivity. Compound 5m showed the highest inhibitory activity,
which increased Doxorubicin accumulation 9.2- fold at 20 µM in overexpressing P-gp
MCF-7/ADR cells. The docking results revealed interactions of compounds 5 within
P-gp protein where a key hydrogen bond interaction could be observed between O of
the furan ring and the H at amine of Gln721.
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4. Experimental procedure
4.1. Chemistry
4.1.1. Materials and methods
All solvents and reagents were obtained from commercial sources without further
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purification. H NMR and C NMR spectra were recorded on Bruker Avance DRX
spectrometer at 600 and 150 MHz or 400 and 100 MHz. Chemical shifts are reported

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as δ values in parts per million (ppm), while tetramethylsilane (TMS) was used as an
internal standard. Peak multiplicities are expressed as follows: s, singlet; d, doublet; t,
triplet; q, quartet; dd, doublet of doublets; td, triplet of doublets; ddd, doublet of
doublet of doublets; brs, broad singlet; m, multiplet. Coupling constants (J values) are
given in hertz (Hz). Compounds were dissolved in DMSO-d . Mass spectra were
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recorded on a Q-TOF Global mass spectrometer. Elemental analysis was carried out
with a Flash EA 1112 elemantal analyzer. All the melting points were determined with
a Cole-Parmer melting point apparatus while the thermometer was uncorrected.
Thin-layer chromatography (TLC) was performed using Merck 60 F254 silica gel
plates. Column chromatography was performed using silica gel (200-300 mesh,
Qingdao, China) with a linear solvent gradient.
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4.1.2. General synthesis of compounds 3a-3o
A mixture of 5-substituted phenyl-2-furancarboxylic acid 2 (100 mmol) and thionyl
chloride (500 mmol) was refluxed in anhydrous benzene for 3.5 h. The excess of
thionyl chloride and the solvent were distilled off, and the residue was dissolved in
anhydrous dichloromethane. The solution of 5-substituted phenyl-2-furancarboxylic
chloride in anhydrous dichloromethane was added into tetrahydroquinoline (110
mmol). The mixture was stirred and refluxed for 4 h. After cooling, the solvent was
evaporated off under reduced pressure, and the solid was recrystallized from ethanol
to obtain compounds 3a-3o.
4.1.2.1. (5-Phenylfuran-2-yl)(3,4-dihydroquinolin-1(2H)-yl)-Methanone ( 3a ). yellow
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liquid, yield 92.3%. H NMR (600 MHz, DMSO-d ) δ 7.43 (d, J = 7.5 Hz, 2H), 7.37
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(t, J = 7.6 Hz, 2H), 7.33-7.27 (m, 2H), 7.11 (td, J = 7.4, 1.1 Hz, 1H), 7.05-6.98 (m,
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4H), 3.86 (t, J = 6.5 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H), 1.96 (p, J = 6.5 Hz, 2H); C
NMR (151 MHz, DMSO-d ) δ 159.09, 154.61, 147.27, 139.23, 132.28, 129.66,
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129.31, 129.00, 128.73, 126.09, 125.10, 124.50, 124.46, 119.17, 107.77, 44.65, 26.58,
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24.16. ESIMS(m/z): 304.1330 [M + H] .
4.1.2.2.
[5-(2-Chlorophenyl)-2-furanyl](3,4-dihydroquinolin-1(2H)-yl)-Methanone
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( 3b ). light yellow solid, yield 88.7%, m.p. 146-148 ºC. H NMR (600 MHz,
DMSO-d ) δ 7.54 (dd, J = 8.0, 1.0 Hz, 1H), 7.35 (td, J = 7.7, 1.7 Hz, 1H), 7.31-7.28
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(m, 2H), 7.18 (d, J = 3.6 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.12 (td, J = 7.4, 0.9 Hz,
1H), 7.05-7.02 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 3.86 (t, J = 6.5 Hz, 2H), 2.80 (t, J =
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6.5 Hz, 2H), 1.97 (p, J = 6.5 Hz, 2H); C NMR (151 MHz, DMSO-d ) δ 158.98,
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150.66, 147.55, 139.16, 132.46, 131.22, 130.33, 130.08, 128.80, 128.60, 127.93,
127.83, 126.25, 125.22, 124.42, 118.60, 112.71, 44.63, 26.56, 24.13. Anal. Calcd. (%)
for C H ClNO : C, 71.24; H, 4.61; N, 4.38. Found: C, 71.11；H, 4.77; N, 4.15.
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4.1.2.3.
[5-(3-Chlorophenyl)-2-furanyl](3,4-dihydroquinolin-1(2H)-yl)-Methanone
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( 3c ). light yellow solid, yield 92.7%, m.p. 153-155 ºC. H NMR (600 MHz,
DMSO-d ) δ 7.47-7.40 (m, 4H), 7.28 (d, J = 7.5 Hz, 1H), 7.11 (m, 2H), 7.05-6.96 (m,
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3H), 3.86 (t, J = 6.5 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H), 1.96 (p, J = 6.5 Hz, 2H); C
NMR (151 MHz, DMSO-d ) δ 158.82, 152.80, 147.76, 139.18, 134.23, 132.60,
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131.55, 131.23, 128.64, 128.62, 126.09, 125.27, 124.55, 124.01, 122.99, 119.18,
109.12, 44.55, 26.57, 24.16. Anal. Calcd. (%) for C H ClNO : C, 70.99; H, 4.89; N,
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3.98. Found: C, 71.11；H, 4.77; N, 4.15.

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4.1.2.4.
[5-(3-Chlorophenyl)-2-furanyl](3,4-dihydroquinolin-1(2H)-yl)-Methanone
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( 3d ). white solid, yield 90.1%, m.p. 159-160 ºC. H NMR (600 MHz, DMSO-d ) δ
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7.42-7.34 (m, 3H), 7.33 – 7.28 (m, 2H), 7.17 (d, J = 3.6 Hz, 1H), 7.13 (t, J = 7.4 Hz,
1H), 7.05 (d, J = 3.6 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 3.85
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128.51, 126.12, 126.08, 125.17, 124.51, 119.15, 108.47, 44.67, 26.57, 24.15. Anal.
Calcd. (%) for C H ClNO : C, 71.34; H, 4.47; N, 4.40. Found: C, 71.11；H, 4.77; N,
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4.15.
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4.1.2.5.
[5-(2-Fluorophenyl)-2-furanyl](3,4-dihydroquinolin-1(2H)-yl)-Methanone
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( 3e ). white solid, yield 82.6%, m.p. 150-151 ºC. H NMR (600 MHz, DMSO-d ) δ
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7.42 (td, J = 7.7, 3.6 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H),
7.16-7.10 (m, 4H), 7.05-7.01 (m, 2H), 6.96 (d, J = 7.9 Hz, 1H), 3.85 (t, J = 6.5 Hz,
13
2H), 2.80 (t, J = 6.5 Hz, 2H), 1.97 (p, J = 6.5 Hz, 2H); C NMR (151 MHz,
1
4
DMSO-d ) δ 162.87 (d, J = 243.5 Hz), 158.89, 153.14 (d, J = 3.0 Hz), 147.71,
6
C-F
C-F
3
3
139.20, 132.51, 131.84 (d, JC-F = 8.7 Hz), 131.53 (d, J = 8.6 Hz), 128.70, 126.12,
C-F
4
2
125.22, 124.52, 120.54 (d, JC-F = 2.6 Hz), 119.16, 115.70 (d, J = 21.2 Hz), 111.09
C-F
2
(d, J = 23.7 Hz), 109.07, 44.59, 26.56, 24.16. Anal. Calcd. (%) for C H FNO : C,
C-F
20 16
2
74.58; H, 4.94; N, 4.57. Found: C, 74.75; H, 5.02;N, 4.36.
4.1.2.6.
[5-(3-Fluorophenyl)-2-furanyl](3,4-dihydroquinolin-1(2H)-yl)-Methanone
1
( 3f ). white solid, yield 88.9%, m.p. 156-158 ºC. H NMR (600 MHz, DMSO-d ) δ
6
7.41 (td, J = 7.7, 3.6 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H),

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7.17-7.10 (m, 4H), 7.05-7.00 (m, 2H), 6.95 (d, J = 8.0 Hz, 1H), 3.85 (t, J = 6.5 Hz,
13
2H), 2.80 (t, J = 6.5 Hz, 2H), 1.97 (p, J = 6.5 Hz, 2H); C NMR (151 MHz,
1
4
DMSO-d ) δ 162.87 (d, J = 243.6 Hz), 158.90, 153.13 (d, J = 3.1 Hz), 147.71,
6
C-F
C-F
3
2
139.20, 132.51, 131.84 (d, JC-F = 8.8 Hz), 131.53 (d, J = 8.6 Hz), 128.70, 126.12,
C-F
4
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125.22, 124.52, 120.54 (d, JC-F = 2.6 Hz), 119.16, 115.70 (d, J = 21.2 Hz), 111.09
C-F
2
(d, J = 23.8 Hz), 109.07, 44.59, 26.56, 24.16. Anal. Calcd. (%) for C H FNO : C,
C-F
20 16
2
74.82; H, 5.21; N, 4.19. Found: C, 74.75; H, 5.02;N, 4.36.
4.1.2.7.
[5-(4-Fluorophenyl)-2-furanyl](3,4-dihydroquinolin-1(2H)-yl)-Methanone
1
( 3g ). white solid, yield 90.5%, m.p. 149-150 ºC. H NMR (600 MHz, DMSO-d ) δ
6
1
1
1
1
1
1
1
1
1
1
2
2
2
7.46 (dd, J = 8.8, 5.4 Hz, 2H), 7.28 (d, J = 7.4 Hz, 1H), 7.23 (t, J = 8.8 Hz, 2H), 7.11
(td, J = 7.4, 1.1 Hz, 1H), 7.02 (dd, J = 7.9, 5.5 Hz, 2H), 6.98 (dd, J = 7.9, 5.8 Hz, 2H),
1
3
3.85 (t, J = 6.5 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H), 1.96 (p, J = 6.5 Hz, 2H); C NMR
(151 MHz, DMSO-d ) δ 162.52 (d, J = 246.5 Hz), 159.06, 153.73, 147.29, 139.22,
6
132.33, 128.76, 126.70 (d, J = 8.4 Hz), 126.38 (d, J = 3.0 Hz), 126.09, 125.14, 124.52,
119.22, 116.42 (d, J = 22.0 Hz), 107.68, 44.65, 26.57, 24.16. Anal. Calcd. (%) for
C H FNO : C, 74.86; H, 4.87; N, 4.52. Found: C, 74.75; H, 5.02;N, 4.36.
20
16
2
4.1.2.8.
[5-(2-Nitrophenyl)-2-furanyl](3,4-dihydroquinolin-1(2H)-yl)-Methanone
1
( 3h ). yellow solid, yield 83.8%, m.p. 161-163 ºC. H NMR (600 MHz, DMSO-d ) δ
6
7.91 (d, J = 7.9 Hz, 1H), 7.71 (t, J = 7.3 Hz, 1H), 7.64-7.60 (m, 2H), 7.24 (d, J = 7.3
Hz, 1H), 7.10-7.03 (m, 3H), 6.96 (dd, J = 13.8, 3.6 Hz, 2H), 3.82 (t, J = 6.5 Hz, 2H),
1
3
2.79 (t, J = 6.5 Hz, 2H), 1.95 (p, J = 6.5 Hz, 2H); C NMR (151 MHz, DMSO-d ) δ
6
158.96, 149.49, 148.86, 147.56, 138.79, 133.06, 132.06, 130.58, 129.69, 129.03,

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126.10, 125.21, 124.55, 124.36, 122.40, 118.53, 111.68, 44.85, 26.47, 24.05. Anal.
Calcd. (%) for C H N O : C, 69.10; H, 4.51; N, 8.24. Found: C, 68.96; H, 4.63;N,
2
0
16
2
4
8.04.
4.1.2.9.
[5-(3-Nitrophenyl)-2-furanyl](3,4-dihydroquinolin-1(2H)-yl)-Methanone
1
( 3i ). yellow liquid, yield 88.5%. H NMR (600 MHz, DMSO-d ) δ 8.14 (dd, J = 8.2,
6
1.6 Hz, 1H), 8.06 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.35-7.31
(m, 2H), 7.13 (td, J = 7.5, 1.0 Hz, 1H), 7.05 (d, J = 3.6 Hz, 1H), 7.03-6.97 (m, 2H),
1
3
3.87 (t, J = 6.5 Hz, 2H), 2.82 (t, J = 6.5 Hz, 2H), 1.98 (p, J = 6.5 Hz, 2H); C NMR
(151 MHz, DMSO-d ) δ 158.78, 152.04, 148.77, 148.20, 139.05, 132.63, 131.10,
6
1
1
1
1
1
1
1
1
1
1
2
2
2
131.01, 130.50, 128.70, 126.04, 125.42, 124.51, 123.28, 119.13, 118.62, 110.07,
+
44.60, 26.57, 24.16. ESIMS(m/z): 349.1182 [M + H] .
4.1.2.10.
[5-(4-Nitrophenyl)-2-furanyl](3,4-dihydroquinolin-1(2H)-yl)-Methanone
1
( 3j ). yellow solid, yield 93.0%, m.p. 161-162 ºC. H NMR (600 MHz, DMSO-d ) δ
6
8.22 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 3.7 Hz, 1H), 7.30 (d, J
= 7.5 Hz, 1H), 7.14 (td, J = 7.4, 1.6 Hz, 1H), 7.03 (d, J = 3.7 Hz, 1H), 7.02-6.98 (m,
1
3
2H), 3.87 (t, J = 6.5 Hz, 2H), 2.81 (t, J = 6.5 Hz, 2H), 1.98 (p, J = 6.5 Hz, 2H); C
NMR (151 MHz, DMSO-d ) δ 158.82, 152.18, 148.91, 147.06, 138.96, 135.34,
6
132.55, 128.80, 126.12, 125.40, 125.15, 124.77, 124.52, 119.15, 111.65, 44.73, 26.56,
24.12. Anal. Calcd. (%) for C H N O : C, 68.71; H, 4.86; N, 7.81. Found: C, 68.96;
20
16
2
4
H, 4.63;N, 8.04.
4.1.2.11. [5-(4-Methylphenyl)-2-furanyl](3,4-dihydroquinolin-1(2H)-yl)-Methanone
1
( 3k ). white solid, yield 89.2%, m.p. 152-155 ºC. H NMR (600 MHz, DMSO-d ) δ
6

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7.31 (d, J = 8.0 Hz, 2H, ArH), 7.28 (d, J = 7.4 Hz, 1H, QuH), 7.17 (d, J = 8.0 Hz, 2H,
ArH), 7.10 (td, J = 7.4, 1.2 Hz, 1H, QuH), 7.03-6.99 (m, 1H), 6.98-6.95 (m, 3H), 3.85
1
3
(t, J = 6.5 Hz, 2H), 2.79 (t, J = 6.5 Hz, 2H), 2.29 (s, 3H), 1.96 (p, J = 6.5 Hz, 2H); C
NMR (151 MHz, DMSO-d ) δ 159.10, 154.89, 146.88, 139.27, 138.64, 132.24,
6
129.86, 128.71, 127.02, 126.07, 125.05, 124.52, 124.45, 119.23, 107.03, 44.64, 26.58,
24.17, 21.29. Anal. Calcd. (%) for C H NO : C, 79.59; H, 6.21; N, 4.20. Found: C,
2
1
19
2
79.47; H, 6.03; N, 4.41.
4.1.2.12. [5-(4-Bromophenyl)-2-furanyl](3,4-dihydroquinolin-1(2H)-yl)-Methanone
1
( 3l ). yellow solid, yield 90.8%, m.p. 191-192 ºC. H NMR (600 MHz, DMSO-d ) δ
6
1
1
1
1
1
1
1
1
1
1
2
2
2
7.62-7.55 (m, 2H), 7.45-7.27 (m, 3H), 7.15-7.10 (m, 2H), 7.09-6.96 (m, 3H), 3.85 (t, J
1
3
= 6.5 Hz, 2H), 2.79 (t, J = 6.5 Hz, 2H), 1.96 (p, J = 6.5 Hz, 2H); C NMR (151 MHz,
DMSO-d ) δ 158.99, 153.45, 147.54, 139.13, 132.35, 132.30, 128.84, 128.75, 126.35,
6
126.08, 125.19, 124.52, 122.09, 119.15, 108.55, 44.68, 26.57, 24.15. Anal. Calcd. (%)
for C H BrNO : C, 63.01; H, 4.08; N, 3.82. Found: C, 62.84; H, 4.22; N, 3.66.
2
0
16
2
4.1.2.13. [5-(4-Methoxyphenyl)-2-furanyl](3,4-dihydroquinolin-1(2H)-yl)-Methanone
1
( 3m ). white liquid, yield 83.8%. H NMR (600 MHz, DMSO-d ) δ 7.36 (d, J = 8.8
6
Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.11 (td, J = 7.4, 1.2 Hz, 1H), 7.04-7.01 (m, 1H),
6.97 (dd, J = 8.4, 5.8 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 6.88 (d, J = 3.6 Hz, 1H), 3.85
13
(t, J = 6.5 Hz, 2H), 3.77 (s, 3H), 2.79 (t, J = 6.5 Hz, 2H), 1.96 (p, J = 6.5 Hz, 2H); C
NMR (151 MHz, DMSO-d ) δ 160.01, 159.14, 154.93, 146.55, 139.32, 132.18,
6
128.73, 126.11, 126.07, 125.02, 124.52, 122.47, 119.39, 114.79, 106.13, 55.70, 44.64,
+
26.58, 24.17. ESIMS(m/z): 334.1451 [M + H] .

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4.1.2.14.
[5-(2',4'-di-Fluorophenyl)-2-furanyl](3,4-dihydroquinolin-1(2H)-yl)-Methanone
1
( 3n ). white solid, yield 92.6%, m.p. 133-136 ºC. H NMR (600 MHz, DMSO-d ) δ
6
7.40 (ddd, J = 11.6, 9.3, 2.5 Hz, 1H), 7.29 (d, J = 7.4 Hz, 1H), 7.20 (dd, J = 15.3, 8.5
Hz, 1H), 7.14-7.10 (m, 2H), 7.05-6.97 (m, 3H), 6.87 (t, J = 3.6 Hz, 1H), 3.86 (t, J =
1
3
6.5 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H), 1.97 (p, J = 6.5 Hz, 2H); C NMR (151 MHz,
1
3
1
DMSO-d ) δ 162.39 (dd, J = 249.3 Hz, J = 12.3 Hz), 158.92 (dd, J = 253.2
6
C-F
C-F
C-F
3
4
Hz, J = 12.4 Hz), 158.88, 147.87 (d, J = 2.2 Hz), 147.38, 139.08, 132.41,
C-F
C-F
3
3
128.76, 127.82 (dd, J = 9.94 Hz, J = 9.99 Hz), 126.12, 125.23, 124.48, 118.96,
C-F
C-F
2
3
2
4
1
1
1
1
1
1
1
1
1
1
2
2
114.59 (dd, J = 12.3 Hz, J = 3.8 Hz), 112.78 (dd, J = 21.9 Hz, J = 3.2
C-F
C-F
C-F
C-F
3
Hz), 111.31 (d, J = 10.1 Hz), 105.44 (dd, J = 25.9 Hz, J = 25.9 Hz), 44.66, 26.55,
C-F
24.13. Anal. Calcd. (%) for C H F NO : C, 70.60; H, 4.67; N, 3.95. Found: C, 70.79;
2
0
15
2
2
H, 4.46; N, 4.13.
4.1.2.15.
[5-(2',6'-di-Fluorophenyl)-2-furanyl](3,4-dihydroquinolin-1(2H)-yl)-Methanone
1
( 4o ). white liquid, yield 82.6%. H NMR (600 MHz, DMSO-d ) δ 7.51-7.46 (m, 1H),
6
7.26-7.20 (m, 3H), 7.11-7.03 (m, 3H), 6.99-6.95 (m, 2H), 3.87 (t, J = 6.5 Hz, 2H),
1
3
2.79 (t, J = 6.5 Hz, 2H), 1.96 (p, J = 6.5 Hz, 2H); C NMR (151 MHz, DMSO-d ) δ
6
1
3
159.18, 159.17 (dd, J = 253.0, J = 6.5 Hz), 148.27, 144.28, 138.80, 131.85,
C-F
C-F
3
3
131.44 (dd, J = 10.6 Hz, J = 10.5 Hz), 128.98, 126.13, 125.13, 124.29, 117.97,
C-F
C-F
3
3
2
4
114.37 (dd, J = 5.4 Hz, J = 5.5 Hz), 112.96 (dd, J = 21.4, J = 4.0 Hz),
C-F
C-F
C-F
C-F

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107.71 (dd, J = 16.3 Hz, J = 16.3 Hz), 45.01, 26.50, 24.07. ESIMS(m/z):
C-F
C-F
+
340.1154 [M + H] .
4.1.3. General synthesis of title compounds 4 and 5.
A mixture of 5-substituted phenyl-2-furancarboxylic acid 2 (100 mmol) and
1,2,3,4-tetrahydroisoquinoline
(105
mmol)
or
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (105 mmol) dissolved in anhydrous
dichloromethane, their coupling reaction was then performed in the presence of EDCI
(120 mmol) and HOBt (120 mmol) to provide the different title compounds 4 (4a-4o)
or 5 (5a-5o), respectively.
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2
4.1.3.1. (5-Phenyl-2-furanyl)(3,4-dihydro-2(1H)-isoquinolinyl)-Methanone ( 4a ).
1
white solid, yield 95.1%, m.p. 105-106 ºC. H NMR (600 MHz, DMSO-d6) δ 7.82 (d,
J = 7.6 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.6 Hz, 1H), 7.27-7.13 (m, 6H),
1
3
4.81 (s, 2H), 3.97 (s, 2H), 2.97 (s, 2H); C NMR (151 MHz, DMSO-d6) δ 158.48,
154.26, 146.48, 134.60, 133.19, 129.33, 128.98, 128.47, 128.39, 126.50, 126.36,
126.15, 124.03, 117.90, 107.16. Anal. Calcd. (%) for C H NO : C, 79.30; H, 5.78;
2
0
17
2
N, 4.48. Found: C, 79.19; H, 5.65;N, 4.62.
4.1.3.2. [5-(2-Chlorophenyl)-2-furanyl](3,4-dihydro-2(1H)-isoquinolinyl)-Methanone
1
( 4b ). yellow liquid, yield 97.1%, m.p. 118-119 ºC. H NMR (600 MHz, DMSO-d ) δ
6
7.89 (dd, J = 7.8, 1.4 Hz, 1H), 7.61 (dd, J = 8.0, 1.2 Hz, 1H), 7.50 (td, J = 7.6, 1.2 Hz,
1H), 7.45-7.41 (m, 1H), 7.28-7.20 (m, 6H), 4.77 (s, 2H), 4.01 (s, 2H), 2.96 (s, 2H);
1
3
C NMR (151 MHz, DMSO-d ) δ 158.86, 151.12, 147.33, 135.09, 133.62, 131.34, 1
6

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30.43, 130.20, 129.11, 128.93, 128.26, 128.13, 127.06, 126.87, 126.71, 117.99, 112.5
+
6. ESIMS(m/z): 338.0953 [M + H] .
4.1.3.3. [5-(3-Chlorophenyl)-2-furanyl](3,4-dihydro-2(1H)-isoquinolinyl)-Methanone
1
( 4c ). light yellow solid, yield 93.3%, m.p. 122-124 ºC. H NMR (600 MHz,
DMSO-d ) δ 7.88-7.75 (m, 2H), 7.57-7.42 (m, 2H), 7.31-7.16 (m, 6H), 4.78 (s, 2H),
6
13
3.96 (s, 2H), 2.97 (s, 2H); C NMR (151 MHz, DMSO-d ) δ 158.99, 152.31, 148.95,
6
147.81, 135.90, 135.09, 133.58, 131.36, 131.30, 130.63, 128.92, 127.15, 126.82,
123.41, 118.81, 118.25, 110.35. Anal. Calcd. (%) for C H ClNO : C, 70.98; H, 4.85;
2
0
16
2
N, 3.98. Found: C, 71.11；H, 4.77; N, 4.15.
1
1
1
1
1
1
1
1
1
1
2
2
2
4.1.3.4. [5-(4-Chlorophenyl)-2-furanyl](3,4-dihydro-2(1H)-isoquinolinyl)-Methanone
1
( 4d ). yellow solid, yield 93.3%, m.p. 126-128 ºC. H NMR (600 MHz, DMSO-d ) δ
6
7.82 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 7.30-7.16 (m, 6H), 4.81 (s, 2H),
3.95 (s, 2H), 2.97 (s, 2H); 13C NMR (151 MHz, DMSO-d ) δ 158.95, 153.65, 147.23,
6
135.14, 133.69, 133.44, 129.59, 128.90, 128.72, 127.05, 126.92, 126.69, 126.30,
118.40, 108.40. Anal. Calcd. (%) for C H ClNO : C, 70.99; H, 4.86; N, 4.35. Found:
2
0
16
2
C, 71.11；H, 4.77; N, 4.15.
4.1.3.5. [5-(2-Fluorophenyl)-2-furanyl](3,4-dihydro-2(1H)-isoquinolinyl)-Methanone
1
( 4e ). white solid, yield 90.9%, m.p. 137-138 ºC. H NMR (600 MHz, DMSO-d ) δ
6
7.87 (t, J = 7.8 Hz, 1H), 7.48-7.43 (m, 1H), 7.41-7.34 (m, 2H), 7.30-7.16 (m, 5H),
1
3
7.02 (t, J = 3.4 Hz, 1H), 4.78 (s, 2H), 4.00 (s, 2H), 2.98 (s, 2H); C NMR (151 MHz,
1
3
DMSO-d ) δ 158.86 (C=O), 158.75 (d, J = 250.3 Hz, C-2, Ph), 148.97 (d, J = 5.7 Hz,
6
3
C-5, Fu), 147.17 (C-2, Fu), 135.11, 133.66, 130.77 (d, J = 8.5 Hz, C-4, Ph), 128.91,

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127.07, 126.91 (d, J = 1.9 Hz, C-4, Fu), 126.69, 125.64 (d, J = 3.2 Hz, C-5, Ph),
2
2
118.28 (2C), 117.82 (d, J = 11.8 Hz, C-1, Ph), 116.86 (d, J = 21.1 Hz, C-3, Ph),
3
111.67 (d, J = 10.3 Hz, C-6, Ph). Anal. Calcd. (%) for C H FNO : C, 74.93; H, 4.87;
2
0
16
2
N, 4.58. Found: C, 74.75; H, 5.02;N, 4.36.
4.1.3.6. [5-(3-Fluorophenyl)-2-furanyl](3,4-dihydro-2(1H)-isoquinolinyl)-Methanone
1
( 4f ). white solid, yield 89.6%, m.p. 133-135 ºC. H NMR (600 MHz, DMSO-d ) δ
6
7.64 (t, J = 9.6 Hz, 1H), 7.54 (dd, J = 14.3, 7.8 Hz, 2H), 7.27-7.20 (m, 7H), 4.76 (s,
1
3
1
2H), 3.98 (s, 2H), 2.97 (s, 2H); C NMR (151 MHz, DMSO-d ) δ 163.03 (d, J =
6
4
243.5 Hz, C-3, Ph), 158.91 (C=O), 153.42 (d, J = 3.2 Hz, C-5, Fu), 147.41(C-2, Fu),
3
3
1
1
1
1
1
1
1
1
1
1
2
2
2
135.14, 133.69, 132.05 (d, J = 8.7 Hz, C-1, Ph), 131.72 (d, J = 8.5 Hz, C-5, Ph),
4
2
128.91, 127.05, 126.89, 126.69, 120.61 (d, J = 2.1 Hz, C-6, Ph), 118.34, 115.71 (d, J
2
= 21.2 Hz, C-2, Ph), 111.30 (d, J = 23.6 Hz, C-4, Ph), 109.01. Anal. Calcd. (%) for
C H FNO : C, 74.58; H, 4.86; N, 4.57. Found: C, 74.75; H, 5.02;N, 4.36.
20
16
2
4.1.3.7. [5-(4-Fluorophenyl)-2-furanyl](3,4-dihydro-2(1H)-isoquinolinyl)-Methanone
1
( 4g ). white solid, yield 89.6%, m.p. 133-135 ºC. H NMR (600 MHz, DMSO-d ) δ
6
7.88-7.84 (m, 2H, ArH), 7.36-7.32 (m, 2H, ArH), 7.26-7.19 (m, 5H), 7.13 (d, J = 3.6
1
3
Hz, 1H, FuH), 4.79 (s, 2H), 3.96 (s, 2H), 2.97 (s, 2H); C NMR (151 MHz,
1
DMSO-d ) δ 162.54 (d, J = 246.2 Hz, C-4, Ph), 158.99, 158.98, 153.94, 146.99,
6
3
135.15, 133.72, 128.91, 127.05, 126.85 (d, J = 8.4 Hz, 2C, C-2, C-6, Ph), 126.69,
4
2
126.57 (d, J = 3.1 Hz, C-1, Ph), 118.46, 116.58 (d, J = 22.1 Hz, C-2, C-5, Ph),
107.57. Anal. Calcd. (%) for C H FNO : C, 74.88; H, 5.21; N, 4.28. Found: C,
2
0
16
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74.75; H, 5.02;N, 4.36.

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4.1.3.8. [5-(2-Nitrophenyl)-2-furanyl](3,4-dihydro-2(1H)-isoquinolinyl)-Methanone
1
( 4h ). yellow solid, yield 90.5%, m.p. 181-183 ºC. H NMR (600 MHz, DMSO-d ) δ
6
7.99 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.81 (td, J = 7.7, 1.1 Hz, 1H), 7.68
(t, J = 7.8 Hz, 1H), 7.28-7.14 (m, 6H), 4.81 (d, J = 102.6 Hz, 2H), 3.86 (s, 2H), 2.91
1
3
(s, 2H); C NMR (151 MHz, DMSO-d ) δ 158.27, 150.01, 149.00, 147.59, 135.01,
6
133.50, 133.30, 130.68, 130.21, 128.93, 127.05, 126.71, 124.67, 122.61, 118.45,
111.78. Anal. Calcd. (%) for C H N O : C, 69.04; H, 4.78; N, 7.91. Found: C, 68.96;
2
0
16
2
4
H, 4.63; N, 8.04.
4.1.3.9. [5-(3-Nitrophenyl)-2-furanyl](3,4-dihydro-2(1H)-isoquinolinyl)-Methanone
1
1
1
1
1
1
1
1
1
1
1
2
2
2
( 4i ). yellow solid, yield 93.5%, m.p. 189-192 ºC. H NMR (600 MHz, DMSO-d ) δ
6
8.56 (t, J = 1.8 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.22-8.20 (m, 1H), 7.79 (t, J = 8.0
Hz, 1H), 7.45 (d, J = 3.6 Hz, 1H, FuH), 7.27-7.20 (m, 5H), 4.76 (s, 2H), 3.98 (s, 2H),
1
3
2.98 (s, 2H); C NMR (151 MHz, DMSO-d ) δ 158.91, 152.37, 148.95, 147.78,
6
135.84, 135.13, 133.66, 131.34, 131.29, 130.65, 128.95, 127.11, 126.74, 123.31,
+
118.87, 118.23, 110.05. ESIMS(m/z): 349.1194 [M + H] .
4.1.3.10. [5-(4-Nitrophenyl)-2-furanyl](3,4-dihydro-2(1H)-isoquinolinyl)-Methanone
1
( 4j ). yellow solid, yield 91.1%, m.p. 198-200 ºC. H NMR (600 MHz, DMSO-d ) δ
6
8.32 (d, J = 8.9 Hz, 2H, ArH), 8.04 (d, J = 8.9 Hz, 2H, ArH), 7.46 (d, J = 3.6 Hz, 1H,
1
3
FuH), 7.27-7.20 (m, 5H), 4.75 (s, 2H), 3.96 (s, 2H), 2.97 (s, 2H); C NMR (151 MHz,
DMSO-d ) δ 158.84, 152.52, 148.58, 147.10, 135.58, 135.13, 133.60, 128.90, 127.10,
6
126.94, 126.73, 125.39 (2C), 124.96 (2C), 118.42, 111.63. Anal. Calcd. (%) for
C H N O : C, 68.72; H, 4.86; N, 8.24. Found: C, 68.96; H, 4.63; N, 8.04.
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4.1.3.11.
[5-(4-Methylphenyl)-2-furanyl](3,4-dihydro-2(1H)-isoquinolinyl)-Methanone ( 4k ).
1
white solid, yield 90.0%, m.p. 155-156 ºC. H NMR (600 MHz, DMSO-d ) δ 7.70 (d,
6
J = 8.1 Hz, 2H, ArH), 7.30 (d, J = 8.1 Hz, 2H, ArH), 7.26-7.19 (m, 4H, QuH), 7.18 (d,
J = 3.5 Hz, 1H, FuH), 7.07 (d, J = 3.6 Hz, 1H, FuH), 4.80 (s, 2H), 3.96 (s, 2H), 2.97
13
(s, 2H), 2.35 (s, 3H); C NMR (151 MHz, DMSO-d ) δ 159.05, 155.06, 146.61,
6
138.63, 135.15, 133.76, 130.08 (2C), 128.93, 127.22, 127.03, 126.88, 126.68, 124.56
(2C), 118.46, 106.96, 21.36. Anal. Calcd. (%) for C H NO : C, 79.62; H, 5.89; N,
21
19
2
4.56. Found: C, 79.47; H, 6.03; N, 4.41.
1
1
1
1
1
1
1
1
1
1
2
2
2
4.1.3.12.
[5-(4-Bromophenyl)-2-furanyl](3,4-dihydro-2(1H)-isoquinolinyl)-Methanone ( 4l ).
1
yellow solid, yield 88.1%, m.p. 188-189 ºC. H NMR (600 MHz, DMSO-d ) δ 7.76 (d,
6
J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.28-7.14 (m, 6H), 4.76 (s, 2H), 3.99 (s, 2H),
13
2.97 (s, 2H); C NMR (151 MHz, DMSO-d ) δ 158.97, 153.72, 147.27 (s), 135.16,
6
133.71, 132.51 (2C), 129.07, 128.92, 127.08, 126.93, 126.72, 126.55 (2C), 122.09,
118.42, 108.49. Anal. Calcd. (%) for C H BrNO : C, 62.98; H, 4.05; N, 3.51. Found:
2
0
16
2
C, 62.84; H, 4.22; N, 3.66.
4.1.3.13.
[5-(4-Methoxyphenyl)-2-furanyl](3,4-dihydro-2(1H)-isoquinolinyl)-Methanone ( 4m ).
1
white solid, yield 93.2%, m.p. 136-138 ºC. H NMR (600 MHz, DMSO-d ) δ 7.74 (d,
6
J = 8.7 Hz, 2H), 7.27-7.19 (m, 4H), 7.17 (d, J = 3.4 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H),
1
3
6.99 (d, J = 3.5 Hz, 1H), 4.79 (s, 2H), 3.95 (s, 2H), 3.81 (s, 3H), 2.97 (s, 2H); C

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NMR (151 MHz, DMSO-d ) δ 160.03, 159.07, 155.08, 146.29, 135.16, 133.79,
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128.93, 127.03, 126.89, 126.69, 126.21 (2C), 122.68, 118.63, 115.00 (2C), 106.02,
55.74. Anal. Calcd. (%) for C H NO : C, 75.79; H, 5.94; N, 4.02. Found: C, 75.66;
2
1
19
3
H, 5.74; N, 4.20.
4.1.3.14.
[5-(2',4'-di-Fluorophenyl)-2-furanyl](3,4-dihydro-2(1H)-isoquinolinyl)-Methanone
1
( 4n ). white solid, yield 90.1%, m.p. 129-131 ºC. H NMR (600 MHz, DMSO-d ) δ
6
7.91 (dd, J = 15.3, 8.7 Hz, 1H), 7.46 (ddd, J = 11.6, 9.3, 2.5 Hz, 1H), 7.28-7.21 (m,
1
3
6H), 6.98 (t, J = 3.3 Hz, 1H), 4.78 (s, 2H), 3.98 (s, 2H), 2.97 (s, 2H); C NMR (151
1
3
1
1
1
1
1
1
1
1
1
1
1
2
2
2
MHz, DMSO-d ) δ 162.43 (dd, J = 249.1, J = 12.2 Hz, C-4, Ph), 158.96 (dd, J =
6
3
4
253.1, J = 12.5 Hz, C-2, Ph), 158.82 (C=O), 148.31 (d, J = 2.4 Hz, C-4, Ph), 147.16,
3
3
135.12, 133.66, 128.91, 128.37 (dd, J = 10.0, J = 4.2 Hz, C-6, Ph), 127.06, 126.91,
2
4
2
4
126.70, 118.24, 114.81 (dd, J = 12.1, J = 3.8 Hz, C-1, Ph), 113.02 (dd, J = 21.9, J
3
2
2
= 3.5 Hz, C-5, Ph), 111.17 (d, J = 9.8, C-5, Fu), 105.54 (dd, J = 26.0 Hz, J = 26.0
Hz, C-3, Ph). Anal. Calcd. (%) for C H F NO : C, 70.95; H, 4.59; N, 3.96. Found: C,
2
0
15
2
2
70.79; H, 4.46; N, 4.13.
4.1.3.15.
[5-(2',6'-di-Fluorophenyl)-2-furanyl](3,4-dihydro-2(1H)-isoquinolinyl)-Methanone
1
( 4o ). white solid, yield 85.2%, m.p. 120-122 ºC. H NMR (600 MHz, DMSO-d ) δ
6
7.53 (dq, J = 8.3, 6.4 Hz, 1H), 7.34-7.12 (m, 7H), 7.04 (dd, J = 3.4, 1.6 Hz, 1H), 4.91
1
3
(d, J = 179.6 Hz, 2H), 4.01 (s, 2H), 2.96 (s, 2H); C NMR (151 MHz, DMSO-d ) δ
6
1
3
159.22 (2C, dd, J = 252.4, J = 6.5 Hz, C-2, C-6, Ph), 158.59 (C=O), 148.11, 144.20,

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135.00, 133.62, 131.38 (dd, J = 10.7 Hz, J = 10.7 Hz, C-4, Ph), 128.98, 127.03,
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126.94, 126.70, 117.91, 114.32 (dd, J = 5.5 Hz, J = 5.5 Hz, C-5, Fu), 113.10 (2C, dd,
2
4
2
2
J = 21.5, J = 3.9 Hz, C-3, C-5, Ph), 107.87 (dd, J = 16.0 Hz, J = 16.0 Hz, C-1, Ph).
Anal. Calcd. (%) for C H F NO : C, 70.92; H, 4.31; N, 4.35. Found: C, 70.79; H,
2
0
15
2
2
4.46; N, 4.13.
4.1.3.16.
(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(5-phenyl-2-furyl)methanone ( 5a ).
1
white solid, yield 90.3%, m.p. 112-114 ºC. H NMR (400 MHz, DMSO-d ) δ 7.81 (d,
6
J = 7.9 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H), 7.16 (dd, J = 14.4,
3.5 Hz, 2H), 6.86 (s, 1H), 6.79 (s, 1H), 4.74 (s, 2H), 3.92 (s, 2H), 3.73 (d, J = 4.2 Hz,
1
1
1
1
1
1
1
1
1
1
2
2
2
1
3
6H), 2.89 (s, 2H); C NMR (101 MHz, DMSO-d ) δ 159.01, 154.72, 147.94, 147.86,
6
147.01, 129.88, 129.54, 129.02, 126.66, 125.34, 124.57, 118.28, 112.34, 110.41,
107.70, 56.01, 55.97. Anal. Calcd. (%) for C H NO : C, 72.89; H, 5.62; N, 3.64.
2
2
21
4
Found: C, 72.71; H, 5.82; N, 3.85.
4.1.3.17.
(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(5-(2-chlorophenyl)-2-furyl)methan
one ( 5b ).
1
white solid, yield 88.1%, m.p. 133-134 ºC. H NMR (400 MHz, DMSO-d ) δ 7.89 (d,
6
J = 7.7 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz,
1H), 7.24 (dd, J = 11.1, 3.5 Hz, 2H), 6.85 (s, 1H), 6.79 (s, 1H), 4.70 (s, 2H), 3.95 (s,
1
3
2H), 3.73 (d, J = 3.8 Hz, 6H), 2.87 (s, 2H); C NMR (101 MHz, DMSO-d ) δ 158.83,
6
151.02, 147.95, 147.86, 147.33, 131.35, 130.43, 130.18, 129.09, 128.28, 128.14,

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126.63, 125.22, 117.82, 112.56, 112.32, 110.38, 56.00, 55.96. Anal. Calcd. (%) for
C H ClNO : C,66.69; H, 5.31; N, 3.38. Found: C, 66.42; H, 5.07; N, 3.52.
22
20
4
4.1.3.18.
(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(5-(3-chlorophenyl)-2-furyl)methan
one ( 5c ).
1
white solid, yield 93.3%, m.p. 138-140 ºC. H NMR (400 MHz, DMSO-d ) δ 7.86 (s,
6
1H), 7.77 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.28
(d, J = 3.5 Hz, 1H), 7.19 (d, J = 3.4 Hz, 1H), 6.85 (s, 1H), 6.79 (s, 1H), 4.71 (s, 2H),
13
3.91 (s, 2H), 3.73 (d, J = 4.7 Hz, 6H), 2.87 (s, 2H); C NMR (101 MHz, DMSO-d ) δ
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1
1
1
1
1
1
1
1
1
2
2
2
158.90, 153.07, 147.95, 147.86, 147.46, 134.37, 131.84, 131.51, 128.70, 126.64,
125.27, 124.18, 123.07, 118.15, 112.33, 110.38, 109.11, 56.01, 55.98. Anal. Calcd. (%)
for C H ClNO : C,66.70; H, 4.82; N, 3.76. Found: C, 66.42; H, 5.07; N, 3.52.
2
2
20
4
4.1.3.19.
(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(5-(4-chlorophenyl)-2-furyl)methan
one ( 5d ).
1
white solid, yield 94.9%, m.p. 139-142 ºC. H NMR (400 MHz, DMSO-d ) δ 7.82 (d,
6
J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.19 (dd, J = 3.4 Hz, 3.4 Hz, 2H), 6.85 (s,
1
3
1H), 6.79 (s, 1H), 4.72 (s, 2H), 3.90 (s, 2H), 3.73 (d, J = 4.6 Hz, 6H), 2.87 (s, 2H); C
NMR (101 MHz, DMSO-d ) δ 158.93, 153.59, 147.95, 147.86, 147.24, 133.43,
6
129.61, 128.74, 126.66, 126.30, 125.28, 118.26, 112.31, 110.44, 108.41, 56.01, 55.97.
Anal. Calcd. (%) for C H ClNO : C,66.18; H, 5.36; N, 3.80. Found: C, 66.42; H,
2
2
20
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4.1.3.20.
(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(5-(2-fluorophenyl)-2-furyl)methan
one ( 5e ).
1
white solid, yield 83.3%, m.p. 115-118 ºC. H NMR (400 MHz, DMSO-d ) δ 7.87 (t,
6
J = 7.8 Hz, 1H), 7.46 (dd, J = 13.3, 7.3 Hz, 1H), 7.41 – 7.34 (m, 2H), 7.22 (d, J = 3.4
Hz, 1H), 7.01 (t, J = 3.2 Hz, 1H), 6.86 (s, 1H), 6.79 (s, 1H), 4.72 (s, 2H), 3.95 (s, 2H),
1
3
3.74 (d, J = 3.9 Hz, 6H), 2.89 (s, 2H); C NMR (101 MHz, DMSO-d ) δ 158.84,
6
1
3
158.75 (d, J = 250.2 Hz, C-2, Ph), 148.91 (d, J = 2.7 Hz, C-5, Fu), 147.96, 147.86,
3
147.17, 130.77 (d, J = 8.5 Hz, C-4, Ph), 126.90, 126.88, 126.64, 125.64 (d, J = 3.3
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
Hz, C-5, Ph), 125.25, 118.12, 117.83 (d, J = 11.8 Hz, C-1, Ph), 116.87 (d, J = 21.1
3
Hz, C-3, Ph), 112.31, 111.69 (d, J = 10.4 Hz, C-6, Ph), 56.00, 55.96. Anal. Calcd. (%)
for C H FNO : C,66.99; H, 5.01; N, 3.89. Found: C, 69.28; H, 5.29; N, 3.67.
2
2
20
4
4.1.3.21.
(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(5-(3-fluorophenyl)-2-furyl)methan
one ( 5f ).
1
white solid, yield 88.4%, m.p. 125-126 ºC. H NMR (400 MHz, DMSO-d ) δ 7.64 (t,
6
J = 8.5 Hz, 2H), 7.54 (dd, J = 14.7, 7.3 Hz, 1H), 7.29 – 7.18 (m, 3H), 6.86 (s, 1H),
1
3
6.80 (s, 1H), 4.71 (s, 2H), 3.92 (s, 2H), 3.73 (d, J = 4.2 Hz, 6H), 2.89 (s, 2H); C
1
NMR (101 MHz, DMSO-d ) δ 163.03 (d, J = 243.5 Hz, C-3, Ph), 158.89, 153.36 (d,
6
4
3
J = 3.0 Hz, C-5, Fu), 147.95, 147.86, 147.42, 132.06 (d, J = 8.7 Hz, C-1, Ph),
3
4
131.73 (d, J = 8.6 Hz, C-5, Ph), 126.65, 125.28, 120.61 (d, J = 2.3 Hz, C-6, Ph),
2
2
118.20, 115.71 (d, J = 21.2 Hz, C-2, Ph), 112.32, 111.28 (d, J = 23.7 Hz, C-4, Ph),

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110.40, 109.00, 55.99, 55.96. Anal. Calcd. (%) for C H FNO : C, 69.56; H, 5.45; N,
22
20
4
3.33. Found: C, 69.28; H, 5.29; N, 3.67.
4.1.3.22.
(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(5-(4-fluorophenyl)-2-furyl)methan
one ( 5g ).
1
white solid, yield 91.8%, m.p. 130-132 ºC. H NMR (400 MHz, DMSO-d ) δ 7.85 (dd,
6
J = 7.8, 5.8 Hz, 2H), 7.34 (t, J = 8.6 Hz, 2H), 7.17 (d, J = 3.4 Hz, 1H), 7.13 (d, J = 3.4
Hz, 1H), 6.85 (s, 1H), 6.79 (s, 1H), 4.74 (s, 2H), 3.90 (s, 6H), 3.73 (d, J = 4.5 Hz, 2H),
13
1
2.87 (s, 2H); C NMR (101 MHz, DMSO-d ) δ 162.54 (d, J = 246.2 Hz, C-4, Ph),
6
3
1
1
1
1
1
1
1
1
1
1
2
2
2
158.98, 153.88, 147.94, 147.86, 147.00, 126.84 (d, J = 8.3 Hz, 2C, C-2, C-6, Ph),
4
2
126.67, 126.60 (d, J = 3.1 Hz, C-1, Ph), 125.32, 118.31, 116.60 (d, J = 22.0 Hz, 2C,
C-3, C-5, Ph), 112.32, 110.42, 107.58, 56.02, 55.97. Anal. Calcd. (%) for C H FNO :
2
2
20
4
C, 68.99; H, 4.98; N, 3.92. Found: C, 69.28; H, 5.29; N, 3.67.
4.1.3.23.
(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(5-(2-nitrophenyl)-2-furyl)methano
ne ( 5h ).
1
yellow solid, yield 92.8%, m.p. 158-161 ºC. H NMR (400 MHz, DMSO-d ) δ 7.99
6
(d, J = 7.9 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 7.8
Hz, 1H), 7.25 (d, J = 1.8 Hz, 1H), 7.14 (d, J = 3.4 Hz, 1H), 6.85 (s, 1H), 6.78 (s, 1H),
1
3
4.73 (d, J = 60.2 Hz, 2H), 3.83 (s, 2H), 3.74 (s, 6H), 2.82 (s, 2H); C NMR (101
MHz, DMSO-d ) δ 158.40, 150.01, 149.02, 147.97, 147.87, 147.57, 133.32, 130.66,
6
130.23, 126.58, 125.05, 124.71, 122.65, 118.44, 112.28, 111.76, 110.46, 55.95 (2C,

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CH O-). Anal. Calcd. (%) for C H N O : C, 64.97; H, 5.12; N, 6.53. Found: C,
3
22 20
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6
64.70; H, 4.94; N, 6.86.
4.1.3.24.
(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(5-(3-nitrophenyl)-2-furyl)methano
ne ( 5i ).
1
yellow solid, yield 93.1%, m.p. 163-167 ºC. H NMR (400 MHz, DMSO-d ) δ 8.55 (s,
6
1H), 8.22 (dd, J = 13.2, 8.1 Hz, 2H), 7.78 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 3.5 Hz, 1H),
7.24 (d, J = 3.3 Hz, 1H), 6.99 – 6.64 (m, 2H), 4.52 (s, 2H), 3.91 (s, 2H), 3.73 (d, J =
1
3
5.2 Hz, 6H), 2.82 (s, 2H); C NMR (101 MHz, DMSO-d ) δ 158.82, 152.31, 148.90,
6
1
1
1
1
1
1
1
1
1
1
2
2
2
147.96, 147.88, 147.78, 131.32, 131.25, 130.62, 126.61, 125.19, 123.28, 118.83,
118.12, 112.30, 110.38, 110.02, 55.98, 55.97. Anal. Calcd. (%) for C H N O : C,
2
2
20
2
6
64.41; H, 4.65; N, 7.02. Found: C, 64.70; H, 4.94; N, 6.86.
4.1.3.25.
(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(5-(4-nitrophenyl)-2-furyl)methano
ne ( 5j ).
1
yellow solid, yield 91.7%, m.p. 179-181 ºC. H NMR (400 MHz, DMSO-d ) δ 8.33
6
(d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 3.4 Hz, 1H), 7.25 (d, J = 3.3
Hz, 1H), 6.86 (s, 1H), 6.79 (s, 1H), 4.71 (s, 2H), 3.89 (s, 2H), 3.73 (d, J = 5.4 Hz, 6H),
1
3
2.89 (s, 2H); C NMR (101 MHz, DMSO-d ) δ 158.81, 152.45, 148.58, 147.97,
6
147.87, 147.08, 135.60, 126.64, 125.38 (2C), 125.16, 124.97 (2C), 118.25, 112.29,
111.63, 110.43, 56.02, 55.97. Anal. Calcd. (%) for C H N O : C, 64.92; H, 5.22; N,
22
20
2
6
6.60. Found: C, 64.70; H, 4.94; N, 6.86.

ACCEPTED MANUSCRIPT
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4.1.3.26.
(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(5-(p-tolyl)-2-furyl)methanone
( 5k ):
1
white solid, yield 96.8%, m.p. 143-144 ºC. H NMR (400 MHz, DMSO-d ) δ 7.69 (d,
6
J = 7.9 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 3.5 Hz, 1H), 7.06 (d, J = 3.5 Hz,
1H), 6.85 (s, 1H), 6.79 (s, 1H), 4.75 (s, 2H), 3.91 (s, 2H), 3.73 (d, J = 3.9 Hz, 6H),
13
2.87 (s, 2H), 2.34 (s, 3H); C NMR (101 MHz, DMSO-d ) δ 159.03, 155.00, 147.94,
6
147.86, 146.62, 138.63, 130.08 (2C), 127.24, 126.66, 125.35, 124.55 (2C), 118.32,
112.33, 110.39, 106.94, 56.00, 55.95, 21.36. Anal. Calcd. (%) for C H NO : C,
2
3
23
4
1
1
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72.91; H, 5.98; N, 3.58. Found: C, 73.19; H, 6.14; N, 3.71.
4.1.3.27.
(
6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(5-(4-bromophenyl)-2-furyl)methan
one ( 5l ).
1
yellow solid, yield 82.3%, m.p. 168-171 ºC. H NMR (400 MHz, DMSO-d ) δ 7.76
6
(d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 3.4 Hz, 1H), 7.18 (d, J = 3.3
Hz, 1H), 6.85 (s, 1H), 6.78 (s, 1H), 4.73 (s, 2H), 3.91 (s, 2H), 3.73 (d, J = 4.7 Hz, 6H),
1
3
2.87 (s, 2H); C NMR (101 MHz, DMSO-d ) δ 158.94, 153.63, 147.95, 147.86,
6
147.25, 132.50 (2C), 129.07, 126.66, 126.53 (2C), 125.27, 122.06, 118.25, 112.31,
110.41, 108.48, 56.01, 55.97. Anal. Calcd. (%) for C H BrNO : C, 59.55; H, 4.31;
2
2
20
4
N, 3.38. Found: C, 59.74; H, 4.56; N, 3.17.
4.1.3.28.
(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(5-(4-methoxyphenyl)-2-furyl)meth