New quinoline-triazole conjugates: Synthesis, and antiviral properties against SARS-CoV-2

Article abstract of DOI:10.1016/j.bioorg.2021.105117

At present therapeutic options for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are very limited. We designed and synthesized three sets of small molecules using quinoline scaffolds. A series of quinoline conjugates (10a-l, 11a-c, and 12a-

Full text of DOI:10.1016/j.bioorg.2021.105117

Bioorganic Chemistry 114 (2021) 105117
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
New quinoline-triazole conjugates: Synthesis, and antiviral properties
against SARS-CoV-2
,
,
Israa A. Seliema b, Siva S. Pandaa *, Adel S. Girgisc, Yassmin Moatasimd, Ahmed Kandeild,
Ahmed Mostafad, Mohamed A. Alid, Eman S. Nossiere, Fatma Rasslanf, Aladdin M. Srourg,
Rajeev Sakhujah, Tarek S. Ibrahimi b, Zakaria K.M. Abdel-samiib, Amany M.M. Al-Mahmoudyb
,
a Department of Chemistry and Physics, Augusta University, Augusta, GA 30912, USA
b Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
c Department of Pesticide Chemistry, National Research Centre, Dokki, Giza 12622, Egypt
d Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza 12622, Egypt
e Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
f Department of Microbiology and Immunology, Faculty of Pharmacy (Girls), Al Azhar University, Cairo, Egypt
g Department of Therapeutic Chemistry, National Research Centre, Dokki, Giza 12622, Egypt
h Department of Chemistry, Birla Institute of Technology and Science, Pilani, India
i Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
A R T I C L E I N F O
A B S T R A C T
Keywords:
At present therapeutic options for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are very
limited. We designed and synthesized three sets of small molecules using quinoline scaffolds. A series of quin-
oline conjugates (10a-l, 11a-c, and 12a-e) by incorporating 1,2,3-triazole were synthesized via a modified
microwave-assisted click chemistry technique. Among the synthesized conjugates, 4-((1-(2-chlorophenyl)-1H-
Quinoline
Triazole
Click chemistry
SARS-CoV-2
Molecular docking
1,2,3-triazol-4-yl)methoxy)-6-fluoro-2-(trifluoromethyl)quinoline
(10g)
and
6-fluoro-4-(2-(1-(4-methox-
yphenyl)-1H-1,2,3-triazol-4-yl)ethoxy)-2-(trifluoromethyl)quinoline (12c) show high potency against SARS-CoV-
2. The selectivity index (SI) of compounds 10g and 12c also indicates the significant efficacy compared to the
reference drugs.
1. Introduction:
considered for repurposing to control the COVID-19 pandemic include
chloroquine (CQ) and hydroxychloroquine (HCQ) (Fig. 1). These
In December 2019, an unknown viral infection was identified in a
local fish and wild animal market of Wuhan city (China) [1]. Since then,
the virus has rapidly spread across mainland China followed by the rest
of the world [2,3]. On Feb 11, 2020, the WHO identified the virus as the
severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The
viral infection disease is called as 2019-new coronavirus disease
(COVID-19), and in March 2020 declared the coronavirus outbreak a
global pandemic [4]. As of April 2021, COVID-19 has affected more than
152 million people with 3.18 million deaths worldwide.
exhibited promising responses accompanied with serious side effects
(ventricular arrhythmias, retinopathy, QT prolongation, or cardiac-
related toxicity) [5–11]. Recently, a few quinolone-based small mole-
cules reported their antiviral properties against SARS-CoV-2 [12–20].
New drug development is expensive, time-consuming, and chal-
lenging processes. In the current scenario, molecular hybridization of
bioactive moieties is a powerful and attractive rational drug design
strategy for new drug development because of several advantages such
as a) to achieve selectivity; b) gain desired activity; c) multiple phar-
macological targets; d) lower possible cytotoxicity. Our group has
actively engaged in developing drug conjugates and hybrid conjugates
by this approach [21–26].
As of now, there is no potential antiviral drug available for the
treatment of COVID-19. However, a few vaccines have received
approval from FDA to control the pandemic. The drug repurposing
approach was considered the most accessible pathway for exploring
drugs to control the global pandemic. Several drugs that were
In the present study, we have designed and synthesized a set of novel
quinoline-triazole conjugates with potential antiviral properties against
* Corresponding author.
E-mail address: sipanda@augusta.edu (S.S. Panda).
https://doi.org/10.1016/j.bioorg.2021.105117
Received 7 April 2021; Received in revised form 8 May 2021; Accepted 19 June 2021
Available online 23 June 2021
0045-2068/© 2021 Elsevier Inc. All rights reserved.

I.A. Seliem et al.
Bioorganic Chemistry 114 (2021) 105117
SARS-CoV-2 using the ‘click’ chemistry approach employing various
azides and the alkyne component of the propargyl linked quinolines. We
considered the quinoline scaffold from the repurposed drugs (chloro-
quine and hydroxychloroquine) and triazole because of their importance
in the drug development process and well-known for diversified bio-
logical properties [27–31]. Besides, the presence of electronegative
fluorine atoms may alter the physicochemical properties of the molecule
significantly. This may improve the stability, reducing the cytotoxicity,
in addition to enhancing the overall therapeutic efficacy in our designed
molecules [32].
reactions do work at room temperature but never go to completion even
after 3 days. Our optimized reaction condition able to complete the re-
action in 2 h. All the synthesized compounds were fully characterized by
spectroscopic techniques.
2.3. Antiviral properties
The antiviral properties of the synthesized conjugates (10, 11, and
12) against SARS-CoV-2 were determined by the standard technique
[35–37]. Table 1 exhibits the antiviral properties of the tested com-
pounds and standard references (CQ, HCQ) used expressed as IC50
(concentration necessary for 50% reduction of virus-induced cytopathic
effect (CPE) compared to the virus control experiment). We have also
determined the CC50 (concentration necessary for 50% growth normal
cell line “VERO-E6” inhibition compared to the control experiment) for
all the synthesized conjugates (Fig. 3). We calculated the selectivity
(therapeutical) index (SI), which is the ratio of CC50 relative to IC50 of
the tested conjugate. From the observed biological properties (Table 1),
it has been noticed that conjugate 10g is superior among all the tested
agents revealing potent antiviral inhibition with high selectivity index
relative to the standard references used (IC50 = 0.060, 0.0227, 0.0328
mM; CC50 = 1.585, 0.3777, 0.356 mM, SI = 26.42, 16.64, 10.85; cor-
responding to 10g, CQ and HCQ, respectively). Conjugate 12c also re-
veals enhanced selectivity index relative to the standard references used
with milder antiviral potency (IC50 = 0.204, CC50 = 3.493 mM, SI =
17.12). Additionally, compounds 10i, 11a, 11c, 12a, and 12e also show
promising biological properties with a considerable selectivity index (SI
= 4.51–3.15).
2. Results and discussion
The synthetic protocol was developed for the synthesis of the tar-
geted quinoline-triazole conjugates (Fig. 2) by adopting the well-
established Cu-mediated click chemistry of alkynes 5, 6, and 8 with
varied azides 10. The precursor alkynes 5, 6, and 8 were synthesized by
treating a solution of 6-(un)substituted-2-(trifluoromethyl)quinolin-4
(1H)-ones 3 in DMF with propargyl bromide (4) or 4-bromobut-1-yne
(7) in the presence of potassium carbonate (K2CO3) at room tempera-
ture [33]. (Scheme 1). The azides of aromatic amines 1b–f were syn-
thesized using the previously reported method [25].
2.1. Synthesis of alkynes 5, 6, and 8
A solution of compounds 3a–d in DMF on reaction with propargyl
bromide (4) or 4-bromobut-1-yne (7) in the presence of potassium car-
bonate (K2CO3) at 20 ◦C for 6 h gave predominately O-substituted
quinolines. However, in the case of 3a and 3c on treatment with prop-
argyl bromide 4, we got both N-substituted quinolones and O-
substituted quinolines in a good ratio, which were isolated by column
chromatography (5a,b, and 6a,b). We also observed the formation of N-
substituted quinolones as a minor product when we treated 4-bromobut-
1-yne (7) with 3a–d. The formation of O-substituted quinolones is move
favored over N-substituted quinolines because of the steric and elec-
tronic properties of the CF3 group. The detailed investigation was re-
Some qualitative structure–activity relationship could be assigned
based on observed antiviral properties. The fluoroquinolinyl conjugates
show enhanced antiviral properties than the unsubstituted conjugates as
exhibited in pairs 10f/10b (IC50 = 2.648, 8.466 mM), 10g/10d (IC50
=
0.060, 0.768 mM), 10h/10e (IC50 = 4.471, 85.576 mM) and 12c/12a
(IC50 = 0.204, 0.7678 mM). Probably the fluorine atoms play important
role in enhancing the antiviral properties. Moreover, the o-chlorophenyl
triazolyl conjugates reveal higher antiviral properties than the o-
methoxyphenyl analogues as shown in pairs 10d/10e (IC50 = 0.768,
85.576 mM) and 10g/10h (IC50 = 0.060, 4.471 mM). Additionally,
molecular modeling can estimate the parameters/functional groups
necessary for optimizing antiviral properties.
´
´
ported by Raic-Malic and coworkers [34].
2.2. Synthesis of triazole-quinoline conjugates
Alkynes 5, 6, and 8 were treated with aromatic azides 9 adopting a
modified click chemical technique in presence of CuSO4⋅5H2O and so-
dium D-isoascorbate in n-butanol–water mixture under microwave
2.4. Molecular docking study
◦
irradiation for 2 h at 100 C to afford the desired corresponding con-
Molecular docking is one of the most important computational
techniques widely accessible in medicinal chemical studies for many
jugates 10a–l, 11a–c and 12a–e in good yields (Scheme 2). The
Fig. 1. Examples of repurposing drugs for COVID-19.
2

I.A. Seliem et al.
Bioorganic Chemistry 114 (2021) 105117
Fig. 2. Designing of quinoline-triazole conjugates.
Scheme 1. Synthesis of alkynes 5, 6, and 8.
2.5. Conclusion
purposes of which, determining/predicting the mode of action of an
agent and explaining the observed bio-properties. The tested compounds
against SARS-CoV-2 were subjected for molecular docking study utiliz-
ing PDB ID: 6LU7 “SARS-CoV-2 main protease (Mpro) with an inhibitor
N3” [38,39]. Discovery Studio 2.5 software was used (CDOCKER, force
field: CHARMm, ligand partial charge method: MMFF).
In conclusion, we have synthesized three sets of triazole incorporated
quinolone conjugates in good yields by an optimized facile reaction
condition. Some conjugates showed promising antiviral activity against
SARS-CoV-2. Compound 10g and 12c found the most effective agents
for the SARS-CoV-2. The selectivity index (SI) of compounds also in-
dicates significant efficacy compared to the reference drugs. We believe
the initial investigation and the important scaffold could be further used
as resources for the development of potential drug candidates for SARS-
CoV-2.
From the docking observations (Supplementary Figs. S1 and S2), it
has been noticed that chloroquine and hydroxychloroquine show
hydrogen bonding due to the diethylamino nitrogen interaction with
GLU166 (which is one of the amino acids revealing interaction with the
co-crystallized ligand “N3 inhibitor” in the PDB: 6LU7), and docking
scores ꢀ 46.2, ꢀ 42.3 kcal molꢀ 1 for chloroquine and hydroxy-
chloroquine, respectively. These observations are comparable to their
antiviral properties observed (IC50 = 0.0227, 0.0328 mM, respectively).
Compounds 10g and 12c, which are the most effective antiviral agents
synthesized (IC50 = 0.060, 0.204 mM, respectively) reveal behavior due
to hydrogen bonding observation. Where the triazolyl nitrogen has
hydrogen bonding interaction with the same amino acid (GLU166).
Additionally, the promising agents synthesized 10d, 10i, 12a and 12e
(IC50 = 0.768, 0.331, 0.7678, 0.930 mM, respectively) also exhibit
similar docking observations. However, other analogs show good
docking scores due to false alignment in the protein active site “inter-
action with amino acid(s) other than those overlapped with the co-
crystallized ligand”. These findings support the experimentally
observed weak antiviral properties (e.g. compounds 10c and 10e of IC50
= 113.5, 85.6 mM and docking scores = -37.9, ꢀ 38.5 kcal/mol,
respectively).
3. Experimental section
3.1. Chemistry
Melting points were determined on a capillary point apparatus
equipped with a digital thermometer. NMR spectra were recorded in
CDCl3, DMSO‑d6, on Bruker NMR spectrometer operating at 500 MHz
for 1H (with TMS as an internal standard) and 125 MHz for 13C. High-
resolution mass spectra were recorded with TOF analyzer spectrom-
eter by using electron spray mode. All microwave-assisted reactions
were carried out with a single-mode cavity Discover Microwave Syn-
thesizer (CEM Corporation, NC). The reaction mixtures were transferred
into a 10 mL glass pressure microwave tube equipped with a magnetic
stirrer bar. The tube was closed with a silicon septum and the reaction
mixture was subjected to microwave irradiation (Discover mode; run
3

I.A. Seliem et al.
Bioorganic Chemistry 114 (2021) 105117
Scheme 2. Triazole-quinoline conjugates 10a-l, 11a-c, 12a-e.
Table 1
Antiviral properties of the quinine-triazole conjugates 10, 11, and 12 against SARS-CoV-2.
Entry
Compound
R1
R2
R3
IC50 (mM)a
CC50 (mM)b
SIc
1
10a
10b
10c
10d
10e
10f
H
H
F
0.531
8.466
113.504
0.768
85.576
2.648
0.060
4.471
0.331
nd
2.676
4.114
3.104
2.192
2.183
4.524
1.585
3.408
1.494
nd
5.04
0.49
0.03
2.85
0.03
1.71
26.42
0.76
4.51
nd
2
H
H
CH3
OCH3
H
3
H
H
4
H
Cl
5
H
OCH3
H
H
6
F
CH3
H
7
10g
10h
10i
F
Cl
8
F
OCH3
Cl
H
9
CH3
CH3
OCH3
OCH3
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
10j
OCH3
H
H
10k
10l
F
3.106
1.607
1.310
nd
4.170
1.050
4.831
nd
1.34
0.65
3.69
nd
H
CH3
OCH3
H
11a
11b
11c
12a
12b
12c
12d
12e
CQ
H
H
OCH3
H
CH3
H
OCH3
OCH3
F
0.5265
0.7678
6.609
0.204
0.860
0.930
0.0227
0.0328
1.659
2.960
3.650
3.493
0.982
2.964
0.3777
0.356
3.15
3.86
0.55
17.12
1.14
3.19
16.64
10.85
H
F
H
F
H
OCH3
H
F
OCH3
H
CH3
OCH3
HCQ
nd: not done.
a
IC50: Concentration necessary for 50% reduction of virus-induced cytopathic effect (CPE) compared to the virus control experiment.
b
CC50: Half maximal cytotoxic concentration for the normal cell line (VERO-E6) inhibition compared to the control experiment.
CC50
c
SI (Selectivity index/therapeutical index):
.
IC50
time: 60 s; Power Max-cooling mode).
3.1.1. General procedure for the synthesis of O-alkynyl-oxyquinolines 5a-
d and N-alkynyl-oxyquinolines 6a,c [26,33]
To a suspension of corresponding quinolone 3a–d (1 equiv.) in N, N-
dimethylformamide (DMF; 10 mL), K2CO3 (1.5 equiv.) was added. After
4

I.A. Seliem et al.
Bioorganic Chemistry 114 (2021) 105117
Fig. 3. Dose-response curves for the tested compounds against SARS-CoV-2.
stirring for 30 min, propargyl bromide 4 (1 equiv.) was added and the
reaction mixture was stirred for 6 h. The solvent was removed under
reduced pressure and the crude residue was purified by column chro-
matography. These compounds were characterized by comparing their
spectroscopic data to the reported ones [26,33].
with water then extracted with EtOAc and the combined organic layer
was dried over sodium sulfate, concentrated in a vacuum, and purified
through column chromatography to give the pure quinoline-triazole
derivatives in good yields.
3.1.3.1. 4-((1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(tri-
fluoromethyl)quinoline (10a). White microcrystals, m.p. 173–175 ◦C,
yield 46% (0.28 g). IR: νmax/cmꢀ 1 3052, 2923, 1574, 1515, 1378, 1233,
831, 763; 1H NMR (CDCl3) δ: 8.22 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.5
Hz, 1H), 8.10 (s, 1H), 7.81–7.75 (m, 1H), 7.73 (dd, J = 9.0, 4.6 Hz, 2H),
7.59 (t, J = 7.6 Hz, 1H), 7.28 (s, 1H), 7.24 (t, J = 4.0 Hz, 1H), 7.21 (s,
1H), 5.56 (s, 2H). 13C NMR (CDCl3) δ: 163.9, 162.5, 161.9, 149.4, 149.1,
148.4, 143.3, 133.3, 131.3, 129.9, 127.9, 123.0, 122.9, 122.1, 121.8,
117.2, 117.0, 97.4, 62.7. HRMS m/z for C19H12F4N4O [M+H]+ Calcd.
389.1020. Found: 389.1013.
3.1.2. General procedure for the synthesis of synthesis O-alkynyl-quinolines
8a-c [33]
To a suspension of corresponding quinolone 3a–d (1 equiv.) in N, N-
dimethylformamide (DMF; 10 mL), K2CO3 (1.5 equiv.) was added. After
stirring for 30 min, 4-bromobut-1-yne 7 (1 equiv.) was added and the
reaction mixture was subjected to microwave irradiations for 6 h. The
crude mixture was diluted with water than solid formed filtered off and
crystallized from ethanol. These compounds were characterized by
comparing their spectroscopic data to the reported ones [28].
3.1.3. General procedure for the synthesis of quinoline-triazole conjugates
To a solution of quinoline (1 equiv.) in n-butanol/H2O (2: 1) (3 mL),
CuSO4 (0.05 equiv.), and sodium D-isoascorbate monohydrate
(0.15 equiv.) was added at room temperature. To this mixture, aryl
azide (1.5 mmol) was added and the reaction mixture was subjected to
microwave irradiations at 250 W for 2 h. The crude mixture was diluted
3.1.3.2. 4-((1-(p-Tolyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(tri-
fluoromethyl)quinoline (10b). White microcrystals, m.p. 172–174 ◦C,
yield 54% (0.32 g). IR: νmax/cmꢀ 1 3050, 2930, 1575, 1514, 1372, 1252,
817, 770; 1H NMR (CDCl3) δ: 8.23 (d, J = 8.3 Hz, 1H), 8.15–8.10 (m,
2H), 7.77 (t, J = 7.7 Hz, 1H), 7.64–7.54 (m, 3H), 7.32 (d, J = 8.1 Hz,
2H), 7.28 (s, 1H), 5.55 (s, 2H), 2.41 (s, 3H).13C NMR (CDCl3) δ: 162.2,
5

I.A. Seliem et al.
Bioorganic Chemistry 114 (2021) 105117
149.3, 149.1, 148.4, 139.6, 134.7, 133.0, 131.3, 130.6, 129.8, 127.9,
125.6, 122.8, 122.1, 121.8, 120.8, 120.6, 97.4, 62.8, 21.3. HRMS m/z
for C20H15F3N4O [M+H]+ Calcd. 385.1271. Found: 385.1278.
125.9, 125.5, 121.5, 121.3, 112.5, 106.1, 97.9, 62.9, 56.2. HRMS m/z
for C20H14F4N4O2 [M+H]+ Calcd. 419.1126. Found: 419.1123.
3.1.3.9. 4-((1-(2-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-6-
methyl-2-(trifluoromethyl)quinoline (10i). White microcrystals, m.p.
179–181 ◦C, yield 78% (0.47 g). IR: νmax/cmꢀ 1 3000, 2980, 1575, 1495,
1372, 1251, 847, 767; 1H NMR (CDCl3) δ: 8.15–8.09 (m, 2H), 7.81 (dd,
J = 9.2, 2.7 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.52 (td, J = 9.2, 2.8 Hz,
1H), 7.33–7.31(m, 3H),5.55 (s, 2H), 2.42 (s, 3H). 13C NMR (CDCl3) δ:
162.0, 154.4, 147.0, 138.2, 134.9, 134.4, 133.6, 131.3, 131.1, 130.4,
129.6, 128.8, 128.3, 128.0, 125.6, 120.1, 119.7, 97.4, 62.7, 22.1. HRMS
m/z for C20H14ClF3N4O [M+H]+ Calcd. 419.0881. Found: 419.0883.
3.1.3.3. 4-((1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(tri-
fluoromethyl)quinoline (10c). White microcrystals, m.p. 180–182 ◦C,
yield 54% (0.32 g). IR: νmax/cmꢀ 1 3050, 2980, 1591, 1515, 1370, 1252,
840, 771; 1H NMR (CDCl3) δ: 8.19 (d, J = 8.3 Hz, 1H), 8.13–8.05 (m,
2H), 7.74 (t, J = 7.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.55 (t, J = 7.5 Hz,
1H), 7.25 (d, J = 6.2 Hz, 1H), 6.99 (d, J = 8.5 Hz, 2H), 5.51 (s, 2H), 3.83
(s, 3H). 13C NMR (CDCl3) δ: 162.6, 160.3, 149.2, 148.9, 148.3, 142.8,
131.3, 130.3, 129.7, 127.8, 122.7, 122.5, 122.1, 121.9, 121.8, 120.6,
115.0, 97.3, 62.8, 55.8. HRMS m/z for C20H15F3N4O2 [M+H]+ Calcd.
401.1220. Found: 401.1224.
3.1.3.10. 4-((1-(2-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-6-
methyl-2-(trifluoromethyl)quinoline (10j). White microcrystals, m.p.
185–187 ◦C, yield 65% (0.40 g). IR: νmax/cmꢀ 1 3070, 2968, 1574, 1507,
1374, 1251, 830, 762; 1H NMR (CDCl3) δ: 8.30 (s, 1H), 8.15 (d, J = 8.6
Hz, 1H), 8.02 (s, 1H), 7.83 (dd, J = 7.9, 1.5 Hz, 1H), 7.62 (dd, J = 8.7,
1.3 Hz, 1H), 7.44 (td, J = 8.4, 1.6 Hz, 1H), 7.30 (s, 1H), 7.15–7.07 (m,
2H), 5.58 (s, 2H), 3.89 (s, 3H), 2.53 (s, 3H). 13C NMR (CDCl3) δ: 162.4,
151.2, 146.7, 141.6, 138.3, 133.7, 131.3, 131.1, 130.6, 129.3, 126.2,
125.9, 125.6, 121.9, 121.6, 121.1, 112.5, 97.5, 62.9, 56.2, 22.1. HRMS
m/z for C21H17F3N4O2 [M+Na]+ Calcd. 415.1376. Found: 415.1383.
3.1.3.4. 4-((1-(2-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(tri-
fluoromethyl)quinoline (10d). White microcrystals, m.p. 200–202 ◦C,
yield 44% (0.26 g). IR: νmax/cmꢀ 1 3079, 2979, 1574, 1530, 1369, 1274,
848, 788, 756; 1H NMR (CDCl3) δ: 8.40 (d, J = 8.2 Hz, 1H), 8.30 (t, J =
8.5 Hz, 1H), 8.22 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.74 (t, J = 7.6 Hz,
1H), 7.65–7-62 (m, J = 10.7, 3.9 Hz, 2H), 7.57–7.44 (m, 2H), 7.33 (s,
1H), 5.65 (s, 2H).13C NMR (CDCl3) δ: 162.6, 148.5, 142.2, 132.1, 131.3,
131.1, 130.7, 129.9, 129.8, 128.3, 128.0, 127.9, 125.6, 122.2, 121.9,
121.1, 108.1, 97.5, 62.8. HRMS m/z for: C19H12ClF3N4O [M+H]+ Calcd.
405.0724. Found: 405.0724.
3.1.3.11. 4-((1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-6-
methoxy-2-(trifluoromethyl)quinoline (10k). White microcrystals, m.p.
190–192 ◦C, yield 75% (0.46 g). IR: νmax/cmꢀ 1 3100, 2923, 1590, 1513,
1438, 1373, 1229, 840, 724; 1H NMR (CDCl3) δ: 8.10 (s, 1H), 8.05–7.96
(m, 1H), 7.71 (dd, J = 8.9, 4.5 Hz, 2H), 7.42–7.34 (m, 2H), 7.22–7.20
(m, 3H), 5.52 (s, 2H), 3.89 (s, 3H). 13C NMR (CDCl3) δ: 163.8, 161.8,
161.2, 159.1, 146.7, 146.4, 144.3, 143.2, 133.2, 131.4, 123.8, 122.8,
121.9, 120.8, 117.2, 117.0, 99.9, 97.6, 62.5, 55.9. HRMS m/z for
3.1.3.5. 4-((1-(2-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(tri-
fluoromethyl)quinoline (10e). White microcrystals, m.p. 179–181 ◦C,
yield 61% (0.37 g). IR: νmax/cmꢀ 1 3100, 2931, 1576, 1512, 1368, 1249,
831, 756; 1H NMR (CDCl3) δ: 8.23 (d, J = 8.5 Hz, 1H), 8.15 (d, J = 8.5
Hz, 1H), 8.07 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 9.0 Hz, 2H),
7.58 (t, J = 7.6 Hz, 1H), 7.29 (s, 1H), 7.01 (d, J = 9.0 Hz, 2H), 5.55 (s,
2H), 3.85 (s, 3H).13C NMR (CDCl3) δ: 162.9, 151.2, 131.4, 131.3, 130.6,
129.7, 128.3, 128.0, 127.9, 126.2, 125.9, 125.7, 122.3, 122.2, 121.9,
121.6, 112.5, 97.5, 62.9, 56.2. HRMS m/z for: C20H15F3N4O2 [M+H] +
Calcd. 401.1220. Found: 401.1217.
C
20H14F4N4O2 [M+H]+ Calcd. 419.1126. Found: 419.1123.
3.1.3.12. 6-Methoxy-4-((1-(p-tolyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-
(trifluoromethyl)quinoline (10l). White microcrystals, m.p. 181–183 ◦C,
yield 65% (0.40 g). IR: νmax/cmꢀ 1 3138, 2927, 1578, 1505, 1482, 1378,
1232, 841, 722; 1H NMR (CDCl3) δ: 8.08 (s, 1H), 8.03 (d, J = 9.0 Hz,
1H), 7.61 (d, J = 8.3 Hz, 2H), 7.45–7.37 (m, 2H), 7.32 (d, J = 8.2 Hz,
2H), 7.26 (s, 1H), 5.55 (s, 2H), 3.91 (s, 3H), 2.42 (s, 3H). 13C NMR
(CDCl3) δ: 161.3, 159.1, 146.8, 144.4, 142.9, 139.6, 134.7, 131.5,
130.6, 130.5, 123.9, 123.8, 122.9, 121.7, 120.9, 120.8, 100.0, 97.7,
62.6, 56.0, 21.4. HRMS m/z for C21H17F3N4O2 [M+H]+ Calcd.
415.1376. Found: 415.1377.
3.1.3.6. 6-Fluoro-4-((1-(p-tolyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(tri-
fluoromethyl)quinoline (10f). White microcrystals, m.p. 170–172 ◦C,
yield 75% (0.46 g). IR: νmax/cmꢀ 1 3100, 2925, 1577, 1517, 1478, 1277,
815, 717; 1H NMR (CDCl3) δ: 8.18–8.09 (m, 2H), 7.81 (dd, J = 9.2, 2.7
Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.52 (td, J = 9.2, 2.8 Hz, 1H),
7.38–7.26 (m, 3H), 5.55 (s, 2H), 2.42 (s, 3H).13C NMR (CDCl3) δ: 162.5,
160.5, 145.4, 142.7, 139.7, 134.7, 132.6, 132.5, 130.6, 122.9, 122.7,
121.8, 121.6, 121.4, 120.8, 106.3, 106.1, 97.9, 62.9, 21.3. HRMS m/z
for C20H14F4N4O [M+H]+ Calcd. 403.1177. Found: 403.1176.
3.1.3.13. 1-((1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(tri-
fluoromethyl)quinolin-4(1H)-one (11a). Yellow microcrystals, m.p.
195–197 ◦C, yield 68% (0.41 g). IR: νmax/cmꢀ 1 3000, 2865, 1664, 1598,
1519, 1269, 1150, 830, 762, 740; 1H NMR (CDCl3) δ: 8.13 (d, J = 8.6 Hz,
1H), 8.02 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.56
(d, J = 9.0 Hz, 2H), 7.32 (t, J = 7.7 Hz, 1H), 7.12 (s, 1H), 6.96 (d, J = 9.0
Hz, 2H), 5.66 (s, 2H), 3.83 (s, 3H). 13C NMR (CDCl3) δ: 160.8, 160.2,
140.0, 138.1, 137.9, 132.4, 130.2, 126.0, 126.0, 123.5, 122.4, 121.5,
120.9, 120.8, 116.3, 115.6, 114.9, 114.9, 55.8, 38.9. HRMS m/z for
3.1.3.7. 4-((1-(2-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-6-fluoro-
2-(trifluoromethyl)quinoline
(10g). White
microcrystals,
m.p.
174–176 ◦C, yield 79% (0.48 g). IR: νmax/cmꢀ 1 3050, 2930, 1600, 1574,
1518, 1478, 1233, 852, 761; 1H NMR (CDCl3) δ: 8.18–8.11 (m, 2H), 7.82
(dd, J = 9.1, 2.7 Hz, 1H), 7.66 (dd, J = 6.4, 3.0 Hz, 1H), 7.59 (dd, J =
7.3, 2.0 Hz, 1H), 7.55–7.44 (m, 3H), 7.31 (s, 1H), 5.59 (s, 2H).13C NMR
(CDCl3) δ: 162.1, 160.6, 145.5, 142.0, 134.8, 132.6, 132.5, 131.3,
131.1, 128.8, 128.3, 128.0, 126.0, 121.7, 121.5, 106.3, 106.1, 97.9,
62.9. HRMS m/z for C19H11ClF4N4O [M+H]+ Calcd. 423.0630. Found:
423.0631.
C
20H15F3N4O2 [M+H]+ Calcd. 401.1220. Found: 401.1196.
3.1.3.14. 1-((1-(2-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(tri-
fluoromethyl)quinolin-4(1H)-one (11b). White microcrystals, m.p.
184–186 ◦C, yield 79% (0.48 g). IR: νmax/cmꢀ 1 3138, 2980, 1662, 1598,
1483, 1235, 841, 770, 740; 1H NMR (CDCl3) δ: 8.23–8.16 (m, 2H), 7.84
(d, J = 8.2 Hz, 1H), 7.69 (dd, J = 17.1, 8.6 Hz, 2H), 7.38 (dd, J = 11.1,
4.7 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.11 (s, 1H), 7.07–6.98 (m, 2H),
5.68 (s, 2H), 3.84 (s, 3H). 13C NMR (CDCl3) δ: 170.8, 160.6, 151.1,
142.4, 139.9, 137.8, 137.5, 132.1, 130.3, 126.0, 125.7, 125.4, 123.3,
121.4, 120.8, 116.4, 115.4, 112.3, 56.0, 38.7. HRMS m/z for
3.1.3.8. 6-Fluoro-4-((1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)
methoxy)-2-(trifluoromethyl)quinoline (10h). White microcrystals, m.p.
154–156 ◦C, yield 67% (0.41 g). IR: νmax/cmꢀ 1 3100, 2980, 1599, 1506,
1478, 1249, 837; 1H NMR (CDCl3) δ: 8.31 (s, 1H), 8.12 (dd, J = 9.2, 5.2
Hz, 1H), 7.81–7.79 (m, 2H), 7.52–7.46 (m, 2H), 7.32 (s, 1H), 7.09 (dd, J
= 13.0, 8.0 Hz, 2H), 5.55 (s, 2H), 3.87 (s, 3H).13C NMR (CDCl3) δ: 162.2,
160.4, 151.1, 145.3, 141.3, 132.4, 132.3, 130.6, 128.2, 127.9, 126.1,
6

I.A. Seliem et al.
Bioorganic Chemistry 114 (2021) 105117
C20H15F3N4O2 [M+H]+ Calcd. 401.1220. Found: 401.1214.
3H), 3.48 (t, J = 6.6 Hz, 2H), 2.54 (s, 3H). 13C NMR (CDCl3) δ: 162.4,
160.1, 148.5, 148.2, 146.9, 144.4, 138.0, 133.4, 130.7, 129.7, 122.9,
122.4, 121.8, 121.8, 120.7, 120.4, 115.0, 97.1, 67.9, 55.8, 26.0, 22.1.
HRMS m/z for C22H19F3N4O2 [M+H]+ Calcd. 429.1533. Found:
429.1526.
3.1.3.15. 1-((1-(2-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-6-
methyl-2-(trifluoromethyl)quinolin-4(1H)-one (11c). Yellow microcrys-
tals, m.p. 216–218 ◦C, yield 60% (0.37 g). IR: νmax/cmꢀ 1 3100, 2981,
1664, 1600, 1599, 1512, 1441, 1325, 1254, 830, 748; 1H NMR (CDCl3)
δ: 8.19 (s, 1H), 8.08–8.03 (m, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.60 (s, 1H),
7.51 (d, J = 8.6 Hz, 1H), 7.37 (dd, J = 12.5, 4.9 Hz, 1H), 7.08 (s, 1H),
7.06–6.97 (m, 2H), 5.66 (s, 2H), 3.83 (s, 3H), 2.42 (s, 3H). 13C NMR
(CDCl3) δ: 160.6, 151.3, 138.2, 133.5, 133.1, 133.1, 131.1, 130.9,
130.4, 128.0, 127.9, 126.3, 125.6, 121.3, 120.9, 116.3, 115.6, 112.4,
56.2, 38.8, 21.1. HRMS m/z for C21H17F3N4O2 [M+H]+ Calcd.
415.1330. Found: 415.1331.
3.2. Biological studies
Details of biological studies are mentioned in the supplementary
materials.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
3.1.3.16. 4-(2-(1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)ethoxy)-2-
(trifluoromethyl)-1,4-dihydroquinoline (12a). Yellow microcrystals, m.p.
158–160 ◦C, yield 76% (0.46 g). IR: νmax/cmꢀ 1 3100, 2980, 1575, 1516,
1364, 1250, 838, 767, 725; 1H NMR (CDCl3) δ: 8.20 (d, J = 8.2 Hz, 1H),
8.10 (d, J = 8.2 Hz, 1H), 7.82 (s, 1H), 7.74 (t, J = 7.1 Hz, 1H), 7.60–7.52
(m, 3H), 7.05 (s, 1H), 6.96 (d, J = 8.3 Hz, 2H), 4.60 (t, J = 5.5 Hz, 2H),
3.82 (s, 3H), 3.46 (t, J = 5.5 Hz, 2H). 13C NMR (CDCl3) δ: 162.9, 160.1,
149.7, 149.4, 149.2, 148.4, 144.4, 131.2, 130.7, 130.0, 127.8, 122.4,
121.9, 121.9, 120.6, 120.4, 115.0, 97.1, 68.1, 55.8, 26.0. HRMS m/z for
Acknowledgments
We thank the Egyptian Cultural and Educational Bureau Scholarship.
The authors also thank the Center for Undergraduate Research and
Scholarship (CURS), Translational Research Program (TRP) at Augusta
University and the Egyptian Academy of Scientific Research and Tech-
nology (ASRT) within the program under contract number 7303 for
financial support.
C
21H17F3N4O2 [M+H]+ Calcd. 415.1376. Found: 415.1362.
3.1.3.17. 6-Fluoro-4-(2-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)
ethoxy)-2-(trifluoromethyl)-1,4-dihydroquinoline (12b). Yellow micro-
crystals, m.p. 163–165 ◦C, yield 66% (0.40 g). IR: νmax/cmꢀ 1 3100,
2980, 1598, 1514, 1477, 1411, 1226, 841, 801, 742; 1H NMR (CDCl3) δ:
8.11 (dd, J = 9.1, 5.2 Hz, 1H), 7.87 (s, 1H), 7.76 (dd, J = 9.1, 2.3 Hz,
1H), 7.68–7.65 (m, 2H), 7.51 (t, J = 8.6 Hz, 1H), 7.2–7.17 (m, 2H),7.07
(s, 1H), 4.63 (t, J = 6.4 Hz, 2H), 3.47 (t, J = 6.4 Hz, 2H). 13C NMR
(CDCl3) δ: 163.6, 162.4, 161.7, 160.4, 145.4, 144.6, 133.5, 132.6,
132.6, 122.8, 121.5, 121.3, 120.4, 117.1, 116.9, 106.0, 105.8, 97.5,
68.1, 26.0. HRMS m/z for C20H13F5N4O [M+H]+ Calcd. 421.1082.
Found: 421.1066.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bioorg.2021.105117.
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