One-pot synthesis and biological evaluation of novel 4-[3-fluoro-4-(morpholin-4-yl)]phenyl-1H-1,2,3-triazole derivatives as potent antibacterial and anticancer agents

Article abstract of DOI:10.1002/jhet.3890

In search of better antibacterial and anticancer agents, a series of novel 4-[3-fluoro-4-(morpholin-4-yl)]phenyl-1H-1,2,3-triazole derivatives were synthesized (6a-l and 8a-j) by using 3-fluoro-4-morpholinoaniline, alkyne, and triflyl azide via an in situ

Full text of DOI:10.1002/jhet.3890

Received: 22 October 2019
DOI: 10.1002/jhet.3890
Revised: 19 November 2019
Accepted: 5 December 2019
A R T I C L E
One-pot synthesis and biological evaluation of novel
4-[3-fluoro-4-(morpholin-4-yl)]phenyl-1H-1,2,3-triazole
derivatives as potent antibacterial and anticancer agents
Sirassu Narsimha1,2
| Sathesh Kumar Nukala1 | T. Savitha Jyostna1
|
M. Ravinder2 | M. Srinivasa Rao3 | N. Vasudeva Reddy1
1Department of Chemistry, Kakatiya
Abstract
University, Warangal, India
2Department of Chemistry, Chaitanya
Degree College (Autonomous), Warangal,
India
3Chemical Biology Laboratory, Indian
Institute of Chemical Technology,
Hyderabad, India
In search of better antibacterial and anticancer agents, a series of novel
4-[3-fluoro-4-(morpholin-4-yl)]phenyl-1H-1,2,3-triazole derivatives were syn-
thesized (6a-l and 8a-j) by using 3-fluoro-4-morpholinoaniline, alkyne, and
triflyl azide via an in situ generated 4-(4-azido-2-fluorophenyl)morpholine and
evaluated for their antibacterial and anticancer activity in vitro. Antibacterial
activity against three G+ bacterial strains and anticancer activity against breast
cancer cell line (MCF-7) and cervical carcinoma cell line (HeLa) was evalu-
ated. Among all the tested compounds, 6h, 6i, and 8b exhibited potent
antibacterial activity against tested gram-positive bacterial strains. The anti-
cancer activity screening results of 8f, 8h, and 8i exhibited potent cytotoxic
activity against two cancer cell lines with IC50 values nearer to the standard
drug, doxorubicin. The remaining compounds have shown good to moderate
activity against the tested cell lines. On the basis of the results obtained, a
structure-activity relationship (SAR) is discussed.
Correspondence
N. Vasudeva Reddy, Department of
Chemistry, Kakatiya University, Warangal
TS-506 009, India.
Email: vasujac3@gmail.com
1 | INTRODUCTION
Nitrogen containing heterocyclic compounds plays a
very important role in pharmaceuticals and agrochemi-
After cardiovascular diseases in humans, cancer is one of
the most common causes of morbidity and mortality
worldwide.[1] The biggest challenges for successful cancer
treatment are its unwanted side effects and drug resis-
tance in various types of cancer. The efficacy of many
anticancer drugs is limited by the drug resistance
acquired, and there are a number of side effects because
of their toxicity to normal cells since the currently avail-
able anticancer drugs cannot distinguish between normal
and cancer cells.[2] Similarly, the alarming rates of emerg-
ing and recurring microbial threats associated with
increased antibacterial resistance in hospitals are of great
importance for public health and science worldwide, par-
ticularly with respect to bacteria resistant to multidrug
resistant gram-positive bacteria.[3,4]
cals.[5] Of all the heterocyclic systems in organic chemis-
try, the five-member heterocyclic compounds containing
1,2,3-triazoles and their derivatives are of great impor-
tance because of their wide applications in medical, phar-
maceutical, biochemical, and material sciences.[6–10]
1,2,3-Triazoles act as effective substitutes in bioactive
molecules because they can exhibit hydrogen bonds,
dipole-dipole moments, and π stacking interactions.[11]
1H-1,2,3-triazole containing compounds exhibited a wide
range of biological activities, such as antimicrobial activ-
ity against gram-positive bacteria,[12] as well as important
anticancer agents and a wide variety of human cancer
cells,
including
those
who
resist
multiple
medications.[13–15] Heterocyclic compounds containing
4-(2-fluorophenyl) morpholine have shown potent
J Heterocyclic Chem. 2020;1–11.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
NARSIMHA ET AL.
antibacterial activity, especially gram-positive bacteria.
Linezolid is an potent antibacterial agent that specifically used
for the treatment of gram-possitive infections. The 4-[3-fluoro-
4-(morpholin-4-yl)]phenyl containing 1,2,3-triazole derivatives
has demonstrated potent antibacterial activity reported by the
Phillips research group.[17,18]
With this in mind, the research has begun to study
biologically active properties, especially anticancer and
antibacterial,[19–28] by merging two units of
pharmacophore, both an anticancer active 1,2,3-triazole
scaffold and an antibacterial active 4-(2-fluorophenyl)
morpholine derived from linezolid, which are designed
and synthesized (Figure 1), a substituent at the fourth
position of the 1,2,3-triazole ring adapts the potency of
anticancer and antibacterial activities.
nitrobenzenes and terminal alkynes via an in situ gener-
ated azides. In 2012, Shabber and their group reported
recyclable Cu (II) catalyzed tandem one-pot synthesis of
1-aryl-1,2,3-triazoles from aryl boronic acids and alkynes
via an in situ generated azides at room temperature.[32]
Encouraged by the abovementioned successful syn-
thesis of 1,4-disubstituted 1,2,3-triazoles via in situ gener-
ated azides, we report here an efficient method for the
synthesis of 1,4-disubstituted 1,2,3-triazoles by using
3-fluoro-4-morpholinoaniline, alkyne, and triflyl azide
via an in situ generated 4-(4-azido-2-fluorophenyl)mor-
pholine (Scheme 1).[33]
2 | RESULTS AND DISCUSSION
A
common approach for the synthesis of
1,2,3-triazoles is the copper catalyzed Huisgen [3 + 2]
cycloaddition of alkynes with azides (CuAAC). However,
the one-pot three-component regioselective synthesis of
1,4-disubstituted 1,2,3-triazoles from in situ azides gener-
ated from amines has been found to be a very challenging
task. However, low molecular weight organic azides are
considered unstable entities that can decompose sponta-
neously, with which reactions are difficult or dangerous
to manage.[29] Thus, a one-pot two-step process for the in
situ generation of organic azides is highly required.
Feldman et al[30] reported one-pot synthesis of
1,4-disubstituted 1,2,3-triazoles by using using alkyl/aryl
halides, alkyne, and sodium azide via an in situ gener-
ated azides. Also, Zhao et al[31] reported a successful syn-
The syntheses of the final 4-(2-fluorophenyl)morpholine-
1H-1,2,3-triazole derivatives 6a-l and 8a-j were
performed as outlined in Schemes 2 and 3, starting
from the readily available morpholine
1
and
3,4-difluoronitrobenzene to give the 4-(2-fluoro-
2
4-nitrophenyl)morpholine 3. Reduction of 3 using Pd/C
to give the 3-fluoro-4-morpholinoaniline 4 in good yields
according to published procedures.[16,18] The proposed
mechanism of the formation of in situ azide is shown in
Scheme 4.
One-pot [3 + 2] cycloaddition reaction was performed
by using morpholine derivative 4 with different alkynes
(5a-l and 7a-j) via an in situ generated azide[33,34] to form
final 4-(2-fluorophenyl) morpholine-1H-1,2,3-triazole
derivatives 6a-l and 8a-j in good to excellent yield. Our
thesis
of
1,4-disubstituted
1,2,3-triazoles
from
FIGURE 1 Dual modulator design
through the pharmacophore merging
strategy
SCHEME 1 One-pot synthesis of
1,4-disubstituted 1,2,3-triazoles

NARSIMHA ET AL.
3
SCHEME 2 Reagents and
conditions: (A) CH3CN, reflux, 4 hours
(82% yield); (B) H2, 5% Pd/C, THF,
6 hours (63% Yield); and (C) TfN3,
CuSO4.5H2O, sodium ascorbate, Et3N,
THF: H2O (1:1), 8 to 10 hours, 60ꢀC
SCHEME 3 Reagents and conditions:
(c) TfN3, CuSO4.5H2O, sodium ascorbate, Et3N,
THF: H2O (1:1), 8 to 10 hours, room
temperature (rt): 60ꢀC
SCHEME 4 The proposed mechanism for
the one-pot synthesis of 1,2,3-triazoles
initial investigation began with the [3 + 2] cycloaddition
of in situ generated azide from amine (4), alkyne (5a),
triflyl azide (TfN3), catalyst, base, and solvent. During the
course of the study, the combination of 10 mol% of
CuSO4.5H2O and 10 mol% sodium ascorbate with 3 equiv
of triethylamine (TA) in the presence of 1:1 ratio of THF
and water at 60ꢀC was the optimum reaction condition
for the synthesis of final 1,2,3-triazole derivatives
(Table 1). When TEA was replaced with NaHCO3,
Na2CO3, K2CO3, and Cs2CO3, we could not get the
desired product in good yield compared with TEA
(Table 1, entries 10-13).
The structures of the newly synthesized compounds
(6a-l and 8a-8j) were confirmed by the spectral data
(nuclear magnetic resonance [NMR], infrared [IR], and
electrospray ionization mass spectrometry [ESI-MS]). All
the spectral data of the synthesized compounds were in
full agreement with the proposed structures and also

4
NARSIMHA ET AL.
TABLE 1 Investigation of the reaction conditions for the synthesis of 1,2,3-triazolea
Entry
Base (2 eq)
Solvent, 20 mL
THF
Time, h
Yield, %b
1
9a
10
8
36
2
9b
THF
54
3
9c
THF
10
8
41
4
9d
THF
38
5
9b
H2O
10
10
12
8
50
6
9b
DCM/MeOH
MeOH
36
7
9b
28
8c
9d
10e
11
12
13
9b
THF/H2O(1:1)
THF/H2O(1:1)
H2O and THF/H2O(1:1)
THF/H2O(1:1)
THF/H2O(1:1)
THF/H2O(1:1)
78
9b
8
73
NaHCO3
Na2CO3
K2CO3
Cs2CO3
10
10
10
10
NR and 16
21
29
34
Abbreviation: NR, no reaction.
aReactions were performed with 4 (1.0 mmol), amine (1.5 mmol), TfN3 (1.5 mmol), CuSO4.5H2O (5 mol%), sodium ascorbate (5 mol%), and solvent (20 mL)
at 60ꢀC.
bIsolated yield.
cCuSO4.5H2O (10 mol%), sodium ascorbate (10 mol%), and base (3.0 mmol).
dCuSO4.5H2O (15 mol%), sodium ascorbate (15 mol%), and base (4.0 mmol).
eBase (3.0 mmol).
discussed for a representative compound 8a. In the IR
spectrum, the appearance of sharp absorption bands at
3136, 1660, and 1593 cm−1 are ascribed to CH (triazole),
streptomycin as positive controls. The minimum inhibi-
tory concentrations (MICs) for all the synthesized com-
pounds were reported in μg/mL, and the results are
illustrated in Tables 2 and 3. It is evident from Tables 2
and 3 that the majority of the tested compounds exerted
significant in vitro antibacterial activity against almost all
the tested bacterial strains with MICs ranging from 1.56
to 12.5 μg/mL.
1
C O, and C C stretching frequencies. In the H NMR
spectrum, the signals at δ 8.03-6.96 (Ar and CH-triazole)
and 5.25 (s, 2H, N-CH2) and the [M+] ion peak at m/z
425.10 in the ESI mass spectrum confirmed the structure
of compound 8a.
Compound 6a with the MICs ranging from 25
0.31 to 50 0.37 μg/mL was selected as starting point
for our initial SAR studies, which focused on pheno-
xymethyl group in fourth position of triazole ring. A
wide variety of substituents were introduced to phenoxy
group. As shown in Table 2, most of the compounds
demonstrated significant in vitro antibacterial activities.
The mono fluoro substituted at ortho or para position
2.1 | Antibacterial activity
The title compounds (6a-l and 8a-j) were screened for
their in vitro antibacterial activity against gram-positive
(G+) bacterial strains by the standard broth micro-
dilution technique[35,36] by using penicillin and

NARSIMHA ET AL.
5
TABLE 2 In vitro antibacterial and anticancer activity data of compounds 6a-6l
MIC, μg/mLa
IC50, μM/mLb
Bacillus
subtilis
Staphylococcus
aureus
Staphylococcus
epidermidis
Analogs
MCF-7
Hela
HEK-293
>100
6a
6b
6c
6d
6e
6f
25 0.31
-
25 0.48
50 0.55
-
50 0.37
-
84.85 2.62
>100
96.16 1.05
>100
>100
50 0.25
-
-
>100
>100
>100
-
50 0.67
50 0.33
12.5 0.37
25 0.26
6.25 0.34
3.12 0.65
25 1.37
25 0.41
-
>100
>100
>100
25 0.28
12.5 0.41
25 0.61
3.12 0.22
1.56 0.72
12.5 0.35
50 0.32
-
25 0.18
6.25 0.21
25 0.34
12.5 0.37
3.12 0.85
12.5 0.84
50 0.39
50 1.25
6.25 0.18
1.56 0.45
NT
59.41 1.91
48.19 1.12
81.69 1.82
18.19 1.32
11.18 1.01
28.11 0.64
68.16 0.83
63.65 0.31
NT
67.80 1.65
61.58 1.84
77.12 2.02
33.15 2.14
31.42 1.64
37.84 0.82
50.14 2.06
41.36 0.82
NT
>100
73.63 2.72
68.83 1.82
43.13 1.65
66.59 1.71
41.81 1.58
64.31 2.22
57.22 1.39
NT
6g
6h
6i
6j
6k
6l
Streptomycin 6.25 0.21
3.12 0.25
3.12 0.20
NT
Penicillin
1.56 0.19
NT
NT
NT
NT
Doxorubicin
2.63 0.33
1.23 0.21
5.68 1.56
Note: “-” indicates concentration > 50 μg/mL.
Abbreviations: MIC, minimum inhibitory concentration; NT, not tested.
aMinimum inhibitory concentration (MIC) (μg/mL), ie, the lowest concentration of the test compound to inhibit the growth of bacteria completely.
bValues are mean SD of three replicates.
TABLE 3 In vitro antibacterial and anticancer activity data of compounds 8a-8j
MIC, μg/mLa
IC50, μMb
Bacillus
subtilis
Staphylococcus
aureus
Staphylococcus
epidermidis
Analogs
MCF-7
Hela
HEK-293
8a
8b
8c
8d
8e
8f
6.25 0.31
3.12 0.24
6.25 0.41
25 1.03
25 0.32
25 0.44
25 1.21
50 1.68
25 1.19
12.5 0.45
6.25 0.43
1.56 0.51
12.5 0.23
50 1.27
25 1.18
50 1.27
25 0.89
25 1.51
50 1.47
25 1.68
6.25 0.18
1.56 0.45
NT
25 0.62
50 1.07
25 0.56
50 0.98
3.12 0.21
25 0.49
25 1.35
25 1.14
25 0.25
6.25 0.35
3.12 0.25
3.12 0.20
NT
33.62 1.31
31.63 1.34
61.88 1.29
29.15 0.92
29.41 0.67
8.44 0.22
30.62 1.43
3.12 0.38
5.19 0.31
28.11 0.64
NT
37.52 1.12
36.54 1.12
57.45 1.52
7.44 0.32
67.80 1.65
6.29 0.44
37.66 1.92
2.77 0.64
12.42 0.31
9.84 0.82
NT
44.81 1.42
42.63 1.13
63.87 1.56
38.43 1.24
57.80 1.35
73.63 1.52
44.81 1.31
58.11 1.22
66.38 0.88
44.13 1.32
NT
8g
8h
8i
8j
Streptomycin 6.25 0.21
Penicillin
1.56 0.19
NT
NT
NT
NT
Doxorubicin
2.63 0.33
1.23 0.21
5.68 1.56
Abbreviations: MIC, minimum inhibitory concentration; NT, not tested.
aMinimum inhibitory concentration (MIC) (μg/mL), ie, the lowest concentration of the test compound to inhibit the growth of bacteria completely.
bValues are mean SD of three replicates.

6
NARSIMHA ET AL.
of phenoxy group (compounds 6h and 6i) led to
increase of activities; compound 6i showed fourfold
more potent activity against Bacillus subtilis
(MIC = 1.56 0.72 μg/mL) compared with standard
streptomycin (MIC = 6.25 0.21 μg/mL) and twofold
more potent activity against Staphylococcus aureus
(MIC = 3.12 0.85 μg/mL) compared with standard
streptomycin (MIC = 6.25 0.18 μg/mL) and also
equipotent activity against Staphylococcus epidermidis
(MIC = 3.12 0.65 μg/mL) compared with standard
streptomycin (MIC = 3.12 0.25 μg/mL). Also, com-
pound 6h effectively inhibited the B. subtilis
(MIC = 3.12 0.22 μg/mL; twofold more potent to
streptomycin) and good activity against S. aureus
(HEK-293) by MTT assay[37] using doxorubicin as a posi-
tive control, and the results are tabulated in Tables 2
and 3.
From the screening results in Table 2 (compounds 6a-
6l), it was observed that majority of compounds exhibited
good to moderate anticancer activity against MCF-7 and
HeLa. Among all compounds, 6h and 6i showed good
activity against MCF-7 with IC50 values ranging from
11.18 1.01 to 33.15 2.14 μM. Remaining compounds
have shown moderate to poor activity against MCF-7 and
HeLa with IC50 values ranging from 28.11 0.64 to 96.16
1.05 μM, respectively. On the basis of SAR, it was
observed from experimental data compounds derived from
4-fluoro and 2-fluorophenoxy groups at fourth position on
1,2,3-triazole (6i) and (6h) have exhibited good anticancer
activity against MCF-7 when compared with the others.
From Table 3 (compounds 8a-8j), it is clear that major-
ity of the compounds showed potent activity against tumor
cell lines. Among all the synthesized compounds, 8h, 8i,
and 8f showed the highest cytotoxicity towards both
the cancer cell lines. Compound 8h, which contains
7-hydroxy-4-methylcoumarin at fourth position of
1,2,3-triazole, exhibited potent activity against both MCF-7
and HeLa cell lines with IC50 values 3.12 0.38 and 2.77
0.64 μM, respectively. These results are comparable with
the standard drug, doxorubicin. Similarly, the introduction
of 4-hydroxycoumarin at fourth position of 1,2,3-triazole
(8i) significantly enhanced the cytotoxicity against the two
cancer cell lines MCF-7 and HeLa with IC50 values 8.44
0.22 and 6.29 0.44 μM, respectively. Introduction of
8-hydroxy quinoline at fourth position exhibits potent
activity against MCF-7 (IC50 5.19 0.31 μM) and Hela
(IC50 512.42 0.31 μM). The potential activity of these
compounds (8h, 8i, and 8f) may be attributed due to the
presence of hydroxymethyl heterocyclic compounds fourth
position of triazole ring. Compounds 8d and 8j that
contains 2-mercapto benzothiazole and 2-mercapto
benzoxazole derivatives on triazole exhibit potent cytotox-
icity against Hela, with IC50 values 7.44 0.32 and 9.84
0.82 μM, respectively. These results are comparable with
the standard doxorubicin (MCF-7, IC50 2.63 0.33; and
HeLa, IC50 1.23 0.21 μM). The rest of the compounds
exhibited moderate to poor cytotoxic activity against the
two cancer cell lines with IC50 values ranging from 28.11
0.64 to 67.80 1.65 μM.
(MIC = 12.5 0.37 μg/mL)
(MIC = 6.25 0.34 μg/mL).
and
S.
epidermidis
Introduction of two chloro groups at meta position
led to increase of activity (compound 6f; MIC ranging
from 6.25 0.21 to 12.5 0.41 μg/mL) compared with
mono chloro group at meta position of phenoxy group
(compound 6e; MIC ranging from 25 0.18 to 50
0.33 μg/mL). In addition, presence of methyl and met-
hoxy groups at phenoxy group reduced inhibitory
potency (compounds 6b-d). The 3-(trifluoromethyl) at
meta-position (compound 6j) exhibited good activity
against B. subtilis (MIC = 12.5 0.35 μg/mL) and
S. aureus (MIC = 12.5 0.84 μg/mL).
Likewise, a wide variety of heterocyclic compounds
has been introduced in the fourth position of the
1,2,3-triazole ring (compounds 8a-j). As shown in
Table 3, most of the compounds exhibited significant
in vitro antibacterial activity. Of all the compounds, 8b
was effective and demonstrated equipotent inhibitory
efficacy and a broader antibacterial spectrum than that of
the reference drugs. Compound 8b exhibited excellent
inhibiting activity than the standard streptomycin
(MIC = 6.25 μg/mL) and equipotent to that of penicillin
(MIC = 1.56 μg/ mL) against B. subtilis and S. aureus
with MIC values 3.12 0.24 and 1.56 0.51 μg/mL.
Also, compounds 8a and 8c showed significant activity
against B. subtilis and S. aureus with MIC values ranging
6.25 0.31 to 12.5 0.23 μg/mL. Similarly, compounds
8e and 8j could effectively inhibit the growth of
S. epidermidis with MIC values 3.12 0.21 and 6.25
0.35 μg/mL, while the rest of the compounds have
shown modest activity against all the tested strains with
MIC values ranging from 12.5 to 50 μg/mL.
3 | CONCLUSION
2.2 | Anticancer activity
In conclusion, a new series of 1,2,3-triazole derivatives
containing 4-(2-fluorophenyl) morpholine using 3-fluoro-
4-morpholinoaniline, alkyne, and triflyl azide was syn-
thesized through an in situ generated azide. In this
In vitro anticancer activity was performed against two
cancer lines (MCF-7and HeLa) and normal cell line

NARSIMHA ET AL.
7
method, the separation of the intermediates azide does
not require and should be mainly useful when unstable
azides are required for the synthesis of 1,2,3-triazoles. All
compounds were selected for their in vitro cytotoxic
activity against MCF-7 and HeLa cancer cell lines. Com-
pounds 8f, 8h, and 8i exhibited potent cytotoxic activity
against two cancer cell lines with IC50 values closer to
standard doxorubicin. in vitro antibacterial activity
against three gram-positive bacterial strains and com-
pounds, 6h, 6i, and 8b, showed a potent antibacterial
activity against the bacterial strains analyzed. Further
simple structural modifications of the titled compounds,
which could provide more interesting results and new
lead molecules for further studies.
water, and dried under vacuum for 1 hour, and the crude
product obtained was purified by column chromatogra-
phy (hexane/ethyl acetate gradient) to afford the pure
desired
4-[3-fluoro-4-(morpholin-4-yl)]phenyl-1H-1,-
2,3-triazole derivatives in good yields.
4.2 | 4-(2-fluoro-4-(4-[phenoxymethyl]-
1H-1,2,3-triazol-1-yl)phenyl)
morpholine (6a)
White solid (Yield 78%); mp: 89-91ꢀC; IR (KBr, cm−1):
3145 (CH-triazole), 3082 (CH, Ar), 1592 (C C), 1490
1
(N N); H NMR (400 MHz, CDCl3, δ in ppm): 8.05 (s,
1H, tri), 7.84 (t, J = 4.0 Hz, Ar, 1H), 7.74-7.71 (m, Ar,
1H), 7.53-7.50 (m, Ar, 2H), 7.49-7.30 (m, Ar, 3H),
7.06-7.04 (m, Ar, 1H), 5.27 (s, 2H, O CH2), 3.91-3.87 (m,
4H, morpholine), 3.17-3.13 (m, 4H, morpholine); MS
(ESI) m/z:355 [M + H]+; Anal Cal for C19H19FN4O2: C,
64.40; H, 5.40; N, 15.81; found: C, 64.46; H,
5.35; N, 15.77.
4 | EXPERIMENTAL
4.1 | Materials and methods
All the reactants were purchased from the Aldrich
chemical company. All the reagents and solvents were
purchased from SD. Fine chemicals limited and used
without further purification. Thin-layer chromatography
(TLC) was performed using Merck silica gel 60F254
precoated plates (0.25 mm), and silica gel (particle size
60–120 mesh) was used for column chromatography.
1H and 13C NMR spectra were recorded on a 400-MHz
4.2.1 | 4-(2-fluoro-4-(4-([m-tolyloxy]
methyl)-1H-1,2,3-triazol-1-yl)phenyl)
morpholine (6b)
White solid (Yield 65%); mp: 94-96ꢀC; IR (KBr, cm−1):
3132 (CH, triazole), 3096 (CH, Ar), 1589 (C C), 1496
1
instrument. H NMR spectra were reported relative to
1
Me4Si and residual CDCl3. 13C NMR was reported rela-
tive to CDCl3 or DMSO. Mass spectra were recorded on
a Jeol JMC-300 spectrometer (ESI, 70 eV). Elemental
analyses were performed on Carlo Erba 106 and
PerkinElmer model 240 analyzers. Melting points were
(N N); H NMR (400 MHz, CDCl3, δ in ppm): 7.88 (s,
1H, triazole), 7.62-7.59 (m, 2H, Ar), 7.36-7.29 (m, 3H, Ar),
7.19-7.14 (m, 2H, Ar), 5.23 (s, 2H, O-CH2), 3.93-3.87 (m,
4H, morpholine), 3.18-3.13 (m, 4H, morpholine), 2.26 (s,
3H, Ar-CH3); ESI-MS (m/z): 369 [M + H]+. Anal Cal for
C20H21FN4O2: C, 65.20; H, 5.75; N, 15.21; found: C,
65.27; H, 5.70; N, 15.26.
determined using
uncorrected.
a
Cintex apparatus and are
4.1.1 | General procedure for the
synthesis of 4-[3-fluoro-4-(morpholin-4-yl)]
phenyl-1H-1,2,3-triazole derivatives (6a-l
and 8a-j)
4.2.2 | 4-(4-(4-([3,5-dimethylphenoxy]
methyl)-1H-1,2,3-triazol-1-yl)-
2-fluorophenyl)morpholine (6c)
White solid (Yield 68%); mp: 101-103ꢀC; IR (KBr,
cm−1): 3127 (CH, triazole), 3096 (CH, Ar), 1592 (C C),
1467 (N N); 1H NMR (400 MHz, CDCl3, δ in ppm):
7.63 (brs, 1H, triazole), 7.48-7.42 (m, 2H, Ar), 7.36 (s,
2H, Ar), 7.24-7.20 (m, 1H, Ar), 7.17 (s, 1H, Ar), 5.26 (s,
2H, O CH2), 3.88 (t, J = 4.0 Hz, 4H, morpholine),
3.15-3.12 (m, 4H, morpholine), 2.39 (s, 6H, Ar CH3);
ESI-MS (m/z): 383 [M + H]+. Anal Cal for
C21H23FN4O2: C, 65.95; H, 6.06; N, 14.65; found: C,
65.89; H, 6.02; N, 14.61.
To
a
mixture of alkyne (1.0 mmol), 3-fluoro-
4-morpholinoaniline (1.5 mmol), and triflyl azide
(1.5 mmol) in THF-H2O (20 mL). To this solution, add
TEA, CuSO4.5H2O (10 mmol%), and sodium ascorbate
(10 mmol%). The reaction mixture was stirred for 2 hours
at room temperature and then heated at 60ꢀC for 6 to
8 hours. After completing the reaction by TLC, the reac-
tion mixture was carefully poured into ice water (50 mL).
The resulting solid was filtered, washed with excess

8
NARSIMHA ET AL.
4.2.3 | 4-(2-fluoro-
4-(4-([4-methoxyphenoxy]methyl)-1H-
1,2,3-triazol-1-yl)phenyl)morpholine (6d)
triazole), 7.66-7.58 (m, 4H, Ar) 7.50-7.47 (m, 1H, Ar),
7.20-7.14 (m, 2H, Ar), 5.21 (s, 2H, O CH2), 3.91-3.88 (m,
4H, morpholine), 3.16 (t, J = 4.0 Hz, 4H, morpholine); ESI-
MS (m/z): 434 [M + 2H]+. Anal Cal for C19H18BrFN4O2: C,
52.67; H, 4.19; N, 12.93; found: C, 52.71; H, 4.13; N, 12.87.
White solid (Yield 70%); mp: 108-110ꢀC; IR (KBr, cm−1):
3136 (CH, triazole), 3094 (CH, Ar), 1587 (C C), 1496
1
(N N); H NMR (400 MHz, CDCl3, δ in ppm): 7.96 (s,
1H, triazole), 7.71-7.68 (m, 2H, Ar), 7.63-7.60 (m, 1H, Ar),
7.20-7.13 (m, 2H, Ar), 7.01-6.98 (d, J = 12.0 Hz, 2H, Ar),
5.21 (s, 2H, O-CH2), 3.95-3.90 (m, 4H, morpholine), 3.85
(s, 3H, O-CH3), 3.16 (t, J = 4.0 Hz, 4H, morpholine); ESI-
MS (m/z): 385 [M + H]+. Anal Cal for C20H21FN4O3: C,
62.49; H, 5.51; N, 14.57; found: C, 62.56; H,
5.59; N, 14.51.
4.2.7 | 4-(2-fluoro-4-(4-([2-fluorophenoxy]
methyl)-1H-1,2,3-triazol-1-yl)phenyl)
morpholine (6h)
Pale yellow solid (Yield 54%); mp: 102-104ꢀC; IR (KBr,
cm−1): 3137 (CH, triazole), 3097 (CH, Ar), 1576 (C C),
1
1467 (N N); H NMR (400 MHz, CDCl3, δ in ppm): 8.53
(s, 1H, triazole), 8.31 (d, J = 8.0 Hz, 1H, Ar) 8.19-8.13 (m,
2H, Ar), 7.77-7.72 (m, 1H, Ar), 7.48-7.45 (m, 1H, Ar),
7.21-7.15 (m, 2H, Ar), 5.30 (s, 2H, O CH2), 3.90-3.87 (m,
4H, morpholine), 3.15-3.12 (m, 4H, morpholine); ESI-MS
(m/z): 373 [M + H]+. Anal Cal for C19H18F2N4O2: C,
61.28; H, 4.87; N, 15.05; found: C, 61.35; H,
4.84; N, 15.03.
4.2.4 | 4-(4-(4-([3-chlorophenoxy]
methyl)-1H-1,2,3-triazol-1-yl)-
2-fluorophenyl)morpholine (6e)
Pale yellow solid (Yield 69%); mp: 117-119ꢀC; IR (KBr,
cm−1): 3130 (CH, triazole), 3088 (CH, Ar), 1590 (C C),
1
1486 (N N); H NMR (400 MHz, CDCl3, δ in ppm): 8.06
(s, 1H, triazole), 7.76 (s, 1H, Ar), 7.61 (d, J = 8.0 Hz, 1H,
Ar), 7.49-7.43 (m, 3H, Ar), 7.20-7.14 (m, 2H, Ar), 5.22 (s,
2H, O-CH2), 3.90-3.87 (m, 4H, morpholine), 3.15-3.12 (m,
4H, morpholine); ESI-MS (m/z): 389 [M + H]+. Anal Cal
for C19H18ClFN4O2: C, 58.69; H, 4.67; N, 14.41; found: C,
58.74; H, 4.61; N, 14.47.
4.2.8 | 4-(2-fluoro-4-(4-([4-fluorophenoxy]
methyl)-1H-1,2,3-triazol-1-yl)phenyl)
morpholine (6i)
Pale yellow solid (Yield 59%); mp: 106-108ꢀC; IR (KBr,
cm−1): 3128 (CH, triazole), 3083 (CH, Ar), 1592 (C C),
1
1487 (N N); H NMR (400 MHz, CDCl3, δ in ppm): 8.11
(s, 1H, triazole), 7.82-7.79 (m, 2H, Ar), 7.65-7.62 (m, 1H,
Ar), 7.45-7.42 (m, 1H, Ar), 7.37-7.35 (m, 1H, Ar),
7.30-7.26 (m, 1H, Ar), 7.07-7.05 (m, 1H, Ar), 5.27 (s, 2H,
O CH2), 3.91-3.88 (m, 4H, morpholine), 3.18-3.15 (m,
4H, morpholine); ESI-MS (m/z): 373 [M + H]+. Anal Cal
for C19H18F2N4O2: C, 61.28; H, 4.87;N, 15.05; found: C,
61.32; H, 4.93; N, 15.01.
4.2.5 | 4-(4-(4-([3,5-dichlorophenoxy]
methyl)-1H-1,2,3-triazol-1-yl)-
2-fluorophenyl)morpholine (6f)
Pale yellow solid (Yield 71%); mp: 124-126ꢀC; IR (KBr,
cm−1): 3131 (CH, triazole), 3092 (CH, Ar), 1593 (C C),
1
1489 (N N); H NMR (400 MHz, CDCl3, δ in ppm): 8.08
(s, 1H, triazole), 7.67 (s, 2H, Ar), 7.45-7.42 (m, 2H, Ar),
7.20-7.14 (m, 2H, Ar), 5.25 (s, 2H, O-CH2), 3.88 (t,
J = 4.0 Hz, 4H, morpholine), 3.15-3.12 (m, 4H, mor-
pholine); ESI-MS (m/z): 424 [M + H]+. Anal Cal for
C19H17Cl2FN4O2: C, 53.91; H, 4.05; N, 13.24; found: C,
53.83; H, 4.09; N, 13.17.
4.2.9 | 4-(2-fluoro-
4-(4-((3-(trifluoromethyl)phenoxy)methyl)-
1H-1,2,3-triazol-1-yl)phenyl)morpholine (6j)
Pale yellow solid (Yield 53%); mp: 123-125ꢀC; IR (KBr,
cm−1): 3130 (CH, triazole), 3093 (CH, Ar), 1589 (C C),
1490 (N N); 1H NMR (400 MHz, CDCl3, δ in ppm):
8.12 (s, 1H, triazole), 7.98 (s, 1H, Ar), 7.84-7.79 (m, 1H,
Ar), 7.74-7.62 (m, 2H, Ar), 7.49-7.39 (m, 2H, Ar),
7.12-7.09 (m, 1H, Ar), 5.24 (s, 2H, O-CH2), 3.91-3.87 (m,
4H, morpholine), 3.17-3.13 (m, 4H, morpholine): ESI-
4.2.6 | 4-(4-(4-([4-bromophenoxy]
methyl)-1H-1,2,3-triazol-1-yl)-
2-fluorophenyl)morpholine (6g)
White solid (Yield 68%); mp: 118-120ꢀC; IR (KBr, cm−1):
3130 (CH, triazole), 3095 (CH, Ar), 1591 (C C), 1478
(N N); 1H NMR (400 MHz, CDCl3, δ in ppm): 8.05 (s, 1H,
MS
(m/z):
423
[M + H]+.
Anal
Cal
for
C20H18F4N4O2: C, 56.87; H, 4.30; N, 13.26; found: C,
56.77; H, 4.33; N, 13.21.

NARSIMHA ET AL.
9
4.2.10 | 4-(2-fluoro-4-(4-([3-nitrophenoxy]
methyl)-1H-1,2,3-triazol-1-yl)phenyl)
morpholine (6k)
4.2.13 | 4-((1-[3-fluoro-
4-morpholinophenyl]-1H-1,2,3-triazol-4-yl)
methyl)-2H-benzo[b][1,4]thiazin-3(4H)-one
1,1-dioxide (8b)
Yellow solid (Yield 65%); mp: 137-139ꢀC; IR (KBr,
cm−1): 3122 (CH, triazole), 3086 (CH, Ar), 1595 (C C),
1488 (N N); 1H NMR (400 MHz, CDCl3, δ in ppm):
8.13 (s, 1H, triazole), 8.00 (s, 1H, Ar), 7.95 (d,
J = 4.0 Hz, 1H, Ar), 7.72-7.66 (m, 2H, Ar), 7.47 (d,
J = 8.4 Hz, 1H, Ar), 7.20-7.18 (m, 1H, Ar), 7.15 (d,
J = 4.4 Hz, 1H, Ar), 5.34 (s, 2H, O CH2), 3.90-3.87 (m,
4H, morpholine), 3.18-3.13 (m, 4H, morpholine); ESI-
MS (m/z): 400 [M + H]+. Anal Cal for C19H18FN5O4: C,
57.14; H, 4.54; N, 17.54; found: C, 57.21; H,
4.49; N, 17.48.
White solid (Yield 66%); mp: 171-173ꢀC; IR (KBr, cm−1):
3121 (CH, triazole), 3076 (CH, Ar), 1694 (C O), 1593
(C C), 1499 (N N); H NMR (400 MHz, CDCl3) δ 8.10
(d, J = 8.4 Hz, Ar, 1H), 8.03 (s, 1H, tri), 7.95 (dd, J = 7.7,
1.4 Hz, Ar, 1H), 7.75-7.73 (m, Ar, 1H), 7.47 (dd, J = 12.8,
2.4 Hz, Ar 1H), 7.37 (dt, J = 12.1, 4.6 Hz, Ar, 2H), 7.01 (t,
J = 8.8 Hz, Ar, 1H), 5.35 (s, 2H, N CH2), 4.25 (s,
SO2 CH2, 2H), 3.89-3.87 (m, 4H, morpholine), 3.15-3.12
(m, 4H, morpholine); ESI-MS m/z: 458.34 [M + H]+.
Anal Cal for C21H20FN5O4S: C, 55.13; H, 4.41; N, 15.31;
found: C, 55.09; H, 4.48; N, 15.34.
1
4.2.11 | 4-(2-fluoro-4-(4-([naphthalen-
1-yloxy]methyl)-1H-1,2,3-triazol-1-yl)
phenyl)morpholine (6l)
4.2.14 | 4-(4-(4-([10H-phenothiazin-10-yl]
methyl)-1H-1,2,3-triazol-1-yl)-2-fluoro
phenyl)morpholine (8c)
Pale yellow solid (Yield 66%); mp: 141-143ꢀC; IR (KBr,
cm−1): 3139 (CH, triazole), 3098 (CH, Ar), 1590 (C C),
Yellow solid (Yield 63%); mp:159-161ꢀC; IR (KBr, cm−1):
1
1
1477 (N N); H NMR (400 MHz, CDCl3, δ in ppm): 8.04
3144 (CH, triazole), 1594 (C C), 1514 (N N); H NMR
(s, 1H, triazole), 7.90-7.85 (m, 2H, Ar), 7.71-7.69 (m, 1H,
Ar), 7.63-7.58 (m, 3H, Ar), 7.34-7.25 (m, 4H, Ar), 5.30 (s,
2H, O CH2), 3.91-3.88 (m, 4H, morpholine), 3.17-3.15
(m, 4H, morpholine); ESI-MS (m/z): 405 [M + H]+. Anal
Cal for C23H21FN4O2: C, 68.30; H, 5.23; N, 13.85;
found: C, 68.37; H, 5.29; N, 13.81.
(400 MHz, CDCl3) δ 7.67 (s, 1H, tri), 7.44-7.41 (dd, J = 8.8,
2.5 Hz, Ar, 1H), 7.40-7.32 (dd, J = 8.6, 2.5 Hz, Ar, 1H),
7.15-7.12 (dd, J = 7.6, 1.4 Hz, 2H), 7.07-7.04 (m, Ar, 2H),
6.97-6.91(m, Ar, 3H), 6.81 (d, J = 8.0 Hz, Ar, 2H), 5.28 (s,
2H, N CH2), 3.87 (t, J = 4.0 Hz, 4H, morpholine),
3.12-3.09 (m, 4H, morpholine); 13C NMR (100 MHz,
CDCl3) δ 154.4, 144.6, 139.8, 134.6, 129.8, 129.7, 128.2,
124.3, 124.1, 121.9, 116.8, 116.4, 65.6, 47.8, 43.3; ESI-MS
m/z: 482.30 [M + Na]+. Anal Cal for C25H22FN5OS: C,
65.34; H, 4.83; N, 15.24; found: C, 65.38; H, 4.77; N, 15.29.
4.2.12 | 4-((1-[3-fluoro-
4-morpholinophenyl]-1H-1,2,3-triazol-4-yl)
methyl)-2H-benzo [b][1,4]thiazin-3(4H)-
one (8a)
4.2.15 | 4-(4-(4-(((5-bromobenzo[d]
thiazol-2-yl)thio)methyl)-1H-1,2,3-triazol-
1-yl)-2-fluorophenyl)morpholine (8d)
White solid (Yield 59%); mp: 152-154ꢀC; IR (KBr,
cm−1): 3136 (CH, triazole), 2933 (CH, Ar), 1660 (C O),
1593 (C C), 1472 (N N); H NMR (400 MHz, CDCl3)
1
δ 8.03 (s, 1H, tri), 7.83-7.81 (m, Ar, 1H), 7.50-7.47 (dd,
J = 8.8, 2.5 Hz, Ar, 1H), 7.42-7.29 (m, Ar, 3H), 7.06-6.99
(m, Ar, 2H), 5.25 (s, 2H, N-CH2), 3.90-3.87 (m, 4H,
morpholine), 3.42 (s, 2H, S-CH2), 3.15-3.12 (m, 4H,
morpholine); 13C NMR (100 MHz, CDCl3) δ 164.7,
154.6, 139.6, 138.1, 134.4, 129.6, 129.3, 128.4, 127.7,
126.3, 123.5, 122.4, 121.8, 120.7, 117.4, 65.8, 47.6, 38.5,
33.4; ESI-MS m/z: 425.10 [M]+. Anal Cal for
C21H20FN5O2S: C, 59.28; H, 4.74; N, 16.46; found: C,
59.55; H, 4.83; N, 16.53.
Pale yellow solid (Yield 57%); mp: 169-171ꢀC; IR (KBr,
cm−1): 3152 (CH, triazole), 3077 (CH, Ar),1594 (C C)
1513 (N N); 1H NMR (400 MHz, CDCl3) δ 8.05 (d,
J = 1.8 Hz, Ar, 1H), 7.96 (s, 1H, tri), 7.61 (d, J = 8.4 Hz,
Ar, 1H), 7.46-7.43 (m, Ar, 2H), 7.37 (d, J = 8.7 Hz, Ar,
1H), 7.01 (t, J = 8.8 Hz, Ar, 1H), 4.75 (s, 2H, S CH2),
3.89-3.87 (m, 4H, morpholine), 3.14-3.12 (m, 4H, mor-
pholine); ESI-MS m/z: 505.13 [M + 2H]+. Anal Cal for
C20H17BrFN5OS2: C, 47.43; H, 3.38; N, 13.83; found: C,
47.51; H, 3.29; N, 13.90.

10
NARSIMHA ET AL.
4.2.16 | (1-[3-fluoro-
4-morpholinophenyl]-1H-1,2,3-triazol-4-yl)
methyl 1H-indole-2-carboxylate (8e)
(C C), 1497 (N N); 1H NMR (400 MHz, CDCl3) δ 8.01 (s,
1H, tri), 7.54-7.42 (m, Ar, 3H), 7.06-6.96 (m, Ar, 3H), 6.16
(s, Coumarine H, 1H), 5.34 (s, 2H,O CH2), 3.90-3.88 (m,
4H, morpholine), 3.16-3.14 (m, 4H, morpholine), 2.40 (s,
3H, CH3); ESI-MS m/z: 437.34 [M + H]+. Anal Cal for
C23H21FN4O4: C, 63.30; H, 4.85; N, 12.84; found: C,
63.38; H, 4.81; N, 12.79.
White solid (Yield 50%); mp: 148-150ꢀC; IR (KBr, cm−1):
3447 (NH), 3152 (CH, triazole), 3084 (CH, Ar), 1654 (C O),
1
1587 (C C), 1477 (N N); H NMR (400 MHz, CDCl3) δ
8.93 (s, 1H, NH), 8.07 (s, 1H, tri), 7.68 (d, J = 8.0 Hz, Ar,
1H), 7.50 (dd, J = 12.6, 2.5 Hz, Ar, 1H), 7.49-7.42 (m, Ar,
2H), 7.41-7.29 (m, Ar, 2H), 7.28-7.15(m, Ar, 1H), 7.04 (t,
J = 8.8 Hz, Ar, 1H), 5.57 (s, O CH2, 2H), 3.90-3.88 (m, 4H,
morpholine), 3.16-3.13 (m, 4H, morpholine); ESI-MS m/z:
421.20 [M]+. Anal Cal for C22H20FN5O3: C, 62.70; H,
4.78; N, 16.62; found: C, 62.62; H, 4.69; N, 16.70.
4.2.20 | 4-((1-[3-fluoro-
4-morpholinophenyl]-1H-1,2,3-triazol-4-yl)
methoxy)-2H-chromen-2-one (8i)
White solid (Yield 69%); mp: 178-180ꢀC; IR (KBr, cm−1):
3163 (CH, triazole), 3077 (CH, Ar), 1674 (C O), 1588
(C C), 1483 (N N); 1H NMR (400 MHz, CDCl3) δ 8.08 (s,
1H, tri), 7.83-7.80 (m, Ar, 1H), 7.55-7.50 (m, Ar, 2H),
7.45-7.33 (m, Ar, 2H), 7.31-7.25 (m, Ar, 1H), 7.06 (t,
J = 8.8 Hz, Ar, 1H), 5.90 (s, Coumarine H, 1H), 5.42 (s, 2H,
O CH2), 3.91-3.88 (m, 4H, morpholine), 3.17-3.15 (m, 4H,
morpholine); ESI-MS m/z: 422.17 [M]+. Anal Cal for
C22H19FN4O4: C, 62.55; H, 4.53; N, 13.26; found: C, 62.62; H,
4.59; N, 13.33.
4.2.17 | 4-(2-fluoro-4-(4-([quinolin-
8-yloxy]methyl)-1H-1,2,3-triazol-1-yl)
phenyl)morpholine (8f)
Pale red solid (Yield 64%); mp: 172-174ꢀC; IR (KBr, cm−1):
3147 (CH, triazole), 3046 (CH, Ar), 1588 (C C), 1493
1
(N N); H NMR (400 MHz, CDCl3) δ 8.98-8.95 (m, Ar,
1H), 8.17 (s, 1H, tri), 7.45-7.32 (m, 6H), 7.00 (t, J = 8.6 Hz,
Ar, 2H), 5.62 (s, O CH2, 2H), 3.88-3.86 (m, 4H, mor-
pholine), 3.14-3.12 (m, 4H, morpholine); ESI-MS m/z:
406.19 [M + H]+. Anal Cal for C22H20FN5O2: C, 65.17; H,
4.97; N, 17.27; found: C, 65.22; H, 4.91; N, 17.35.
4.2.21 | 2-(((1-[3-fluoro-
4-morpholinophenyl]-1H-1,2,3-triazol-4-yl)
methyl)thio)benzo[d]oxazole (8j)
Pale red solid (Yield 68%); mp: 163-165ꢀC; IR (KBr,
cm−1): 3133(CH, triazole), 2997 (CH, Ar), 1591 (C C),
1499 (N N); H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H,
tri), 7.64 (d, J = 7.6 Hz, Ar, 1H), 7.47-7.43 (m, Ar, 2H),
7.39-7.36 (m, Ar, 1H), 7.33-7.27 (m, Ar, 2H), 7.00 (t,
J = 8.8 Hz, Ar, 1H), 4.70 (s, 2H, S-CH2), 3.89-3.87 (m, 4H,
morpholine), 3.14-3.11 (m, 4H, morpholine); ESI-MS m/
z: 412.15 [M + H]+. Anal Cal for C20H18FN5O2S: C,
58.38; H, 4.41; N, 17.02; found: C, 58.43; H,
4.37; N, 17.08.
4.2.18 | 7-bromo-4-((1-[3-fluoro-
4-morpholinophenyl]-1H-1,2,3-triazol-4-yl)
methyl)-2H-benzo[b][1,4]oxazin-3(4H)-
one (8g)
1
Pale yellow solid (Yield 60%); mp: 164-166ꢀC; IR (KBr,
cm−1): 3141 (CH, triazole), 3094 (CH, Ar), 1659 (C O),
1
1580 (C C), 1496 (N N); H NMR (400 MHz, CDCl3) δ
7.96 (s, 1H, tri), 7.50-7.45 (m, Ar, 2H), 7.40-7.37 (m, Ar, 1H),
7.19-7.13 (m, Ar, 2H), 7.01 (t, J = 8.8 Hz, Ar, 1H), 5.21 (s,
N CH2, 2H), 4.63 (s, 2H, O CH2), 3.88 (t, J = 4.4 Hz, 4H,
morpholine), 3.14 (t, J = 4.4 Hz, 4H, morpholine); ESI-MS
m/z: 488.37 [M + 2H]+. Anal Cal for C21H19BrFN5O3: C,
51.65; H, 3.92; N, 14.34; found: C, 51.59; H, 3.84; N, 14.43.
ACKNOWLEDGMENTS
The authors are thankful to the director of Indian
Institute of Chemical Technology in Hyderabad for
providing spectral data. The authors are thankful to
the head, Department of Bio-Technology, Kakatiya
University, and Warangal for providing data of biolog-
ical activity.
4.2.19 | 7-((1-[3-fluoro-
4-morpholinophenyl]-1H-1,2,3-triazol-4-yl)
methoxy)-4-methyl-2H-chromen-2-one
(8h)
ORCID
Sirassu Narsimha https://orcid.org/0000-0002-1844-
2937
N. Vasudeva Reddy https://orcid.org/0000-0002-8776-
6986
White solid (Yield 51%); mp: 180-182ꢀC; IR (KBr, cm−1):
3155 (CH, triazole), 3016 (CH, Ar), 1704 (C O), 1587

NARSIMHA ET AL.
11
[23] N. V. Reddy, N. S. Kumar, S. Narsimha, B. K. Swamy,
T. S. Jyostna, Y. N. M. Reddy, Chem. Res. 2016, 25, 1781.
[24] T. R. Kumar, S. Narsimha, B. K. Swamy, V. R. Chary,
M. Estari, N. V. Reddy, J. Saudi Chem. Soc. 2017, 21, 795.
[25] B. K. Swamy, S. Narsimha, T. R. Kumar, Y. N. Reddy,
N. V. Reddy, ChemistrySelect. 2017, 2, 4001.
[26] S. Narsimha, S. B. Kumara, R. N. Vasudeva, Synth. Commun.
2018, 48, 1220.
[27] S. Narsimha, B. Kumaraswamy, N. S. Kumar, G. Ramesh,
R. Y. Narasimha, RSC Adv. 2016, 6, 74332.
[28] S. Narsimha, S. B. Kumara, R. Y. Narasimha, R. N. Vasudeva,
Chem. Heterocycl. Compd. 2018, 54(12), 1161.
[29] J. E. Hein, V. V. Fokin, Chem. Soc. Rev. 2010, 39, 1302.
[30] A. K. Feldman, B. Colasson, V. V. Fokin, Org. Lett. 2004, 6,
3897.
REFERENCES AND NOTES
[1] F. Bray, A. Jemal, N. Grey, J. Ferlay, D. L. Forman, Oncol.
2012, 13, 790.
[2] B. W. Stewart, C. P. Wild, World Cancer Report, International
Agency for Research on Cancer, Lyon, France 2014.
[3] National Nosocomial Infections Surveillance (NNIS) System,
Am. J. Infect. Control. 2004, 32, 470.
[4] H. Goossens, Chemotherapy 2005, 51, 177.
[5] B. F. A. Wahab, E. A. Latif, H. A. Mohamed, G. E. A. Awad,
Eur. J. Med. Chem. 2012, 52, 263.
[6] Y. L. Angell, K. Burgess, Chem. Soc. Rev. 2007, 36, 1674.
[7] S. K. Mamidyala, M. G. Finn, Chem. Soc. Rev. 2010, 39, 1252.
[8] R. P. Jadhav, H. N. Raundal, A. A. Patil, V. D. J. Bobade, Saudi
Chem. Soc. 2017, 21(2), 152.
[9] M. K. Reddy, Y. J. Rao, G. L. D. J. Krupadanam, Saudi Chem.
Soc. 2015, 19(4), 372.
[10] R. Hanselmann, G. E. Job, G. Johnson, R. L. Lou,
J. G. Martynow, M. M. Reeve, Org. Process Res. Dev. 2010,
14, 152.
[11] S. G. Agalave, S. R. Maujan, S. Chem. Asian J. 2011, 6, 2696.
[12] M. J. Genin, D. A. Allwine, D. J. Anderson, M. R. Barbachyn,
D. E. Emmert, S. A. Garmon, D. R. Graber, K. C. Grega,
J. B. Hester, D. K. Hutchinson, J. Med. Chem. 2000, 43, 953.
[13] F. Pagliai, T. Pirali, E. D. Grosso, R. D. Brisco, G. C. Tron,
G. Sorba, A. A. Genazzani, J. Med. Chem. 2006, 49, 467.
[14] Z. Xu, S. J. Zhao, Y. Liu, Eur. J. Med. Chem. 2019, 183,
111700.
[31] F. Zhao, Z. Chen, K. Xie, R. Yang, Y.-B. Jiang, Chin. Chem.
Lett. 2016, 27(1), 109.
[32] S. Mohammed, A. K. Padala, B. A. Dar, B. Singh, B. Sreedhar,
R. A. Vishwakarma, S. B. Bharate, Tetrahedron. 2012, 68, 8156.
[33] Q. Liu, Y. Tor, Org. Lett. 2003, 5(14), 2571.
[34] J. Raushel, S. M. Pitram, V. V. Fokin, Org. Lett. 2008, 10(16),
3385.
[35] M. Mallie, J. M. Bastide, A. Blancard, et al., Int. J. Antimicrob.
Agents. 2005, 25, 321.
[36] P. Subramaniam, N. Nandan, Contemp. Clin. Dent. 2011,
2, 287.
[37] T. Mosmann, J. Immunol. Methods. 1983, 65, 55.
[15] K. Lal, P. Yadav, Anti-Cancer Agents Med. Chem. 2018, 18, 21.
[16] S. J. Brickner, D. K. Hutchinson, M. R. Barbachyn,
P. R. Manninen, D. A. Ulanowicz, S. A. Garmon, K. C. Grega,
S. K. Hendges, D. S. Toops, C. W. Ford, G. E. Zurenko, J. Med.
Chem. 1996, 39, 673.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
[17] O. A. Phillips, E. E. Udo, M. E. Abdel-Hamid, R. Varghese,
Eur. J. Med. Chem. 2009, 44, 3217.
[18] O. A. Phillips, E. E. Udo, A. A. M. Ali, N. Al-Hassawi, Bioorg.
Med. Chem. 2003, 11, 35.
[19] B. K. Swamy, S. Narsimha, N. V. Reddy, B. Priyanka, M. S.
J. S. Rao, Chem. Soc. 2016, 81, 233.
[20] B. K. Swamy, S. Narsimha, T. R. Kumar, Y. N. Reddy,
N. V. Reddy, ChemistrySelect. 2017, 2, 9595.
[21] S. Narsimha, T. R. Kumar, N. S. Kumar, S. Yakub,
N. V. M. Reddy, Chem. Res. 2014, 23, 5321.
How to cite this article: Narsimha S, Nukala SK,
Savitha Jyostna T, Ravinder M, Srinivasa Rao M,
Vasudeva Reddy N. One-pot synthesis and
biological evaluation of novel 4-[3-fluoro-4-
(morpholin-4-yl)]phenyl-1H-1,2,3-triazole
derivatives as potent antibacterial and anticancer
agents. J Heterocyclic Chem. 2020;1–11. https://doi.
org/10.1002/jhet.3890
[22] S. Narsimha, N. S. Kumar, B. K. Swamy, N. V. Reddy,
S. K. Althaf Hussain, M. S. Rao, Bioorg. Med. Chem. Lett. 2016,
26, 1639.