Synthesis, antimicrobial activity, and molecular docking study of formylnaphthalenyloxymethyl-triazolyl-N-phenylacetamides

Article abstract of DOI:10.1002/jhet.3628

In the present study, substituted formylnaphthalenyloxymethyl-triazolyl-N-phenylacetamide derivatives (6a–k) have been designed and synthesized employing click chemistry approach and evaluated for their in vitro antifungal and antibacterial activities. All the newly synthesized compounds were thoroughly characterized by ¹H NMR, ¹³C NMR, and HRMS spectral techniques. Among the screened compounds, 6d, 6e, 6j, and 6k have shown good antifungal and antibacterial activities. Compound 6k has shown very effective antimicrobial activity. We further performed exploratory docking studies on microbial DNA gyrase to rationalize the in vitro biological data and to demonstrate the mechanism of antimicrobial activity. This is the first report to demonstrate the formylnaphthalenyloxymethyl, triazole, and N-phenylacetamide hybrids as potential antimicrobial agents.

Full text of DOI:10.1002/jhet.3628

Month 2019
Synthesis, antimicrobial activity, and molecular docking study of
formylnaphthalenyloxymethyl-triazolyl-N-phenylacetamides
Mahesh B. Muluk,a Sambhaji T. Dhumal,b Pramod S. Phatak,a Naziya N. M. A. Rehman,c Prashant P. Dixit,c
d
b
a
*
Prafulla B. Choudhari, Ramrao A. Mane, and Kishan P. Haval
aDepartment of Chemistry, Dr. Babasaheb Ambedkar Marathwada University Sub-Campus, Osmanabad 413501,
Maharashtra, India
bDepartment of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, Maharashtra, India
cDepartment of Microbiology, Dr. Babasaheb Ambedkar Marathwada University, Sub-Campus, Osmanabad 413501,
Maharashtra, India
dDepartment of Pharmaceutical Chemistry, Bharati Vidhyapeeth College of Pharmacy, Kolhapur 416013, Maharashtra,
India
*E-mail: havalkp@gmail.com
Received December 15, 2018
DOI 10.1002/jhet.3628
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
In the present study, substituted formylnaphthalenyloxymethyl-triazolyl-N-phenylacetamide derivatives
(6a–k) have been designed and synthesized employing click chemistry approach and evaluated for their
in vitro antifungal and antibacterial activities. All the newly synthesized compounds were thoroughly char-
acterized by 1H NMR, 13C NMR, and HRMS spectral techniques. Among the screened compounds, 6d, 6e,
6j, and 6k have shown good antifungal and antibacterial activities. Compound 6k has shown very effective
antimicrobial activity. We further performed exploratory docking studies on microbial DNA gyrase to ratio-
nalize the in vitro biological data and to demonstrate the mechanism of antimicrobial activity. This is the first
report to demonstrate the formylnaphthalenyloxymethyl, triazole, and N-phenylacetamide hybrids as poten-
tial antimicrobial agents.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
received significant attention due to their broad range of
biological activities such as antitubercular [13],
antimicrobial [14], anticancer [15], anti-inflammatory [16],
antimalarial [17], anti-HIV [18], anti-diabetic [19], and
anti-oxidant [20]. These can be synthesized by copper(I)
catalyzed azide-alkyne cyloaddition “click” reaction [21].
Recently, Lal et al. have reported molecular hybrid
triazolyl-naphthaldehye oxime derivatives possessing
antimicrobial activity [22]. In view of these findings
and in our continuing efforts on the synthesis of
bioactive organic compounds [23], herein, we have
reported the synthesis and antimicrobial activity of the
The microbial resistance is an important public health
concern worldwide, despite of growing knowledge about
infectious diseases and availability of various antibiotics
and chemotherapeutics [1]. In the USA alone, antibiotic-
resistant bacteria cause at least 2 million infections and
23,000 deaths a year [2]. Therefore, the innovation and
development of new effective antimicrobial agents with
novel chemical structures and mechanisms to address the
drug resistance and improve the antimicrobial potency is
of prime interest [3]. The molecular hybridization has
emerged as one of the best synthetic strategies to
synthesize effective lead compounds with novel
mechanism of action and structural modification to
improve their binding affinity and activity [4]. Literature
revealed that some molecular hybrid compounds having
broad spectrum of biological activities (Fig. 1) [5–8].
substituted
formylnaphthalenyloxymethyl-triazolyl-N-
phenylacetamide derivatives (6a–k) via click chemistry
approach.
RESULTS AND DISCUSSIONS
Compounds bearing N-phenylacetamide unit have been
identified as significant anticancer [9], antimicrobial [10],
human sirtuin 2 inhibitor [11], and other biological
activities [12]. 1,4-Disubstituted 1,2,3-triazoles have
Chemistry. The title compounds, new substituted for
mylnaphthalenyloxymethyl-triazolyl-N-phenylacetamide
derivatives (6a–k), have been synthesized starting from
© 2019 Wiley Periodicals, Inc.

M. B. Muluk, S. T. Dhumal, P. S. Phatak, N. N. M. A. Rehman,
P. P. Dixit, P. B. Choudhari, R. A. Mane and K. P. Haval
Vol 000
Figure 1. Some bioactive molecular hybrid compounds.
commercially available 2-hydroxy-1-naphthaldehyde (1).
The key intermediate, 2-(prop-2-yn-1-yloxy)-1-
carbon, respectively. The HRMS spectrum further
strengthens the structure assigned to 2-(4-(((1-
formylnaphthalen-2-yl)oxy)methyl)-1H-1,2,3-triazol-1-
yl)-N-phenylacetamide (6a) as it displays [M-H]À ion
peak at m/z 385.1302 for its molecular formula
C22H18N4O3.
naphthaldehyde (2) was prepared from 2-hydroxy-1-
naphthaldehyde (1) and propargyl bromide in the
presence of anhydrous K2CO3 in DMF at room
temperature for 10 h (Scheme 1). In the second step,
substituted 2-azido-N-phenylacetamides (5a–k) were
obtained from the corresponding substituted amines (3a–
k) on reaction with acetyl chloride followed by sodium
azide (Scheme 2). The copper(I) catalyzed cycloaddition
reaction of 2-(prop-2-yn-1-yloxy)-1-naphthaldehyde (2)
with substituted 2-azido-N-phenylacetamides (5a–k)
furnished the corresponding substituted formylnaphtha
lenyloxymethyl-triazolyl-N-phenylacetamides (6a–k) with
82–90% yields (Scheme 3).
Antibacterial and antifungal activities.
The in vitro
antimicrobial activity of the synthesized compounds
(6a–k) was evaluated by using agar well diffusion
method [24]. Various potent microbial pathogens were
used for this study. For assessing antibacterial activity,
Gram-positive bacterial pathogens, Staphylococcus
aureus,
Bacillus
cereus,
Bacillus
megaterium,
Micrococcus glutamicum, and Bacillus subtilis and
Gram-negative pathogens, Escherichia coli, Salmonella
typhi, Shigella boydii, Enterobacter aerogenes,
Pseudomonas aerogenosa, and Salmonella abony were
used. Furthermore, antifungal activity of synthesized
compounds was determined against Aspergillus niger,
Saccharomyces cerevisiae, and Candida albicans.
Tetracyclin and Nystatin were used as standard
antibacterial and antifungal reference compounds,
respectively. The inoculums of each bacterial and fungal
pathogen were developed by growing them overnight in a
nutrient broth medium at 37°C, and then this broth was
used for the study. The bacterial suspension was diluted
by using sterile saline to adjust the turbidity to the 0.5
McFarland standards. The Mueller Hinton agar plates
were inoculated with 200-μL diluted suspension of each
pathogen. Wells were punched in the agar medium. All
synthesized compounds (6a–k) were dissolved to get
final concentration of 2 mg/mL in DMSO; 100 μL of
each compound solution was placed in a well; 100 μL of
DMSO solution without any compound was also placed
in a well to check its activity against the pathogenic
culture. Petri dishes were incubated for 24 h at 37°C.
After complete incubation, the antimicrobial activity of
The structures of all the synthesized products were
established by using 1H NMR, 13C NMR, and HRMS
data. The 1H NMR spectrum of compound (6a) that
displays two characteristic peaks at
δ 5.35 and
5.54 ppm as singlets confirms the presence of OCH2
and NCH2, respectively. The amido-NH appeared as a
singlet at δ 10.42 confirming the presence of 1,2,3-
triazole ring in compound (6a). The characteristic peak
of aldehyde (CHO) is observed at 10.79 ppm. In 13C
NMR spectrum of (6a), the peaks appeared at δ 51.2
and 62.9 confirm the presence of OCH2 and NCH2
methylene carbons, respectively. Whereas the signals at
162.42 and 190.43 ppm due to the amide and aldehyde
Scheme 1. Synthesis of 2-(prop-2-yn-1-yloxy)-1-naphthaldehyde (2).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis, Antimicrobial Activity, and Molecular Docking Study of
Formylnaphthalenyloxymethyl-triazolyl-N-phenylacetamides
Scheme 2. Synthesis of substituted 2-azido-N-phenylacetamides (5a–k).
Scheme 3. Synthesis of substituted formylnaphthalenyloxymethyl-triazolyl-N-phenylacetamides (6a–k).
the synthesized compounds (6a–k) was measured by the
zone of inhibition around wells as bacterial growth
inhibition.
Minimum inhibitory concentration.
Minimum inhi-
bitory concentration (MIC) is the lowest concentration of
an antimicrobial (compounds) drug that will inhibit the
visible growth of a microorganism after overnight
incubation. The MIC was determined for the most potent
selected antimicrobial compounds 6j and 6k. The MIC
was determined against S. aureus, E. coli, and B. cereus.
The MIC was determined by following the method and
guidelines of Clinical and Laboratory Standard Institute.
The results are shown in Table 2.
Molecular docking study. Molecular docking analysis
was utilized to predict the mechanism of action of the
synthesized derivatives for antimicrobial potential [25].
All the molecules exhibited binding energies in the
Out of 11 synthesized compounds, compound 6k with a
4-chloro substituted benzene ring displayed notable
activity against all the pathogens. The maximum zone of
inhibition, that is, 19 and 17 mm, was observed against
bacterial pathogens, B. cereus and S. aureus, respectively.
Compound 6j having a 3-chloro substituted benzene ring
was also found to have good antimicrobial activity. The
maximum inhibition activity of 6j was observed against
pathogen E. coli, whereas compounds 6d and 6e with 3-
methyl and 2-methyl substituted benzene rings, respecti-
vely, have also shown good antimicrobial activity (Table 1).
Table 1
Antibacterial and antifungal activity in zone of inhibition (mm) of compounds 6a–k.
Compounds
Pathogens
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
Standarda
Salmonella typhi
Enterobacter aerogenes
Bacillus subtilis
—
—
08
—
—
—
—
09
—
—
—
—
07
—
—
08
—
—
—
—
—
08
—
—
06
—
—
—
12
—
12
—
—
—
—
13
—
—
—
—
—
—
—
11
14
12
13
—
15
11
16
—
10
—
13
14
12
—
14
10
—
16
—
08
12
14
—
—
16
—
—
—
—
—
—
—
—
09
—
—
—
—
—
—
—
—
—
—
—
—
—
10
—
—
—
—
—
—
—
13
—
—
—
—
12
—
—
—
—
—
15
—
—
—
—
—
—
—
—
—
—
07
—
—
—
—
13
14
10
09
12
13
—
17
14
12
11
11
14
—
14
15
16
15
14
13
11
16
17
14
16
12
19
11
27
33
34
25
30
30
27
29
25
27
24
26
33
31
Candida albicans
Pseudomonas aerogenosa
Salmonella abony
Bacillus megaterium
Escherichia coli
Staphylococcus aureus
Shigella boydii
Saccharomyces cerevisiae
Aspergillus niger
Bacillus cereus
Micrococcus glutamicum
Diameter of zone of inhibition is given in millimeter (mm).
aTetracyclin and Nystatin were used as standard antibacterial and antifungal reference compounds, respectively.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. B. Muluk, S. T. Dhumal, P. S. Phatak, N. N. M. A. Rehman,
P. P. Dixit, P. B. Choudhari, R. A. Mane and K. P. Haval
Vol 000
Table 2
Absorption, distribution, metabolism, and excretion
prediction.
Good efficacy and acceptable absorption,
MIC in μg/mL of compounds 6j and 6k.
distribution, metabolism, and excretion (ADME) profile
are the most important properties of any successful drugs.
All the synthesized derivatives (6a–k) were scrutinized
for ADME prediction using Swiss ADME portal [26]. All
the molecules showed excellent ADME parameters with
low Lipinski violation, which is desirable for the oral
absorption of drug candidates, and the results are shown in
Table 3.
Compounds
Pathogens
6j
6k
Standard
Staphylococcus aureus
Escherichia coli
Bacillus cereus
180
70
90
40
120
35
6.5
4.5
5
MIC, minimum inhibitory concentration.
range of À33.62 to À60.10 kcal/mol. Compound 6j
showed aromatic interaction with HIS99, hydrophobic
interaction with PRO79, ILE94, and Van der Waal
interactions with ARG136, GLY119, HIS99, ILE94,
HIS55, and GLU50 (Fig. 2). Compound 6k showed
Docking analysis.
Molecular docking analysis was
performed to predict possible mode of action of the
synthesized triazole derivatives. Crystal structure of the
DNA gyrase of E. coli was utilized for docking analysis.
Crystal structure of DNA gyrase (PDB ID: 5l3j) was
downloaded from the free protein database www.rcsb.org
Crystal structure of the downloaded DNA gyrase was
refined prior to the docking analysis via removal of the
water and addition of the hydrogen atoms so that native
geometry of the protein will be retained. Ligands were
prepared in Vlife engine module and optimized via
Merck molecular force field. Biopredicta module of the
Vlife MDS was utilized for docking analysis.
aromatic
interaction
with
HIS99,
hydrophobic
interaction with PRO79, ILE94, and Van der Waal
interactions with HIS99, ILE94, HIS55, and GLU50
(Fig. 3). Compound 6d showed aromatic interaction
with HIS99, hydrophobic interaction with PRO79,
ILE94, LEU98, HIS99, GLY119, and Van der Waal
interactions with ARG136, GLY119, HIS99, ILE94,
PRO79, ARG76, HIS55, and GLU50 (Fig. 4).
Figure 2. Binding mode of 6j into the active site of DNA gyrase. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 3. Binding mode of 6k into the active site of DNA gyrase. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis, Antimicrobial Activity, and Molecular Docking Study of
Formylnaphthalenyloxymethyl-triazolyl-N-phenylacetamides
Figure 4. Binding mode of 6d into the active site of DNA gyrase. [Color figure can be viewed at wileyonlinelibrary.com]
Table 3
ADME prediction and bioavailability score.
Entry
MW
Rotatable bonds
H-bond acceptors
H-bond donors
MR
Log P
Bioavailability score
6a
6b
6c
6d
6e
6f
6g
6h
6i
372.38
402.4
417.37
386.4
386.4
417.37
386.4
7
8
8
7
7
8
7
8
7
7
7
5
6
7
5
5
7
5
6
5
5
5
1
1
1
1
1
1
1
1
1
1
1
104.57
111.06
113.39
109.54
109.54
113.39
109.54
111.06
109.58
109.58
109.58
2.69
3
2.4
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
2.99
2.99
2.45
2.81
2.36
3.09
3.09
3.04
402.4
406.82
406.82
406.82
6j
6k
ADME, acceptable absorption, distribution, metabolism, and excretion.
EXPERIMENTAL
melting point was in good agreement with the reported [7].
Yield: 72%, mp 108–112°C.
All reagents were purchased from Merck and Aldrich and
used without further purification. Melting points were
determined in open capillaries and are uncorrected. 1H NMR
spectra were recorded on a Bruker DRX-300 and 400 MHz
NMR spectrometer using tetramethylsilane (TMS) as an
internal standard and chemical shifts are in δ (ppm). 13C NMR
spectra were recorded on a Bruker DRX-75 and 100-MHz
NMR in CDCl3/DMSO-d6. High-resolution mass spectra
(HRMS) were obtained using Agilent 6520 (Q-TOF) ESI-
HRMS instrument. The purity of the titled and intermediate
compounds was checked by thin-layer chromatography (TLC)
using silica-gel, 60F254 aluminum sheets as an adsorbent, and
visualization was accomplished by iodine/ultraviolet light.
General procedure for the synthesis of substituted 2-azido-
N-phenylacetamides (5a–k).
The chloroacetyl chloride
(1.5 mmol) was added dropwise in aqueous solution of
substituted anilines (3a–k) (1.0 mmol) at 0°C and stirred for 8–
10 h at room temperature. The progress of reaction was
monitored by TLC. After completion of reaction, the reaction
mixture was poured on crushed ice. The solid obtained were
filtered and recrystallized from ethanol to furnish the
corresponding substituted 2-chloro-N-phenylacetamides (4a–k).
Then, the obtained substituted 2-chloro-N-phenylacetamides
(4a–k) (1.0 mmol) and sodium azide (1.0 mmol) were stirred in
DMSO for 5–6 h at room temperature. After completion of
reaction, the water was added in reaction mixture and extracted
with ethyl acetate to give the corresponding substituted 2-
azido-N-phenylacetamides (5a–k).
Procedure for the synthesis of 2-(prop-2-yn-1-yloxy)-1-
naphthaldehyde (2).
To a mixture of 2-hydroxy-1-
naphthaldhyde (1.0 mmol) and anhydrous potassium carbonate
(1.5 mmol) in dimethyformamide (DMF) (10 mL), propargyl
bromide (80% in toluene, 1.5 mmol) was added slowly at 0°C
and stirred for 10 h. After the completion of the reaction as
monitored by TLC, ice-cold water was added to it. The obtained
solid compound was filtered and crystallized from ethanol. The
General procedure for the synthesis of substituted
formylnaphthalenyloxymethyl-triazolyl-N-phenylacetamides
(6a–k).
2-(Prop-2-yn-1-yloxy)-1-naphthaldehyde
(2)
(1.0 mmol) and substituted 2-azido-N-phenylacetamides (5a–k)
(1.0 mmol) were stirred in the presence of CuSO4.5H2O
(20 mol%) and sodium ascorbate (20 mol%) in PEG-400 at
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. B. Muluk, S. T. Dhumal, P. S. Phatak, N. N. M. A. Rehman,
P. P. Dixit, P. B. Choudhari, R. A. Mane and K. P. Haval
Vol 000
room temperature. The progress of the reaction was monitored by
TLC. After completion of the reaction, the reaction mixture was
poured on ice. The white solid obtained was filtered, washed
with water, and crystallized in ethanol to furnish the
(m, 3H, Ar─H), 7.42 (bs, 2H, Ar─H), 7.55–7.65 (m, 1H,
Ar─H), 7.75 (d, J = 8.4 Hz, 1H, Ar─H), 7.87–7.88 (m, 1H,
Ar─H), 8.17–8.31 (m, 2H, merged signals, Triazolyl-H &
Ar─H), 9.10 (d, J = 7.6 Hz, 1H, Ar─H), 9.75 (s, 1H,
Amido-NH), 10.75 (s, 1H, CHO); 13C NMR (100 MHz,
CDCl3 + DMSO-d6) δ = 18.2, 63.3, 70.3, 115.7, 115.8,
116.8, 124.4, 125.5, 125.6, 126.5, 126.7, 128.9, 129.2, 130.4,
131.1, 131.1, 132.5, 135.7, 138.6, 163.5, 163.5, 164.9, 192.3;
HRMS: m/z Calcd for C23H20N4O3 [M-H]À: 399.1457 and
found 399.1451.
corresponding
substituted
formylnaphthalenyloxymethyl-
triazolyl-N-phenylacetamides (6a–k) with 82–90% yields.
2-(4-(((1-Formylnaphthalen-2-yl)oxy)methyl)-1H-1,2,3-
triazol-1-yl)-N-phenylacetamide (6a).
Yield: 86%; mp 150–
152°C; 1H NMR (400 MHz, DMSO-d6) δ = 5.35 (s, 2H, OCH2),
5.54 (s, 2H, NCH2), 7.07 (t, J = 7.2 Hz, 1H, Ar─H), 7.29 (t,
J = 7.6 Hz, 2H, Ar─H), 7.44 (t, J = 7.6 Hz, 1H, Ar─H), 7.58–
7.62 (m, 3H, Ar─H), 7.75 (d, J = 9.2 Hz, 1H, Ar─H), 7.88 (d,
J = 8.0 Hz, 1H, Ar─H), 8.22 (d, J = 8.8 Hz, 1H, Ar─H), 8.31 (s,
1H, Triazolyl-H), 9.14 (d, J = 8.8 Hz, 1H, Ar─H), 10.42 (s, 1H,
Amido-NH), 10.79 (s, 1H, CHO); 13C NMR (100 MHz,
CDCl3 + DMSO-d6) δ = 51.2, 62.9, 113.6, 114.9, 118.1, 122.4,
122.8, 122.9, 123.6, 126.9, 127.2, 127.5, 128.50, 129.1, 136.4,
136.7, 160.1, 161.5, 162.4, 190.4; HRMS: m/z Calcd for
C22H18N4O3 [M-H]À: 385.1298 and found 385.1302.
2-(4-(((1-Formylnaphthalen-2-yl)oxy)methyl)-1H-1,2,3-
triazol-1-yl)-N-(3-nitrophenyl)acetamide (6f). Yield: 90%; mp
1
174–175°C; H NMR (400 MHz, DMSO-d6) δ = 5.31 (s, 2H,
OCH2), 5.45 (s, 2H, NCH2), 7.33–7.38 (m, 1H, Ar─H), 7.41–
7.46 (m, 1H, Ar─H), 7.50–7.58 (m, 1H, Ar─H), 7.70–7.75 (m,
1H, Ar─H), 7.82–7.88 (m, 1H, Ar─H), 8.06–8.14 (m, 2H,
Ar─H), 8.51 (bs, 1H, Triazolyl-H), 9.10 (d, J = 6.4 Hz, 1H),
10.75 (s, 1H, CHO), 10.83 (s, 1H, Amido-NH); 13C NMR
(100 MHz, DMSO-d6) δ = 52.3, 63.1, 113.4, 115.3, 116.3,
118.3, 123.9, 124.8, 125.2, 126.8, 128.4, 128.6, 129.7, 130.4,
130.6, 137.5, 139.5, 147.9, 162.9, 165.1, 191.3; HRMS: m/z
Calcd for C22H17N5O5 [M-H]À: 430.1152 and found 430.0980.
2-(4-(((1-Formylnaphthalen-2-yl)oxy)methyl)-1H-1,2,3-
2-(4-(((1-Formylnaphthalen-2-yl)oxy)methyl)-1H-1,2,3-
triazol-1-yl)-N-(3-methoxyphenyl)acetamide (6b).
Yield:
90%; mp 220–221°C; 1H NMR (400 MHz, CDCl3 + DMSO-
d6) δ = 3.71 (s, 3H, OCH3), 5.32 (s, 2H, OCH2), 5.52 (s,
2H, NCH2), 6.61 (d, J = 6.0 Hz, 1H, Ar─H), 7.07–7.08 (m,
1H, Ar─H), 7.15–7.17 (m, 1H, Ar─H), 7.27–7.93 (m, 5H,
Ar─H), 8.17–8.32 (m, 2H, merged signals, Triazolyl-H &
Ar─H), 9.10 (d, J = 8.4 Hz, 1H, Ar─H), 10.41 (s, 1H,
Amido-NH), 10.75 (s, 1H, CHO); 13C NMR (100 MHz,
CDCl3 + DMSO-d6) δ = 52.8, 55.6, 63.3, 105.8, 110.1,
112.2, 112.30, 115.6, 115.6, 116.8, 124.4, 125.6, 128.9,
129.1, 129.2, 130.5, 131.1, 138.6, 139.7, 160.1, 163.5, 164.7,
192.4; HRMS: m/z Calcd for C23H20N4O4 [M-H]À: 415.1407
and found 415.1407.
triazol-1-yl)-N-(p-tolyl)acetamide (6g). Yield: 88%; mp 180–
1
181°C; H NMR (400 MHz, DMSO-d6) δ = 2.21 (s, 3H, CH3),
5.20 (s, 2H, OCH2), 5.42 (s, 2H, NCH2), 7.01 (bs, 1H, Ar─H),
7.36 (bs, 1H, Ar─H), 7.53–7.57 (m, 3H, Ar─H), 7.70–7.77 (m,
1H, Ar─H), 8.04 (bs, 2H, merged signals, Triazolyl-H &
Ar─H), 9.10 (bs, 1H, Ar─H), 10.11 (s, 1H, Amido-NH), 10.75
(s, 1H, CHO); 13C NMR (100 MHz, DMSO-d6): δ = 21.1, 52.9,
63.7, 116.0, 116.9, 119.8, 124.5, 125.5, 127.1, 128.2, 128.6,
129.9, 130.4, 131.2, 133.38, 136.5, 138.5, 163.6, 164.5, 191.9;
HRMS: m/z Calcd for C23H20N4O3 [M-H]À: 399.1457 and
found 399.1281.
2-(4-(((1-Formylnaphthalen-2-yl)oxy)methyl)-1H-1,2,3-
2-(4-(((1-Formylnaphthalen-2-yl)oxy)methyl)-1H-1,2,3-
triazol-1-yl)-N-(4-nitrophenyl)acetamide (6c).
Yield: 83%;
mp 162–164°C; 1H NMR (400 MHz, DMSO-d6) δ = 5.43 (s,
2H, OCH2), 5.55 (s, 2H, NCH2), 7.45 (bs, 1H, Ar─H), 7.61–
7.71 (m, 2H, Ar─H), 7.84 (bs, 3H, Ar─H), 8.07–8.29 (m, 4H,
merged signals, Triazolyl-H & Ar─H), 9.15 (bs, 1H, Ar─H),
10.81 (s, 1H, CHO), 11.06 (s, 1H, Amido-NH); 13C NMR
(100 MHz, DMSO-d6) δ = 52.8, 63.4, 115.8, 116.7, 119.5,
124.3, 125.3, 125.6, 127.1, 128.8, 129.1, 130.3, 131.1, 138.3,
143.1, 144.9, 163.4, 165.7, 191.8; HRMS: m/z Calcd for
C22H17N5O5 [M-H]À: 430.1152 and found 430.1153.
triazol-1-yl)-N-(4-methoxyphenyl)acetamide (6h).
Yield:
1
89%; mp 230–232°C; H NMR (400 MHz, DMSO-d6) δ = 3.70
(s, 3H, OCH3), 5.26 (s, 2H, OCH2), 5.49 (s, 2H, NCH2), 6.80 (d,
J = 8.8 Hz, 2H, Ar─H), 7.40 (t, J = 8.6 Hz, 1H, Ar─H), 7.45 (d,
J = 8.8 Hz, 2H, Ar─H), 7.56 (t, J = 8.6 Hz, 1H, Ar─H), 7.70 (d,
J = 9.2 Hz, 1H, Ar─H), 7.84 (d, J = 8.0 Hz, 1H, Ar─H), 8.17 (d,
J = 9.2 Hz, 1H, Ar─H), 8.26 (bs, 1H, Triazolyl-H), 9.10 (d,
J = 8.4 Hz, 1H, Ar─H), 10.28 (s, 1H, Amido-NH), 10.74 (s, 1H,
CHO); 13C NMR (100 MHz, DMSO-d6): δ = 52.3, 63.1, 113.4,
115.3, 116.3, 118.3, 123.9, 124.8, 125.2, 127.1, 127.4, 128.4,
128.6, 129.8, 130.4, 130.6, 137.9, 139.5, 147.9, 162.9, 165.1,
191.3; HRMS: m/z Calcd for C23H20N4O4 [M + H]+: 417.1563
and found 417.0943.
2-(4-(((1-Formylnaphthalen-2-yl)oxy)methyl)-1H-1,2,3-
triazol-1-yl)-N-(m-tolyl)acetamide (6d). Yield: 87%; mp 160–
1
163°C; H NMR (400 MHz, DMSO-d6) δ = 2.24 (s, 3H, CH3),
5.26 (s, 2H, OCH2), 5.45 (s, 2H, NCH2), 6.82 (d, J = 5.2 Hz,
1H, Ar─H), 7.08–7.12 (m, 1H, Ar─H), 7.29–7.37 (m, 2H,
Ar─H), 7.53–7.63 (m, 2H, Ar─H), 7.78–7.87 (m, 2H, Ar─H),
8.10–8.18 (m, 2H, merged signals, Triazolyl-H & Ar─H), 9.09
(d, J = 7.2 Hz, 1H, Ar─H), 10.29 (s, 1H, Amido-NH), 10.74 (s,
1H, CHO); 13C NMR (100 MHz, DMSO-d6) δ = 21.5, 52.7,
63.8, 115.8, 116.7, 116.8, 119.7, 120.1, 124.9, 124.9, 125.2,
126.6, 127.1, 129.1, 129.1, 129.9, 130.1, 138.3, 138.6, 139.1,
163.1, 164.5, 191.5; HRMS: m/z Calcd for C23H20N4O3 [M-
H]À: 399.1457 and found 399.1456.
N-(2-Chlorophenyl)-2-(4-(((1-formylnaphthalen-2-yl)oxy)
methyl)-1H-1,2,3-triazol-1-yl)acetamide (6i). Yield: 84%; mp
1
138–139°C; H NMR (400 MHz, DMSO-d6) δ = 5.42 (s, 2H,
OCH2), 5.48 (s, 2H, NCH2), 7.12 (t, J = 8.4 Hz, 1H, Ar─H),
7.24 (t, J = 8.4 Hz, 1H, Ar─H), 7.37–7.40 (m, 2H, Ar─H),
7.53–7.57 (m, 1H, Ar─H), 7.66–7.69 (m, 1H, Ar─H), 7.76–
7.82 (m, 2H, Ar─H), 7.90 (bs, 1H, Ar─H), 8.16 (d, J = 8.8 Hz,
1H, Triazolyl-H), 9.08 (d, J = 8.4 Hz, 1H, Ar─H), 9.95 (s, 1H,
Amido-NH), 10.73 (s, 1H, CHO); 13C NMR (100 MHz,
CDCl3 + DMSO-d6): δ = 52.6, 63.3, 114.8, 116.9, 124.6, 125.0,
125.3, 126.1, 126.3, 126.4, 127.5, 128.6, 128.7, 129.7, 129.8,
131.2, 134.4, 137.8, 162.3, 163.1, 164.8, 191.6; HRMS: m/z
Calcd for C22H17ClN4O3 [M-H]À: 419.0911 and found 419.0910.
2-(4-(((1-Formylnaphthalen-2-yl)oxy)methyl)-1H-1,2,3-
triazol-1-yl)-N-(o-tolyl)acetamide (6e).
Yield: 85%; mp 200–
202°C; 1H NMR (400 MHz, DMSO-d6) δ = 2.22 (s, 3H,
CH3), 5.38 (s, 2H, OCH2), 5.52 (s, 2H, NCH2), 7.06–7.17
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis, Antimicrobial Activity, and Molecular Docking Study of
Formylnaphthalenyloxymethyl-triazolyl-N-phenylacetamides
[2] (a) Li, B.; Webster, T. J. J Orthop Res 2018, 36, 22; (b)
Jasovský, D.; Littmann, J.; Zorzet, A.; Cars, O. Ups J Med Sci 2016,
121, 159.
N-(3-Chlorophenyl)-2-(4-(((1-formylnaphthalen-2-yl)oxy)
methyl)-1H-1,2,3-triazol-1-yl)acetamide (6j). Yield: 82%; mp
1
146–147°C; H NMR (400 MHz, DMSO-d6) δ = 5.28 (s, 2H,
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2011, 21, 510; (d) Kamat, S. R.; Salunkhe, R. S.; Choudhari, P. B.;
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44, 1351; (e) Kondhare, D. D.; Gyananath, G.; Tamboli, Y.; Kumbhar,
S. S.; Choudhari, P. B.; Bhatia, M. S.; Zubaidha, P. K. Med Chem Res
2017, 26, 987.
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Barreiro, E. J.; Carlos Fraga, A. M. Curr Med Chem 2007, 14, 1829; (b)
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Chem 2018, 77, 236.
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Jaglan, S. Eur J Med Chem 2017, 126, 944.
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Chem 2014, 80, 83; (b) Pawar, C. D.; Sarkate, A. P.; Karnik, K. S.;
Shinde, D. B. Egyp J Basic Appl Sci 2017, 4, 310; (c) Chahroura, O.;
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S. Chin J Chem 2016, 34, 1236.
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230.
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P.; Kumar, A. Med Chem Res 2016, 25, 644.
[15] (a) Reddy, V. G.; Bonam, S. R.; Reddy, T. S.; Akunuri, R. K.;
Naidu, V. G. M.; Nayak, V. L.; Bhargava, S. K.; Kumar, H. M. S.; Srihari,
P.; Kamal, A. Eur J Med Chem 2018, 144, 595; (b) Bollu, R.; Palem, J.
D.; Bantu, R.; Guguloth, V.; Nagarapu, L.; Polepalli, S.; Jain, N. Eur J
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OCH2), 5.46 (s, 2H, NCH2), 6.99 (d, J = 6.0 Hz, 1H, Ar─H),
7.20 (t, J = 8.4 Hz, 1H, Ar─H), 7.37 (bs, 2H, Ar─H), 7.53 (t,
J = 8.4 Hz, 1H, Ar─H), 7.61 (d, J = 8.0 Hz, 1H, Ar─H), 7.70–
7.79 (m, 2H, Ar─H), 8.10–8.18 (m, 2H, merged signals,
Triazolyl-H & Ar─H), 9.09 (d, J = 8.4 Hz, 1H, Ar─H), 10.54
(s, 1H, Amido-NH), 10.74 (s, 1H, CHO); 13C NMR (100 MHz,
DMSO-d6) δ = 52.4, 63.3, 115.6, 116.5, 117.9, 118.9, 123.7,
124.1, 125.1, 126.7, 128.6, 128.8, 129.9, 130.8, 130.9, 133.3,
133.4, 138.1, 140.1, 142.5, 163.2, 164.8, 191.2; HRMS: m/z
Calcd for C22H17ClN4O3 [M-H]À: 419.0911 and found 419.0911.
N-(4-Chlorophenyl)-2-(4-(((1-formylnaphthalen-2-yl)oxy)
methyl)-1H-1,2,3-triazol-1-yl)acetamide (6k). Yield: 87%; mp
1
158–160°C; H NMR (400 MHz, DMSO-d6) δ = 5.26 (s, 2H,
OCH2), 5.44 (s, 2H, NCH2), 7.18 (bs, 2H, Ar─H), 7.36 (bs, 1H,
Ar─H), 7.51 (m, 3H, Ar─H), 7.75 (m, 2H, Ar─H), 8.07–8.13
(m, 2H, merged signals, Triazolyl-H & Ar─H), 9.09 (d,
J = 8.4 Hz, 1H, Ar─H), 10.46 (s, 1H, Amido-NH), 10.73 (s, 1H,
CHO); HRMS: m/z Calcd for C22H18N4O3 [M-H]À: 419.9725
and found 419.0739.
CONCLUSIONS
In conclusion,
a
series of new substituted
formylnaphthalenyloxymethyl-triazolyl-N-phenylacetami
des (6a–k) were synthesized and evaluated for their
antibacterial and antifungal activities. Compounds 6j and
6k having 3-chloro and 4-chloro substituted benzene
rings, respectively, have shown very good antibacterial
and antifungal activities. However, compounds 6d and 6e
with methyl substituents at 3-position and 4-position,
respectively, also displayed notable antimicrobial activity.
In addition, the molecular docking study revealed that
synthesized molecules are potent DNA gyrase inhibitors.
Thus, these four compounds 6d, 6e, 6j, and 6k can be
considered as competent candidates for further study to
invent new broad spectrum antibiotics.
Acknowledgments. The authors are thankful to Dr. Babasaheb
Ambedkar Marathwada University, Aurangabad for providing
necessary facilities. One of the authors M. B. M. is grateful to
UGC New Delhi, India, for financial assistance in the form of
NET Senior Research Fellowship.
[16] Moussa, G.; Alaaeddine, R.; Alaeddine, L. M.; Nassra, R.;
Belal, A. S. F.; Ismail, A.; El-Yazbi, A. F.; Abdel-Ghany, Y. S.; Hazzaa,
A. Eur J Med Chem 2018, 144, 635.
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2014, 84, 420.
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet