Synthesis, crystal structure and antimicrobial potential of some fluorinated chalcone-1,2,3-triazole conjugates

Article abstract of DOI:10.1016/j.ejmech.2018.05.055

A simple and green synthesis of some fluorinated chalcone-triazole hybrids from propargylated chalcones and organic azides catalyzed by cellulose supported copper nanoparticles click reaction is reported. All the synthesized compounds were well characterized by various analytical and spectroscopic methods. The X-rays crystallographic study of compounds 6k revealed the self assembling properties. The antimicrobial screening results of all the synthesized compounds revealed that most of the triazole hybrids exhibited significant efficacy against tested bacterial and fungal strains. The activity results showed the synergistic effect of biological activity when two pharmacophoric units, i.e. chalcone and 1,2,3-triazole are conjugated. Further, docking simulation of the most active compounds 6p into Escherichia coli topoisomerase II DNA Gyrase B was also carried out.

Full text of DOI:10.1016/j.ejmech.2018.05.055

Accepted Manuscript
Designed chalcone-1,2,3-triazole conjugates as potential antimicrobial agents
synthesis, crystal structure and antimicrobial potential of some fluorinated
chalcone-1,2,3-triazole conjugates
Pinki Yadav, Kashmiri Lal, Lokesh Kumar, Ashwani Kumar, Anil Kumar, Avijit K. Paul,
Rajnish Kumar
PII:
S0223-5234(18)30480-X
10.1016/j.ejmech.2018.05.055
EJMECH 10466
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 10 March 2018
Revised Date: 18 May 2018
Accepted Date: 31 May 2018
Please cite this article as: P. Yadav, K. Lal, L. Kumar, A. Kumar, A. Kumar, A.K. Paul, R. Kumar,
Designed chalcone-1,2,3-triazole conjugates as potential antimicrobial agents synthesis, crystal
structure and antimicrobial potential of some fluorinated chalcone-1,2,3-triazole conjugates, European
Journal of Medicinal Chemistry (2018), doi: 10.1016/j.ejmech.2018.05.055.
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ACCEPTED MANUSCRIPT
Designed chalcone-1,2,3-triazole conjugates as potential antimicrobial agents

ACCEPTED MANUSCRIPT
Synthesis, crystal structure and antimicrobial potential of some fluorinated chalcone-1,2,3-
triazole conjugates
Pinki Yadav,1 Kashmiri Lal,1* Lokesh Kumar,1 Ashwani Kumar,2 Anil Kumar3, Avijit K. Paul4,
and Rajnish Kumar5
1Department of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar,
Haryana 125001, India
2Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and
Technology, Hisar, Haryana 125001, India
3Department of Bio and Nanotechnology, Guru Jambheshwar University of Science and
Technology, Hisar, Haryana 125001, India
4Department of Chemistry, National Institute of Technology, Kurukshetra, Haryana 136119,
India
5Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research,
Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden
*Corresponding author: klal_iitd@yahoo.com (Kashmiri Lal)
Abstract
A simple and green synthesis of some fluorinated chalcone-triazole hybrids from propargylated
chalcones and organic azides catalyzed by cellulose supported copper nanoparticles click
reaction is reported. All the synthesized compounds were well characterized by various
analytical and spectroscopic methods. The X-rays crystallographic study of compounds 6k
revealed the self assembling properties. The antimicrobial screening results of all the synthesized
compounds revealed that most of the triazole hybrids exhibited significant efficacy against tested
bacterial and fungal strains. The activity results showed the synergistic effect of biological
activity when two pharmacophoric units, i.e. chalcone and 1,2,3-triazole are conjugated. Further,
docking simulation of the most active compounds 6p into Escherichia coli topoisomerase II
DNA Gyrase B was also carried out.

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Key words: Fluoronated compounds, Chalcones, 1,2,3-triazoles, antimicrobial activity, docking
studies
1. Introduction
The development of fluorine containing scaffolds has gain a real interest especially in organic
and pharmaceutical areas due to their unique chemical and physiological properties.1-4 Due to
unique properties of fluorine, there is an enormous progress of fluorine-containing drugs which
continue to stimulate research on fluorine in medicinal chemistry for drug discovery.5
Fluorination of an organo-molecule significantly affects its biological properties. Introduction of
fluorine atom could somewhere alter the course and biological activity of the compounds. Due to
the size of the fluorine atom and its electro negativity, the insertion of a fluorine atom or a
trifluoromethyl (CF3) group in the moiety also changes both pharmacodynamics and
pharmacokinetics of the molecule. Somewhere the replacement of the oxidizable C-H bond by a
C-F bond acts as a key factor that increases the biological half life of a drug and also increases its
metabolic stability.5
1,2,3-triazoles are the important class of heterocyclic compounds that received enhanced
significant attention from last decade because of the wide applications in the field of
pharmaceutical, biochemical and material science.6-11 1,4-Disubstituted 1,2,3-triazoles have
attracted significant attention because of their broad range of biological activities including
antimicrobial,12-17
anticancer,18-23
antitubercular,24-26
antiviral,27
anti-inflammatory,28
antimalarial,29 anti-HIV,30 antidiabetic,31-32 anti-oxidant,33 antiallergic,34 etc. These are attractive
connecting units, since they are stable to oxidative/reductive conditions, metabolic degradation
and participate in hydrogen bonding and dipole-dipole interactions.35 The cellulose supported
copper nanoparticles catalyzed cycloaddition between terminal alkynes and organic azides is an
excellent method for the click synthesis of 1,2,3-triazoles in eco-friendly conditions in good
yield.36 The insertion of 1,2,3-triazoles and fluorine atom in the substrate led to excellent
pharmacological activity like anticancer activity,37 antimicrobial activity,38 antitubercular
activity,39 etc.
In addition, chalcones, also known as α,β-unsaturated ketones, are not only important
precursors for synthetic manipulation but also form a major component of the natural products.40-
41
Chalcones as well as their synthetic analogues show enormous biological activities42-47 and

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widely used as frameworks in drug design. The presence of double bond in conjugation with
carbonyl functionalities is known to be responsible for the biological activities. In view of this,
Yadav et al. efficiently synthesized benzaldehyde chalcone-triazole analogs for anticancer
activity towards human cancer cell lines and the study revealed that analog I was found as
potential anticancer agent (Figure 1).19 Interestingly, among the series of novel 1,2,3-triazole-
chalcone hybrids, compounds II and III in Figure 1 showed broad-spectrum antimicrobial
activity and antiplasmodial activity with MIC values of 6.25 µg/mL and IC50 values of 8.86
µg/mL, respectively.48 Recently we have also reported some naphthaldehyde linked 1,2,3-
triazoles as good antimicrobial compounds. Moreover, chalcones have also been reported as
biologically active molecules. Therefore, it was envisioned that the conjugation of chalcone and
naphthaldehyde linked 1,2,3-triazoles may lead to better antimicrobial agents. Therefore, on the
basis of aforementioned and as a part of our programme towards the development of triazole
based molecules of biological importance it was planned to synthesize some fluorinated
chalcone-triazole hybrids. Herein we report the synthesis of a series of chalcone-1,2,3-triazole
hybrids in water as potential antimicrobial agents.

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Figure 1: Structures of some biological active fluorinated 1,2,3-triazoles
Figure 2: Design of chalcone-1,2,3-triazole conjugates
2. Results and Discussion
2.1 Chemistry
The synthetic route for propargylated chalcones and chalcone-triazole hybrids is
presented in scheme 1 and 2. Commercially available 2-hydroxynaphthaldehyde (1) was
subjected to O-alkylation with 1.2 eq of propargyl bromide in presence of K2CO3 (1.5 eq) in
DMF at room temperature. Propargylated naphthaldehyde (2) thus obtained was further
condensed with variedly substituted acetophenones (3a-3c) via base catalyzed Claisen-Schmidt
condensation in presence of NaOH (60 %) to furnish propargylated chalcones in excellent yield
(4a-4c) and recrystallized with ethyl acetate/hexane.

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Scheme 1: Reagent and conditions: (i) propargyl bromide, K2CO3, acetone, reflux (ii)
acetophenones (3a-3c), NaOH (60 %), Ethanol, RT, 4 h.
The synthesis of the substituted 1,2,3-triazoles (6a-6r) was accomplished from
propargylated chalcones utilizing azide-alkyne cycloaddition reaction with appropriate azide
using cellulose supported copper nanoparticles (Scheme 2).36 Propargylated chalcones (4a-4c)
were then subjected to click reaction with sodium azide and various benzyl bromides (5a-5d;
method A) and organic azides (5e-5f; method A) catalyzed by cellulose supported copper
nanoparticles in water at 70 °C to yield 1,2,3-triazoles (6a-6r) in good yield. The organic azides
(5e-5f) were synthesized from aniline derivatives via reported method.49 The cellulose supported
copper catalyst can be reused to next turn without loss of significant activity. The reactions
proceeded very smoothly and afforded the desired products in excellent yield. The plausible
mechanism for the transformation of Propargylated chalcones and Sod./ Aryl azides in to
chalcone-triazole derivatives (scheme1; supplementary material).36

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Scheme 2: Reagent and conditions: (i) NaOH (60 %), Ethanol, RT, 4 h (ii) Method A: copper
nanoparticles; sodium azide; water; 70 °C; 4-7 h, Method B: copper nanoparticles;
water; 70 °C; 4-7 h.
1
The chemical structures of all the synthesized compounds (6a-6r) were confirmed by FTIR, H
NMR, 13C NMR and MS data.
IR analysis
The IR spectra of propargyl chalcones (4a-4c) exhibited two bands at 3178-3275 and
2114-2133 cm-1 due to alkyne ≡C-H stretching and C≡C stretching, respectively and were not
present in the spectra of all the triazoles (6a-6r). The IR spectrum of compound 6n exhibited a
characteristic band due to =C-H stretching of triazole at 3151 cm-1. The synthesized triazole 6n
displayed two absorption bands at 1579 cm-1 and 1658 cm-1, which were assigned to the
stretching vibrations of =C-H and C=O stretching, respectively.
1H NMR analysis

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1
The H NMR spectrum of compound 6n exhibited two characteristic doublets at δ 8.04
and δ 8.58 with a coupling constant (J) of 15.6 Hz. The high value of coupling constant
established the E-geometry of double bond in chalcones. A characteristic singlet at δ 7.70 due to
triazolyl proton confirmed the formation of triazole ring. Two singlets of methylene protons of
NCH2 and OCH2 each integrating for two protons resonated in the region δ 5.46 and δ 5.62.
19F NMR analysis
The 19F NMR spectrum of 6n showed a signal at δ -117.95 (dd, J1 = 22.56, J2 = 7.57 Hz)
which confirmed the presence of 2-fluoro benzene in the compound.
13C NMR analysis
The 13C NMR spectrum of 6n exhibited peaks of C-4 and C-5 carbon atoms of triazole at
δ 143.18 and δ 123.12, respectively. The signal due to Cα and Cβ carbon atoms of the α,β-
unsaturated carbonyl moiety of compound 6n were observed at δ 121.45 and δ 143.49,
respectively. The peak in the region δ 189.52 was attributed to the carbonyl carbon atom. Two
peaks of methylene carbons of OCH2 and NCH2 appeared at δ 62.52 and δ 47.61, respectively.
Mass analysis
The mass spectrum of compound 6n showed a peak at m/z 510.1 (M+H)+, which is in
good agreement with the molecular formula of the compound. The chemical shifts of proton and
carbon atoms were designated on the basis of DEPT-135, HSQC and HMBC spectra.
X-rays crystallography
X-rays crystallography of the compound 6k (recrystallized from ethanol) confirmed the
anticipated structure (Figure 3; Table 1 in supplementary material). Compound 6k crystallizes in
monoclinic crystal system with the space group P21/c. The asymmetric unit contains one
crystallographically independent molecule. Crystal structure shows that the plane of chalcone
group and triazole group is different. Five–membered triazole ring is almost in gauche
conformation with respect to the central biphenyl ring of the chalcone. Hence, the attached
flurobenzene ring is almost perpendicular to the chalcone moiety. The molecular structure is
stabilized by nonclassical hydrogen-bonding interactions. Here, the hydrogen donor atom is
carbon and acceptors are F, N and O atoms (Table 2 in supplementary material). C–H···O
interactions are mainly observed for intramolecular stabilization whereas C–H···F and C–H···N
interactions are observed for supramolecular stabilization (Figure 4). In the packing structure,
one can find the 21 screw-axis is extended along the crystallographic b-axis. .It is noteworthy that

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the weak C–H···F and C–H···N interactions are responsible for the three-dimensional packing and
such week interactions can play a crucial role for the biological activity.
Figure 3: Ortep diagram of the compound 6k

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Figure 4: Hydrogen bonded supramolecular packing diagram of the compound 6k (Pink color
dotted lines correspond to the observed hydrogen boning interactions).
2.2 Pharmacology
Antimicrobial activity
The target compounds and chalcone alkynes were examined towards Gram-positive
bacteria S. epidermidis (MTCC 6880), B. subtilis (MTCC 441), Gram-negative bacteria E. coli
(MTCC 16521), P. aeruginosa (MTCC 424) and two fungal strains viz. A. niger (MTCC 8189)
and C. albicans (MTCC 227) by standard serial dilution method.50 Ciprofloxacin and
Fluconazole were used as standard drug for antibacterial and antifungal analysis, respectively.
Minimum inhibitory concentrations (MIC in µmol/mL) of all the synthesized compounds as well
as positive controls II and III (Fig. 1) are depicted in Table 1.
Table 1: In vitro antimicrobial screening of the compounds 4a-4c; 6a-6r (MIC in µmol/mL).
B.
S.
P.
C.
Entry
Compounds
E. coli
A. niger
subtilis epidermidis aeruginosa albicons
1.
2.
0.0731 0.0731
0.0637 0.0637
0.1462
0.1274
0.0731
0.0637
0.0731
0.0637
0.0731
0.1274
4a
4b

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3.
0.0700 0.1400
0.0119 0.0239
0.0116 0.0116
0.0116 0.0116
0.0058 0.0058
0.0237 0.0474
0.0108 0.0217
0.0263 0.0263
0.0063 0.0253
0.0126 0.0253
0.0032 0.0253
0.0130 0.0261
0.0118 0.0236
0.0128 0.0063
0.0063 0.0063
0.0063 0.0126
0.0032 0.0063
0.0253 0.0126
0.0230 0.0459
0.0700
0.0119
0.0116
0.0232
0.0058
0.0474
0.0217
0.0526
0.0253
0.0253
0.0253
0.0522
0.0236
0.0063
0.0063
0.0063
0.0032
0.0253
0.0230
0.0047
----
0.0700
0.0119
0.0232
0.0232
0.0116
0.0474
0.0108
0.0263
0.0126
0.0253
0.0253
0.0261
0.0236
0.0128
0.0248
0.0063
0.0063
0.0253
0.0230
0.0047
----
0.0700
0.0119
0.0232
0.0232
0.0058
0.0474
0.0217
0.0526
0.0063
0.0126
0.0063
0.0130
0.0118
0.0128
0.0063
0.0063
0.0032
0.0126
0.0115
----
0.0700
0.0119
0.0232
0.0232
0.0058
0.0237
0.0108
0.0526
0.0253
0.0126
0.0126
0.0522
0.0118
0.0063
0.0063
0.0063
0.0032
0.0126
0.0459
----
4c
6a
6b
6c
6d
6e
6f
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
Ciprofloxacin 0.0047 0.0047
Fluconazole
II44
----
----
----
----
0.0102
>0.191
0.0714
0.0051
0.0956
0.1428
0.0956
>0.143
-----
>0.191
>0.143
III44
-----
The preliminary in vitro antibacterial screening indicated that the majority of the
synthesized compounds exhibited good activity. Compound 6p with 4-nitro group was found to
be more active than the standard with MIC value of 0.0032 µmol/mL against E. coli and S.
epidermidis. Moreover, 6j also showed excellent potency against E. coli with the MIC value of
0.0032 µmol/mL and was found to be more active than standard used. In case of B. subtilis,
compounds 6d exhibited high potency amongst all the tested compounds with MIC values of

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0.0058 µmol/mL. In case of P. aeruginosa, compounds 6o and 6p were found to be more active
compared to the all other tested compounds with MIC values of 0.0063 µmol/mL.
Most of the synthesized hybrids also exhibited good antifungal activity. Compound 6p
showed better potency compared to Fluconazole (MIC = 0.0102 µmol/mL) against A. niger and
C. albicans with MIC value of 0.0032 µmol/mL. Similarly, 6h, 6j, 6n and 6o showed excellent
activity against A. niger and C. albicans with the MIC value of 0.0032 µmol/mL which is better
than Fluconazole (MIC = 0.0102 µmol/mL). Against C. albicans, 6d with bromine group
exhibited comparable activity to that of standard with MIC values of 0.0054 µmol/mL.
Structure Activity Relationship
i)
Most of the fluorinated triazoles exhibited good results than the non-fluorinated
compound 6a.51
ii)
The synthesized triazole analogues with a substituted benzene showed better activity
than naphthaldehyde-chalcone alkynes (4a-4c), exhibiting the significance of 1,2,3-
triazole. These outcomes revealed the additive effect of biological activity when two
pharmacophoric moieties, i.e. chalcone and 1,2,3-triazole are conjugated.52
Compounds with electron withdrawing substituents on benzene displayed more
activity than having electron releasing groups.53
iii)
iv)
v)
It was observed that compounds with nitro and methoxy substituents on benzene ring
demonstrated better activity against majority of the microorganisms under test.
Molecule 6p containing p-nitro group exhibited good antifungal activity and was
more effective than Fluconazole.
vi)
vii)
Activity results also revealed that most of the triazole hybrids exhibited superior
antifungal potency compared to antibacterial activity.
Further, the biological activity of the synthesized compounds has been compared with
the positive control (II and III; Fig. 1) reported in the literature.44 It was observed that
all the synthesized triazoles were found to be more potent than the positive control II
and III against all the tested microbial strains.
Docking studies
The docking simulations most potent antibacterial compound 6p into ligand binding
region of E. coli topoisomerase II DNA gyrase B were carried out to get probable modes of
binding. The most stable binding conformation of 6p into active site of topoisomerase II DNA

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gyrase B and cartoon diagram are shown in Figure 5 and Figure 6, respectively. The carbonyl
group participated in hydrogen bonding with His95, Ala96 and Ser121 residues. Triazole ring as
well as phenyl ring attached to triazole is engaged in pi-alkyl interactions with Ile 78, while same
phenyl ring also demonstrated pi-alkyl interactions with Val120. The phenyl ring showed pi-
alkyl interactions with Ala 96 and pi-sigma interactions with Ile 90. Hence, it can be thought that
these chalcone triazole conjugates possibly inhibit DNA topoisomerase.
Figure 5: Binding conformation of compound 6p into topoisomerase II DNA Gyrase showing
different interactions i.e hydrogen bond (green lines), pi-alkyl (pink lines), pi-sigma
(magenta lines).

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Figure 6: Cartoon diagram of topoisomerase II DNA Gyrase alongwith docked 6p.
Molecular dynamics studies
We performed a 50 ns molecular dynamics simulation of ligand-protein complex obtained after
molecular docking study in order to reveal the dynamics of ligand binding into the active site of
enzyme. MD simulation gives important insight into the dynamics of interaction between the
partners and the overall stability of the complex which overcomes the limitation of x-ray
crystallography or molecular docking as these methods provides a still picture of the interaction.
The Fig. 7A represent the all atom (blue), backbone (green) root means square deviation
(RMSD) plot for the protein and ligand RMSD (magenta) plot. The RMSD plot indicates that the
protein remains stable throughout the 50 ns simulation period with very small fluctuations at the
starting point of simulation. The ligand RMSD remains fluctuating owing to its dynamic nature
and in order to accommodate and bind itself strongly in the protein binding pocket. It is also
observed that the ligand RMSD stabilized during the later half of simulation period. Further,
radius of gyration plot of Cα atoms of protein provided a measure of overall compactness of the
protein structure during simulation (Fig. 7B).
Additionally, in order to evaluate the flexibility of the protein structure throughout the
simulation, we calculated root mean square fluctuation (RMSF) of individual amino acid
residues of the protein (Fig. 7C). The whole protein had a RMSF value between 0.05 to 0.45
indicating a simulation.

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Figure 7: Qualitative analysis of the Molecular dynamics trajectory. RMSD plot of protein
and ligand (A). Radius of gyration plot of the protein (B). RMSF plot of the protein (C) and the
plot of hydrogen bonds formed between protein and ligand during the 50 ns simulation period.
(D).
One of important forces involved during protein ligand interaction is the hydrogen bonding and it
plays an indispensable role in stabilizing the protein-ligand complex. The average number of
hydrogen bonds formed during the simulation was calculated using a soft cut-off value of 3.5 Å
with the help of h-bond utility in GROMACS and are plotted in Fig. 7D. It was observed that the
ligand not only preserved the hydrogen bonds formed during the docking simulation, but also
makes new hydrogen bonds and thus stabilizes the complex. Especially, during the later half of
the simulation period, compound forms on an average 3 hydrogen bonds with the protein. It
indicates that the compound stabilizes itself into the binding pocket of the protein through
formation of additional contacts with the binding site amino acid residues.

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Finally, we extracted the coordinates from trajectory at 0, 15 and 50 ns time interval and made a
comparison. The structures are given in Fig. 7
3. Conclusion
We have synthesized some new fluorinated-chalcone-1,2,3-triazoles with potential
antimicrobial activity from substituted propargylated chalcones and organic azides by click
reaction under environmentally benign conditions. The X-ray crystallographic studies suggested
that molecular structure is stabilized by nonclassical hydrogen-bonding interactions. The
antimicrobial evaluation revealed that most of the compounds showed significant activity. The
antimicrobial screening results demonstrated the additive effect of activity when two
pharmacophoric moieties, i.e. 1,2,3-triazole and chalcone are connected. Docking studies also
showed that compound 6k interacts with DNA topoisomerase via various non covalent
interactions. Additionally, molecular dynamics study was also performed to get an insight into
the dynamics of ligand interaction.
4. Materials and Methods
4.1. Experimental section
General
All the melting points (ºC) were recorded in open capillaries and are uncorrected. The IR
spectra were taken on SHIMAZDU IR AFFINITY-I FTIR spectrophotometer using potassium
1
bromide (KBr). The H NMR and 13C NMR spectra were obtained at 400 and 100 MHz,
respectively on Bruker Avance III 400 nano bay using tetramethysilane (TMS). DEPT-135,
HMQC (heteronuclear multiple quantum coherence) or HSQC (heteronuclear single quantum
coherence) and HMBC (heteronuclear multiple bond correlation), 19F NMR experiments were
also parformed out for characterization of some compounds. MS spectra were recorded on Q-
TOF micromass (ESI-MS) Waters high resolution mass spectrometer. The analytical TLC was
recorded on readymade silica gel plates (SIL G/UV254, ALUGRAM) and visualized under
ultraviolet lamp. Starting materials were procured from Aldrich, Across, Hi-media, S. D. fine,
SRL etc. and were used as recieved.

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Single-Crystal Structure Determination
A suitable light yellow single crystal was carefully selected under a polarizing
microscope and glued to a thin glass fiber with a cyanoacrylate (superglue) adhesive. The single-
crystal data were collected on a Bruker D8 Advance diffractometer at 295(2) K. The data were
reduced using SAINTPLUS,54 and an empirical absorption correction was applied using the
SADABS program.55 The structure was solved and refined using SHELXL9756 present in the
WinGx suit of programs (Version 1.63.04a).57 All the hydrogen atoms were located from
difference Fourier map and refined using the riding model. The final refinement included atomic
positions for all of the atoms, anisotropic thermal parameters for all of the non-hydrogen atoms,
and isotropic thermal parameters for all the non-hydrogen atoms. Full-matrix least-squares
refinement against F2 was carried out using the WinGx package of programs. Details of the
structure solution and final refinements for the structure are given in Table 1. The
crystallographic data for the compound can be found in CCDC No: 1587460 by free of charge
from
www.ccdc.cam.ac.uk/data_request/cif.
General procedure for the synthesis of chalcone alkyne (4a-4c)19:
An aqueous solution of NaOH (3 mL, 60%) was added dropwise to a solution of
substituted acetophenone 3 (1 mmol) and 4- -propargylated naphthaldehyde 2 (1 mmol) in
The
Cambridge
Crystallographic
Data
Center
(CCDC)
via
O
ethanol (5-10 mL) with constant stirring. The reaction mixture was stirred for 3-4 h at room
temperature. Upon completion of the reaction as monitored by the TLC, reaction mixture was
diluted with ice cold water and filtered. The solid thus obtained was washed with ethanol 2-3
times followed by water and recrystallized from methanol: chloroform (7:3) to yield the
chalcones (4a-4c).
(E)-3-(4-methoxyphenyl)-1-(2-(prop-2-yn-1-yloxy)naphthalen-1-yl)prop-2-en-1-one (4a), Yield
89%; Yellow solid; mp 168–170 °C; IR (KBr, cm–1): 3283, 3056 (C-H), 2930, 2862, 2127
(C≡C), 1658 (C=O), 1592 (C=C), 1575, 1520, 1426, 1377, 1344, 1296, 1253, 1215, 1176, 1068,
1
1036, 1008, 989, 778, 743, 692, 642, 586, 537. H NMR (CDCl3, 400 MHz): 2.61 (t, 1H), 3.90
(s, OCH3, 3H), 4.92 (s, 2H, OCH2), 7.01 (d,
2H), 7.83 (d, = 8.4 Hz, 1H), 7.89 (d, = 9.2 Hz, 1H), 7.96 (d,
8.15 (m, 2H), 8.28 (d, = 8.4 Hz, 2H), 8.47 (d,
= 15.6 Hz, 1H, =C-H). 13C NMR (CDCl3, 100
MHz): δ 189.35 (C=O), 163.38, 154.76, 136.48, 133.04, 131.44, 131.32, 130.98, 129.62, 128.61,
J
= 8.0 Hz, 2H), 7.38-7.46 (m, 2H), 7.54-7.59 (m,
J
J
J
= 15.6 Hz, 1H, =C-H), 8.11-
J
J

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127.98, 127.48, 124.45, 123.75, 119.05, 114.39, 113.82, 78.56, 57.18 (OCH2), 55.48 (OCH3).
MS: m/z (M+) Cacld. for C23H18O3 : 342.1; found: 343.0 (M+H)+.
(E)-3-(4-bromophenyl)-1-(2-(prop-2-yn-1-yloxy)naphthalen-1-yl)prop-2-en-1-one (4b), Yield
91%; Yellow solid; mp 170–172 °C; IR (KBr, cm–1): 3287, 3058 (C-H), 2932, 2864, 2128
(C≡C), 1662 (C=O), 1596 (C=C), 1577, 1520, 1430, 1373, 1349, 1297, 1258, 1217, 1179, 1062,
1
1038, 1002, 988, 770, 739, 689, 639, 587, 540. H NMR (CDCl3, 400 MHz): 2.62 (t, 1H), 4.94
(s, 2H,OCH2), 7.39-7.44 (m, 1H), 7.46 (d,
J
= 8.0 Hz, 1H), 7.56-7.61 (m, 1H), 7.66 (d,
= 8.0 Hz, 1H), 7.91 (m, 1H), 7.94 (d, = 15.6 Hz, 1H, =C-H), 7.98 (d,
= 8.4 Hz, 2H), 8.51 (d,
J
= 8.4
= 8.0
Hz, 2H), 7.84 (d,
Hz, 2H), 8.27 (d,
J
J
J
J
J
= 15.6 Hz, 1H, =C-H). 13C NMR (CDCl3, 100 MHz):
δ 190.07 (C=O), 155.07, 137.84, 137.23, 133.06, 131.87, 130.24, 129.56, 128.70, 127.77,
127.71, 127.29, 124.56, 123.53, 118.42, 114.14, 78.37, 57.15 (OCH2). MS: m/z (M+) Cacld. for
C22H15BrO2 : 390.0; found: 391.1 (M+H)+.
(E)-3-(4-nitrophenyl)-1-(2-(prop-2-yn-1-yloxy)naphthalen-1-yl)prop-2-en-1-one (4c), Yield
83%; Yellow solid; mp 174–176 °C; IR (KBr, cm–1): 3287, 3058 (C-H), 2928, 2872, 2131
(C≡C), 1656 (C=O), 1594 (C=C), 1576, 1524, 1428, 1379, 1346, 1297, 1261, 1215, 1177, 1069,
1
1037, 1010, 983, 777, 746, 696, 644, 589, 538. H NMR (CDCl3, 400 MHz): 2.64 (t, 1H), 4.96
(s, 2H, OCH2), 7.40-7.48 (m, 2H), 7.58-7.63 (m, 1H), 7.85 (d,
J
= 8.0 Hz, 1H), 7.93 (m, 1H),
= 15.6 Hz, 1H, =C-H). 13C
7.97 (d, = 15.6 Hz, 1H, =C-H), 8.38 (d, = 8.4 Hz, 2H), 8.55 (d, J
J
J
NMR (CDCl3, 100 MHz): δ 189.72 (C=O), 155.23, 143.38, 139.08, 133.06, 132.45, 129.57,
128.80, 127.93, 126.83, 124.66, 123.79, 123.28, 117.64, 113.37, 76.30, 56.89 (OCH2). MS: m/z
(M+) Cacld. for C22H15NO4 : 352.1; found: 353.3 (M+H)+.
General procedure for the synthesis of triazoles (6a-6r)36, 38
:
A suspension of propargylated chalcones (4a-4c) (1 mmol), substituted benzyl bromides
(1 mmol), sodium azide (1.2 mmol), water (2 mL) and cellulose supported CuI nanoparticles (0.1
g) was heated at 70 °C for 4-7 h. Upon completion of reaction as monitored by TLC, the reaction
mixture was filtered and residue was washed with ethyl acetate three times (3×30 mL). The
organic extract was washed with water followed by brine and dried over Na2SO4 and
concentrated under vacuum. The solid obtained was recrystallized from methanol: chloroform
(7:3) to yield the pure products (6a-6r).
(E)-3-(2-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-yl)-1-(4-bromophenyl)prop-
2-en-1-one (6a), Yield 88%; Yellow solid; mp 184–186 °C; IR (KBr, cm–1): 3177, 3162 (C-H,

ACCEPTED MANUSCRIPT
triazole), 3048 (C-H), 2953, 2879, 1669 (C=O), 1594 (C=C), 1578, 1524, 1459, 1399, 1289,
1
1258, 1222, 1178, 1078, 1048, 1010, 828, 777, 520. H NMR (CDCl3, 400 MHz): δ 5.44 (s, 2H,
NCH2), 5.52 (s, 2H, OCH2), 7.20–7.22 (m, 2H), 7.31–7.33 (m, 3H), 7.43-7.47 (m, 2H), 7.56 (s,
1H, triazolyl–H), 7.56-7.60 (m, 1H), 7.64 (d,
J
= 8.8 Hz, 2H), 7.85-7.92 (m, 5H), 8.04 (d,
J =
15.6 Hz, 1H, =C-H), 8.25 (d, = 8.8 Hz, 2H), 8.49 (d,
J
J
= 15.6 Hz, 1H, =C-H). 13C NMR
(CDCl3, 100 MHz): δ 189.92 (C=O), 155.82, 143.94 (C-4), 137.75, 137.13, 134.23, 133.13,
132.12, 131.19 130.20, 129.38, 129.17, 128.88, 128.02, 127.77, 127.70, 126.90, 124.42, 123.40,
122.91 (C-5), 117.95, 114.19, 63.21 (OCH2), 54.32 (NCH2). MS: m/z (M+) Cacld. for
C29H22BrN3O2 : 523.1; found: 525.7 (M+2H)+.
(E)-1-(4-bromophenyl)-3-(2-((1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-
1-yl)prop-2-en-1-one (6b), Yield 89%; Yellow solid; mp 188–190 °C; IR (KBr, cm–1): 3189,
3148 (C-H, triazole), 3046 (C-H), 2949, 2879, 1658 (C=O), 1591 (C=C), 1577, 1522, 1458,
1397, 1295, 1258, 1218, 1177, 1075, 1045, 1009, 828, 774, 520. 1H NMR (CDCl3, 400 MHz): δ
5.44 (s, 2H, NCH2), 5.58 (s, 2H, OCH2), 7.06-7.11 (m, 2H), 7.23 (t,
(m, 1H), 7.43-7.48 (m, 2H), 7.56-7.58 (m, 2H), 7.60-7.67 (m, 2H), 7.83-7.93 (m, 5H, triazolyl–
H, =C-H + 3ArH), 8.26 (d, = 8.0 Hz, 1H), 8.49 (d,
= 15.6 Hz, 1H, =C-H). 13C NMR (CDCl3,
J = 8.0 Hz, 1H), 7.32–7.34
J
J
100 MHz): δ 189.90 (C=O), 161.71, 159.23, 155.83, 143.88 (C-4), 137.65, 137.10, 133.14,
132.11, 131.85, 131.11, 131.03, 130.18, 129.35, 128.71, 127.69, 126.87, 124.84, 124.40, 123.38,
123.15, 121.63, 121.51 (C-5), 117.88, 115.98, 116.77, 114.12, 63.10 (OCH2), 47.94 (NCH2).
MS: m/z (M+) Cacld. for C29H21BrN3O2 : 541.1; found: 543.8 (M+2H)+.
(E)-1-(4-bromophenyl)-3-(2-((1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-
1-yl)prop-2-en-1-one (6c), Yield 87%; Yellow solid; mp 196–198 °C; IR (KBr, cm–1): 3179,
3149 (C-H, triazole), 3052 (C-H), 2947, 2882, 1655 (C=O), 1593 (C=C), 1576, 1524, 1458,
1397, 1295, 1258, 1218, 1177, 1075, 1045, 1009, 828, 774, 520. 1H NMR (CDCl3, 400 MHz): δ
5.46 (s, 2H, NCH2), 5.51 (s, 2H, OCH2), 6.91-6.94 (m, 1H), 6.98 (d,
(m, 1H), 7.26-7.32 (m, 2H), 7.45 (t, = 8.0 Hz, 2H), 7.56-7.61 (m, 2H), 7.63-7.65 (m, 2H), 7.84-
7.93 (m, 5H, triazolyl–H, =C-H + 3ArH), 8.25 (d, = 12 Hz, 1H), 8.48 (d, = 15.6 Hz, 1H, =C-
J = 8.0 Hz, 1H), 7.01–7.06
J
J
J
H). 13C NMR (CDCl3, 100 MHz): δ 189.90 (C=O), 164.18, 161.72, 155.72, 144.18 (C-4), 137.80,
137.08, 136.56, 133.06, 132.15, 131.89, 130.87, 130.79, 130.19, 129.37, 128.74, 127.80, 127.73,
126.91, 124.45, 123.48, 123.45, 123.39, 122.99 (C-5), 117.98, 116.02, 115.81, 115.08, 114.86,

ACCEPTED MANUSCRIPT
114.16, 63.18 (OCH2), 53.52 (NCH2). MS: m/z (M+) Cacld. for C29H21BrN3O2 : 541.1; found:
543.8 (M+2H)+.
(E)-1-(4-bromophenyl)-3-(2-((1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-
1-yl)prop-2-en-1-one (6d), Yield 88%; Yellow solid; mp 196–198 °C; IR (KBr, cm–1): 3182,
3153 (C-H, triazole), 3074 (C-H), 2946, 2884, 1655 (C=O), 1594 (C=C), 1577, 1531, 1459,
1398, 1296, 1257, 1220, 1179, 1077, 1046, 1009, 827, 775, 522. 1H NMR (CDCl3, 400 MHz): δ
5.44 (s, 2H, NCH2), 5.48 (s, 2H, OCH2), 6.98-7.03 (m, 2H), 7.19-7.22 (m, 2H), 7.43–7.47 (m,
2H), 7.56-7.60 (m, 2H), 7.65 (d,
8.25 (d, = 12 Hz, 1H), 8.47 (d,
J
J
= 8.0 Hz, 2H), 7.83-7.92 (m, 5H, triazolyl–H, =C-H + 3ArH),
= 15.6 Hz, 1H, =C-H). 13C NMR (CDCl3, 100 MHz): δ 189.88
J
(C=O), 164.09, 161.54, 155.69, 144.03 (C-4), 137.80, 137.08, 133.06, 132.12, 131.90, 130.18,
129.95, 129.38, 128.72, 127.80, 127.73, 126.95, 124.46, 123.40, 122.79 (C-5), 118.03, 116.29,
116.08, 114.20, 63.23 (OCH2), 53.54 (NCH2). MS: m/z (M+) Cacld. for C29H21BrN3O2 : 541.1;
found: 543.8 (M+2H)+.
(E)-1-(4-bromophenyl)-3-(2-((4-fluorophenyl-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-
yl)-prop-2-en-1-one (6e), Yield 92%; Yellow solid; mp 188–190 °C; IR (KBr, cm–1): 3184, 3156
(C-H, triazole), 3049 (C-H), 2953, 2876, 1657 (C=O), 1592 (C=C), 1575, 1530, 1467, 1388,
1
1295, 1259, 1219, 1170, 1084, 1049, 1008, 829, 776, 520. H NMR (CDCl3, 400 MHz): δ 5.52
(s, 2H, OCH2), 7.21-7.26 (m, 2H), 7.45–7.49 (m, 1H), 7.51 (d,
J = 9.2 Hz, 1H), 7.55-7.58 (m,
2H), 7.60-7.62 (m, 1H), 7.64-7.67 (m, 2H), 7.82-7.87 (m, 3H), 7.90-7.97 (m, 2H), 8.06 (s, 1H,
13
triazolyl-H), 8.27 (d,
J
= 8.4 Hz, 1H), 8.54 (d,
J
= 15.6 Hz, 1H, =C-H). C NMR (CDCl3, 100
MHz): δ 189.72 (C=O), 155.83, 144.57 (C-4), 137.93, 137.11, 133.12, 132.26, 131.91, 130.08,
129.47, 128.74, 127.83, 126.96, 124.55, 123.45, 122.49 (C-5), 122.41, 121.22, 118.08, 116.97,
116.74, 114.12, 63.21 (OCH2). MS: m/z (M+) Cacld. for C28H19BrFN3O2 : 527.1; found: 529.8
(M+H)+.
(E)-1-(4-bromophenyl)-3-(2-((1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)
naphthalene-1-yl)prop-2-en-1-one (6f), Yield 92%; Yellow solid; mp 196–198 °C; IR (KBr,
cm–1): 3187, 3164 (C-H, triazole), 3039 (C-H), 2948, 2879, 1657 (C=O), 1590 (C=C), 1578,
1
1520, 1458, 1398, 1287, 1264, 1218, 1170, 1068, 1040, 1011, 829, 776, 520. H NMR (CDCl3,
400 MHz): δ 5.56 (s, 2H, OCH2), 7.45-7.51 (m, 2H), 7.55-7.62 (m, 3H), 7.68 (t,
J = 8.0 Hz, 1H),
7.74 (d, = 8.0 Hz, 1H), 7.85-7.92 (m, 5H), 7.95 (d, = 9.2 Hz, 1H), 8.06 (m, 1H), 8.21 (s, 1H,
J
J

ACCEPTED MANUSCRIPT
13
triazolyl–H), 8.26 (d,
J = 8.4 Hz, 1H), 8.52 (d, J = 15.6 Hz, 1H, =C-H). C NMR (CDCl3, 100
MHz): δ 189.72 (C=O), 155.58, 144.94 (C-4), 137.95, 137.13, 137.02, 133.03, 132.74, 132.40,
132.18, 131.89, 130.63, 130.07, 129.57, 128.76, 127.85, 127.80, 127.63, 125.64, 125.61, 124.58,
123.50, 123.39 (C-5), 121.88, 121.01, 117.38, 114.27, 63.21 (OCH2). MS: m/z (M+) Cacld. for
C29H19BrF3N3O2 : 577.1; found: 579.2 (M+2H)+.
(E)-3-(2-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-yl)-1-(4-methoxyphenyl)
prop-2-en-1-one (6g), Yield 79%; Yellow solid; mp 188–190 °C; IR (KBr, cm–1): 3182, 3152
(C-H, triazole), 3044 (C-H), 2948, 2877, 1657 (C=O), 1590 (C=C), 1575, 1520, 1457, 1398,
1
1294, 1256, 1217, 1170, 1074, 1040, 1008, 827, 776, 520. H NMR (CDCl3, 400 MHz): δ 3.92
(s, OCH3, 3H), 5.44 (s, 2H, NCH2), 5.48 (s, 2H, OCH2), 7.00 (d,
Hz, 1H), 7.19 (d, = 1.6 Hz, 1H), 7.29-7.32 (m, 3H), 7.42-7.47 (m, 2H), 7.56 (s, 1H, triazolyl–
H), 7.57 (dd, = 4.0 Hz, 1H), 7.84 (d,
= 8.0 Hz, 2H), 8.26 (d,
J = 8.0 Hz, 2H), 7.17 (d, J = 2.4
J
J
J
= 8.0 Hz, 1H), 7.87-7.91 (m, 2H, =C-H +1ArH), 8.02 (d,
13
J
J
= 8.0 Hz, 1H), 8.43 (d,
J
= 15.6 Hz, 1H, =C-H). C NMR (CDCl3,
100 MHz): δ 189.23 (C=O), 163.37, 155.41, 144.17 (C-4), (C-4), 136.56, 134.28, 133.03,
131.59, 131.30, 130.93, 129.40, 129.11, 128.78, 128.63, 127.99, 127.60, 127.49, 124.33, 123.62,
122.98 (C-5), 118.59, 114.43, 113.85, 63.43 (OCH2), 55.52 (NCH2), 54.25 (OCH3). MS: m/z
(M+) Cacld. for C30H25N3O3 : 475.2; found: 476.0 (M+H)+.
(E)-3-(2-((2-fluorobenzyl-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-yl)-1-(4-methoxy
phenyl)prop-2-en-1-one (6h), Yield 90%; Yellow solid; mp 192–194 °C; IR (KBr, cm–1): 3186,
3158 (C-H, triazole), 3047 (C-H), 2958, 2873, 1658 (C=O), 1591 (C=C), 1575, 1522, 1458,
1399, 1290, 1256, 1218, 1170, 1084, 1043, 1013, 827, 777, 522. 1H NMR (CDCl3, 400 MHz): δ
3.92 (s, 3H, OCH3), 5.44 (s, 2H, NCH2), 5.48 (s, 2H, OCH2), 7.00 (d,
(m, 2H), 7.31–7.32 (m, 3H), 7.42-7.47 (m, 2H), 7.54-5 (m, 2H, triazolyl–H + 1ArH), 7.84 (d,
8.0 Hz, 1H), 7.89 (dd, = 4.0 Hz, 1H), 7.89 (d, = 15.6 Hz, 1H, =C-H), 8.02 (d, = 12 Hz, 2H),
8.26 (d, = 12.0 Hz, 1H), 8.43 (d,
= 16.0 Hz, 1H, =C-H). 13C NMR (CDCl3, 100 MHz): δ
J = 8.0 Hz, 2H), 7.17-7.19
J
=
J
J
J
J
J
189.12 (C=O), 163.37, 155.30, 144.17 (C-4), 136.56, 134.28, 133.03, 131.59, 131.30, 130.93,
129.40, 129.11, 128.78, 128.63, 127.99, 127.60, 127.49, 124.33, 123.62, 122.98 (C-5), 118.59,
114.43, 113.85, 109.14, 63.43 (OCH2), 55.52 (NCH2), 54.25 (OCH3). MS: m/z (M+) Cacld. for
C30H24FN3O3 : 492.8; found: 493.9 (M+H)+.
(E)-3-(2-((3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-yl)-1-(4-methoxy

ACCEPTED MANUSCRIPT
phenyl)prop-2-en-1-one (6i), Yield 88%; Yellow solid; mp 188–190 °C; IR (KBr, cm–1): 3186,
3155 (C-H, triazole), 3049 (C-H), 2958, 2867, 1659 (C=O), 1594 (C=C), 1576, 1524, 1457,
1399, 1294, 1257, 1218, 1170, 1075, 1040, 1008, 828, 776, 520. 1H NMR (CDCl3, 400 MHz): δ
3.92 (s, 3H, OCH3), 5.46 (s, 2H, NCH2), 5.48 (s, 2H, OCH2), 6.90-7.04 (m, 4H), 7.23-7.27 (m,
2H), 7.43-7.47 (m, 2H), 7.55-7.59 (m, 2H), 7.60 (s, 1H, triazolyl–H), 7.84 (d,
J = 8.0 Hz, 2H),
7.88 (d,
J
= 15.6 Hz, =C-H, 1H), 8.08 (d,
J
= 12 Hz, 2H), 7.90 (d,
J
= 8.0 Hz, 2H), 8.02 (d, J =
13
8.0 Hz, 2H), 8.26 (d,
J
= 8.0 Hz, 2H), 8.43 (d,
J
= 15.6 Hz, 1H, =C-H). C NMR (CDCl3, 100
MHz): δ 189.21 (C=O), 164.15, 163.38, 161.69, 155.31, 144.48 (C-4), 136.69, 136.67, 136.62,
131.61, 131.24, 130.93, 129.44, 128.65, 127.67, 127.52, 124.37, 123.65, 123.47, 123.03 (C-5),
118.72, 115.92, 115.71, 114.85, 114.46, 113.85, 63.49 (OCH2), 55.52 (NCH2), 53.57 (OCH3).
MS: m/z (M+) Cacld. for C30H24FN3O3 : 492.8; found: 493.9 (M+H)+.
(E)-3-(2-((4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-yl)-1-(4-methoxy
phenyl)prop-2-en-1-one (6j), Yield 86%; Yellow solid; mp 184–186 °C; IR (KBr, cm–1): 3186,
3155 (C-H, triazole), 3048 (C-H), 2949, 2876, 1657 (C=O), 1591 (C=C), 1576, 1524, 1458,
1399, 1295, 1256, 1219, 1177, 1078, 1047, 1012, 828, 776, 520. 1H NMR (CDCl3, 400 MHz): δ
3.92 (s, 3H, OCH3), 5.44 (s, 2H,NCH2), 5.45 (s, 2H, OCH2), 6.95-7.01 (m, 4H), 7.15-7.19 (m,
2H), 7.42-7.46 (m, 2H),7.55-7.59 (m, 2H), 7.70 (s, 1H, triazolyl–H), 7.87 (d,
J = 8.0 Hz, 2H),
7.96 (d, = 8.0 Hz, 2H), 8.04 (d, = 15.6 Hz, 1H, =C-H). 8.08 (d, = 12 Hz, 2H), 8.42 (d, J =
J
J
J
15.6 Hz, 1H, =C-H) 13C NMR (CDCl3, 100 MHz): δ 189.19 (C=O), 164.06, 163.41, 161.58,
155.30, 144.41 (C-4), 136.69, 132.96, 131.58, 131.24, 130.92, 130.16, 130.13, 129.93, 129.84,
129.44, 128.64, 127.70, 127.53, 124.38, 123.65, 122.81 (C-5), 118.77, 116.23, 116.01, 114.49,
113.86, 63.54 (OCH2), 55.52 (NCH2), 53.48 (OCH3). MS: m/z (M+) Cacld. for C30H24FN3O3 :
492.8; found: 493.9 (M+H)+.
(E)-3-(2-((4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-yl)-1-(4-methoxy
phenyl)prop-2-en-1-one (6k), Yield 90%; Yellow solid; mp 200–202 °C; IR (KBr, cm–1): 3188,
3158 (C-H, triazole), 3064 (C-H), 2956, 2878, 1657 (C=O), 1591 (C=C), 1575, 1522, 1457,
1399, 1295, 1256, 1218, 1177, 1074, 1048, 1008, 828, 776, 520. 1H NMR (CDCl3, 400 MHz): δ
3.48 (s, 3H, OCH3), 5.54 (s, 2H, OCH2), 6.90-6.93 (m, 2H), 7.16-7.20 (m, 2H), 7.44-7.51 (m,
2H), 7.57-7.65 (m, 3H), 7.86 (d,
8.28 (d, = 8.8 Hz, 1H), 8.49 (d,
J
= 8.0 Hz, 2H), 7.92-7.97 (m, 2H), 8.07 (s, 1H, triazolyl–H),
= 15.6 Hz, =C-H, 1H). 13C NMR (CDCl3, 100 MHz): δ 192.36
J
J
(C=O), 168.17, 160.65, 155.23, 146.17, 143.73 (C-4), 142.35, 139.16, 138.94, 131.99, 131.05,

ACCEPTED MANUSCRIPT
130.36, 130.26, 130.22, 130.18, 130.16, 130.08, 130.00, 129.89, 128.78, 123.57 (C-5), 122.47,
120.92, 119.15, 118.99, 117.62, 115.03, 102.36, 61.86, (OCH2), 53.57 (OCH3). MS: m/z (M+)
Cacld. for C29H22FN3O3 : 479.1; found: 480.2 (M+H)+.
(E)-1-(4-methoxyphenyl)-3-(2-((1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)
naphthalene-1-yl)prop-2-en-1-one (6l), Yield 90%; Yellow solid; mp 192–194 °C; IR (KBr,
cm–1): 3185, 3159 (C-H, triazole), 3064 (C-H), 2958, 2868, 1657 (C=O), 1592 (C=C), 1575,
1
1522, 1457, 1388, 1294, 1257, 1218, 1170, 1077, 1040, 1009, 827, 777, 520. H NMR (CDCl3,
400 MHz): δ 3.80 (s, 3H, OCH3), 5.52 (s, 2H, OCH2), 6.88 (d,
2H), 7.55-7.63 (m, 2H), 7.69 (d, = 8.0 Hz, 1H), 7.83-7.93 (m, 4H), 7.98 (d,
8.08 (m, 1H), 8.24 (s, triazolyl–H, 1H). 8.26 (d, = 8.4 Hz, 1H), 8.47 (d, = 15.6 Hz, =C-H,
J
= 8.8 Hz, 2H), 7.43-7.46 (m,
J
J
= 8.8 Hz, 2H),
J
J
1H). 13C NMR (CDCl3, 100 MHz): δ 189.15 (C=O), 163.38, 155.26, 145.21 (C-4), 137.16,
136.69, 132.98, 131.69, 131.13, 130.84, 130.51, 129.55, 128.69, 127.74, 127.61, 125.42, 124.48,
123.67, 123.29 (C-5), 121.10, 118.87, 117.39, 114.41, 113.82, 63.50 (OCH2), 55.22, 29.70.
HRMS: m/z (M+) Cacld. for C29H22FN3O3 : 479.1645 found: (M+H)+. MS: m/z (M+) Cacld. for
C30H22F3N3O3 : 529.1; found: 530.0 (M+H)+.
(E)-3-(2-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-yl)-1-(4-nitrophenyl)prop-2-
en-1-one (6m), Yield 86%; Yellow solid; mp 186–188 °C; IR (KBr, cm–1): 3178, 3162 (C-H,
triazole), 3046 (C-H), 2958, 2876, 1658 (C=O), 1592 (C=C), 1576, 1522, 1458, 1388, 1296,
1
1257, 1218, 1176, 1075, 1046, 1009, 827, 777, 520. H NMR (CDCl3, 400 MHz): δ 5.46 (s, 2H,
NCH2), 5.62 (s, 2H, OCH2), 7.04–7.12 (m, 2H), 7.30–7.36 (m, 2H), 7.45-7.49 (m, 2H), 7.61 (t,
1H), 7.70 (s, 1H, triazolyl–H), 7.85 (d,
15.6 Hz, =C-H, 1H), 8.14 (d, = 12 Hz, 2H), 8.28 (d,
8.58 (d,
= 15.6 Hz, =C-H, 1H). 13C NMR (CDCl3, 100 MHz): δ 189.56 (C=O), 164.15, 161.74,
J
= 8.0 Hz, 1H), 7.95 (d,
J
= 8.0 Hz, 2H), 8.04 (d,
J =
J
J
= 8.0 Hz, 1H), 8.32 (d,
J
= 8.0 Hz, 2H),
J
156.22, 149.99, 143.82, 143.17 (C-4), 138.80, 132.71, 129.63, 128.83, 127.94, 126.42, 124.55,
123.77, 123.15 (C-5), 117.38, 116.04, 115.83, 115.04, 114.82, 113.92, 62.87 (OCH2), 53.66
(NCH2). MS: m/z (M+) Cacld. for C29H22N4O4 : 490.1; found: 491.2 (M+H)+.
(E)-3-(2-((1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-yl)-1-(4-nitro
phenyl)prop-2-en-1-one (6n), Yield 89%; Yellow solid; mp 194–196 °C; IR (KBr, cm–1): 3183,
3156 (C-H, triazole), 3057 (C-H), 2938, 2849, 1656 (C=O), 1593 (C=C), 1572, 1524, 1459,
1
1395, 1356, 1295, 1256, 1218, 1170, 1075, 1040, 1012, 827, 777, 520. H NMR (CDCl3, 400
MHz): δ 5.46 (s, 2H, NCH2), 5.62 (s, 2H, OCH2), 7.04–7.12 (m, 2H), 7.30–7.36 (m, 2H), 7.45-

ACCEPTED MANUSCRIPT
7.49 (m, 2H), 7.61 (t, 1H), 7.70 (s, 1H, triazolyl–H), 7.85 (d,
2H), 8.04 (d, = 15.6 Hz, =C-H, 1H). 8.14 (d, J = 12 Hz, 2H), 8.28 (d,
= 8.0 Hz, 2H), 8.58 (d,
J
= 8.0 Hz, 2H), 7.95 (d,
= 8.0 Hz, 1H), 8.32 (d,
= 15.6 Hz, =C-H, 1H). C NMR (CDCl3, 100 MHz): δ 189.52 (C=O),
J = 8.0 Hz,
J
J
J
13
J
161.79, 159.27, 156.15, 149.85, 143.49, 143.18 (C-4), 138.41, 133.22, 132.56, 131.18, 131.10,
130.70, 130.67, 129.61, 129.30, 128.82, 127.91, 126.28, 124.90, 124.50, 123.75, 123.23, 123.12
(C-5), 121.59, 121.45, 117.20, 115.98, 115.77, 62.52 (OCH2), 47.61 (NCH2). MS: m/z (M+)
Cacld. for C29H21FN4O4 : 508.1; found: 509.1 (M+H)+.
(E)-3-(2-((1-(3-fluorobenzyl-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-yl)-1-(4-nitro
phenyl)prop-2-en-1-one (6o), Yield 91%; Yellow solid; mp 192–194 °C; IR (KBr, cm–1): 3184,
3157 (C-H, triazole), 3048 (C-H), 2938, 2857, 1657 (C=O), 1591 (C=C), 1576, 1522, 1458,
1
1398, 1345, 1295, 1257, 1217, 1179, 1074, 1043, 1008, 827, 776, 520. H NMR (CDCl3, 400
MHz): δ 5.45 (s, 2H, NCH2), 5.56 (s, 2H, OCH2), 7.22–7.25 (m, 2H), 7.31–7.33 (m, 2H), 7.46 (t,
J
= 8.0 Hz, 2H), 7.58-7,62 (m, 2H, triazolyl–H + 1ArH), 7.85 (d,
8.0 Hz, 1H), 8.02 (d, = 15.6 Hz, =C-H, 1H), 8.15 (d, = 8.0 Hz, 2H), 8.27 (d,
8.32 (d, = 8.0 Hz, 2H), 8.57 (d,
= 15.6 Hz, =C-H, 1H). 13C NMR (CDCl3, 100 MHz): δ 189.56
J
= 8.0 Hz, 1H), 7.94 (d,
J =
J
J
J
= 8.0 Hz, 1H),
J
J
(C=O), 156.32, 149.99, 143.56, 143.19 (C-4), 138.72, 134.20, 133.26, 132.70, 129.62, 129.32,
129.16, 128.89, 128.01, 127.92, 126.35, 124.52, 123.78, 123.13, 122.97 (C-5), 117.29, 113.91,
62.87 (OCH2), 54.35 (NCH2). MS: m/z (M+) Cacld. for C29H21FN4O4 : 508.1; found: 509.1
(M+H)+.
(E)-3-(2-((1-(4-fluorobenzyl-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-yl)-1-(4-nitro
phenyl)prop-2-en-1-one (6p), Yield 94%; Yellow solid; mp 188–190 °C; IR (KBr, cm–1): 3184,
3157 (C-H, triazole), 3054 (C-H), 2948, 2876, 1654 (C=O), 1590 (C=C), 1576, 1521, 1458,
1
1399, 1356, 1295, 1257, 1218, 1170, 1075, 1048, 1008, 827, 777, 520. H NMR (CDCl3, 400
MHz): δ 5.46 (s, 2H, NCH2), 5.53 (s, 2H, OCH2), 7.01 (t,
7.45-7.48 (m, 2H), 7.59 (s, 1H, triazolyl–H), 7.61 (d, = 8.0 Hz, 1H), 7.85 (d,
7.94 (d, = 8.0 Hz, 1H), 8.00 (d, = 15.6 Hz, =C-H, 1H). 8.16 (d,
8.0 Hz, 1H), 8.34 (d, = 8.0 Hz, 2H), 8.55 (d,
J
= 8.0 Hz, 2H), 7.23–7.26 (m, 2H),
J
J
= 8.0 Hz, 1H),
J
J
J
= 8.0 Hz, 2H), 8.26 (d, J =
13
J
J
= 15.6 Hz, =C-H, 1H). C NMR (CDCl3, 100
MHz): δ 189.53 (C=O), 164.11, 156.21, 150.00, 143.74, 143.17 (C-4), 138.83, 133.19, 132.69,
130.07, 129.98, 129.89, 129.63, 129.35, 128.83, 127.95, 126.46, 124.50, 123.78, 123.16, 122.81
(C-5), 117.43, 116.31, 116.09, 113.96, 62.92 (OCH2), 53.59 (NCH2). MS: m/z (M+) Cacld. for
C29H21FN4O4 : 508.1; found: 509.1 (M+H)+.

ACCEPTED MANUSCRIPT
(E)-3-(2-((4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-yl)-1-(4-nitrophenyl)
prop-2-en-1-one (6q), Yield 87%; Yellow solid; mp 198–200 °C; IR (KBr, cm–1): 3185, 3157
(C-H, triazole), 3064 (C-H), 2958, 2897, 1657 (C=O), 1595 (C=C), 1576, 1530, 1458, 1388,
1
1295, 1257, 1217, 1174, 1077, 1040, 1018, 827, 777, 520. H NMR (CDCl3, 400 MHz): δ 5.57
(s, 2H,OCH2), 7.23-7.27 (m, 2H), 7.46–7.54 (m, 2H), 7.60-7.63 (m, 1H), 7.71-7.74 (m, 2H), 7.87
(d,
J
= 8.0 Hz, 1H), 7.98-8.01 (m, 1H), 8.06 (d,
J
= 15.6 Hz, =C-H, 1H). 8.13-8.16 (m, 3H), 8.28-
13
8.30 (m, 3H), 8.61 (d,
J
= 15.6 Hz, =C-H, 1H). C NMR (CDCl3, 100 MHz): δ 189.40 (C=O),
163.52, 156.21, 154.86, 143.25 (C-4), 142.88, 138.58, 134.49, 133.18, 132.64, 132.25, 132.23,
129.40, 129.34, 128.87, 128.27, 127.68, 126.81, 126.53, 126.32, 124.64, 123.77, 123.21, 122.43
(C-5), 122.31, 121.21, 117.03, 116.83, 113.90, 62.91 (OCH2). MS: m/z (M+) Cacld. for
C28H19FN4O4 : 493.4; found: 494.5 (M+H)+.
(E)-1-(4-nitrophenyl)-3-(2-((1-(3-trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)
naphthalene-1-yl)prop-2-en-1-one (6r), Yield 89%; Yellow solid; mp 194–196 °C; IR (KBr,
cm–1): 3185, 3157 (C-H, triazole), 3057 (C-H), 2953, 2839, 1657 (C=O), 1589 (C=C), 1576,
1
1524, 1457, 1379, 1294, 1257, 1217, 1177, 1074, 1049, 1008, 827, 775, 522. H NMR (CDCl3,
400 MHz): δ 5.62 (s, 2H, OCH2), 6.63 (m, 2H), 7.45-7.54 (m, 3H), 7.67 (t,
J = 8.0 Hz, 1H), 7.72
(d,
J
= 8.0 Hz, 1H), 7.83-7.92 (m, 5H), 8.12 (d,
J
= 8.4 Hz, 1H), 8.08 (m, 1H), 8.20 (s, 1H,
13
triazolyl–H), 8.44 (d,
J
= 15.6 Hz, =C-H, 1H), 9.26 (d,
J
= 8.0 Hz, 1H). C NMR (CDCl3, 100
MHz): δ 191.73 (C=O), 162.31, 156.20, 144.62 (C-4), 141.70, 137.63, 137.22, 131.53, 131.14,
130.67, 130.04, 129.79, 129.03, 128.53, 128.31, 128.20, 125.75, 125.71, 125.22, 124.91, 123.68
(C-5), 121.07, 121.01, 117.66, 117.62, 117.57, 113.97, 113.92, 113.76, 63.21 (OCH2). MS: m/z
(M+) Cacld. for C29H19F3N4O4 : 544.1; found: 545.2 (M+H)+.
Pharmacology
The antimicrobial activities were carried out by following the procedure as reported by Kaushik
58
et al
.
Docking details
The most potent compound 6p was docked into the active sites of Docking studies were
carried out by following procedure as given by Kaushik et al using Auto Dock Vina 1.1.2.58
Molecular dynamics simulation
A 50 ns long molecular dynamics simulation of the docked complex between 1kzn and 6p was
carried out in order to elucidate the binding mode of 6p into the active site of 1kzn as described

ACCEPTED MANUSCRIPT
earlier59 using GROMACS 5.1.4 code and Gromos43a1 force field 60-61.The force field
parameters of ligand 6p were obtained from PRODRG web server62. Briefly, the docked
complex of 1kzn-6p obtained from molecular docking was solvated in a cubic box of 255.26 nm3
using simple point charge (SPC/E) water model keeping a distance of 1.0 nm between each side.
The final simulation system was solvated and ionized with Na+ and Cl− ions at a concentration
of 100 mM and the final system consisting of one protein molecule, one ligand molecules, 7465
water molecules, 24 Na+ and 15 Cl− ions was minimized using the steepest descent algorithm
until the maximum force became less than 500 kJ/mol/nm.
Position restrained equilibration was performed in association with constant Numbers of
particles, Volume and Temperature (NVT) and constant number of particles, Pressure, and
Temperature (NPT) also called as isothermal-isobaric ensemble.NVT equilibration was
performed at constant temperature at 300K using V-rescale (modified Berendsen thermostat)
temperature coupling 63for a time duration of 500 ps. After stabilization of temperature the NPT
equilibration was performed using both temperature and Parrinello–Rahman pressure coupling
64to maintain the system at 300 K temperature and 1 bar pressure along with coupling constant of
0.1 picosecond (ps) for temperature and 2 ps for pressure. Position restraints were applied during
both NVT and NPT ensemble equilibration. Long-range electrostatic interactions and van der
Walls interactions were calculated using the Particle mesh Ewald (PME) method 65, and the cut-
off for short-range van der Waals was set to 1 nm. All bonds were constrained using LINCS
66
algorithm and the time step of the simulation was set to 0.002 ps. Finally, a 50 ns production
simulation was performed.
The analysis of MD trajectory was performed using modules present in GROMACS 5.1.4. The
trajectory was analyzed quantitatively by determining RMSD, RMSF and radius of gyration
using rms, rmsf, and gyrate functionalities. Structural analysis was performed by analyzing the
hydrogen bonds formed throughout the simulation period of 50 ns using the h-bond utility.
Graphs were plotted using the XMgrace program67.
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgement

ACCEPTED MANUSCRIPT
This work was carried out under the financial support from Haryana State Council for
Science & Technology (HSCST) in the form of Junior Research Fellowship (Pinki Yadav) and
PURSE program No. SR/PURSE 2/40(G) from DST, New Delhi. The authors are also thankful
to SAIF, IIEST, Shibpur and APJ Abdul Kalam Central instrumentation laboratory, Guru
Jambheshwar University of Science & Technology, Hisar, India for single crystal X-ray analysis
and NMR spectra of the compounds, respectively. The computations/simulations were performed
on resources provided by the Swedish National Infrastructure for Computing (SNIC) at National
Supercomputer Centre at Linköping University (NSC).
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