Synthesis, Docking, and Biological activities of novel Metacetamol embedded [1,2,3]-triazole derivatives

Article abstract of DOI:10.1016/j.molstruc.2021.130786

ERα controls the breast tissue development and progression of breast cancer. In our search for novel compounds to target Estrogen Receptor Alpha Ligand-Binding Domain, we identified “N-(3-((1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide” derivatives as lead compounds. The Docking studies indicated good docking score for Metacetamol derivatives when docked into the 1XP6. A series of metacetamol derivatives have been synthesized, characterized and evaluated for cytotoxicity, anti bacterial and anti oxidant activities. Among the tested twelve hybrid compounds, “7a, 7g, 7h and 7i” derivatives showed promising cytotoxicity with IC₅₀ value of <22 μg/mL against MCF-7 cell line. The Compounds “7a, 7d, 7e, 7f, 7h, 7i, 7j, 7k and 7l” showed outstanding anti oxidant activity with IC₅₀ value of <30 μM, whereas Compounds “7a, 7b, 7c, 7d, 7g, 7j, 7k and 7l” showed moderate anti bacterial activity with the MIC value of <300 μM.

Full text of DOI:10.1016/j.molstruc.2021.130786

Journal of Molecular Structure 1242 (2021) 130786
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, Docking, and Biological activities of novel Metacetamol
embedded [1,2,3]-triazole derivatives
Hima Bindhu Joolakantia,b, Ramanjaneyulu Kamepallib, Jeevanreddy Miryalaa,
Satyanarayana Battua,∗
a Department of chemistry, Osmania University, Hyderabad, 500007, India
b Department of Pharmaceutical Chemistry, Vishnu Institute of Pharmaceutical Education and Research, Narsapur 502 313, India
a r t i c l e i n f o
a b s t r a c t
Article history:
ERα controls the breast tissue development and progression of breast cancer. In our search for novel
compounds to target Estrogen Receptor Alpha Ligand-Binding Domain, we identified “N-(3-((1H-1,2,3-
triazol-4-yl)methoxy)phenyl)acetamide” derivatives as lead compounds. The Docking studies indicated
good docking score for Metacetamol derivatives when docked into the 1XP6. A series of metacetamol
derivatives have been synthesized, characterized and evaluated for cytotoxicity, anti bacterial and anti
oxidant activities. Among the tested twelve hybrid compounds, “7a, 7g, 7h and 7i” derivatives showed
promising cytotoxicity with IC50 value of <22 μg/mL against MCF-7 cell line. The Compounds “7a, 7d, 7e,
7f, 7h, 7i, 7j, 7k and 7l” showed outstanding anti oxidant activity with IC50 value of <30 μM, whereas
Compounds “7a, 7b, 7c, 7d, 7g, 7j, 7k and 7l” showed moderate anti bacterial activity with the MIC value
of <300 μM.
Received 3 February 2021
Revised 24 May 2021
Accepted 25 May 2021
Available online 30 May 2021
Keywords:
Metacetamol
Triazole
MCF-7 cell line
Antioxidant activity
Antibacterial activity
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
structural elaboration of paracetamol. Metacetamol, also known as
3-hydroxyacetanilide and AMAP (N-Acetyl-meta-aminophenol) is a
Breast cancer is the most common cancer in women next to
lung cancer as a cause of cancer mortality [1]. There are many
established risk factors for breast cancer, but the “hormones, es-
trogen and/or progesterone are known to be capable of increasing
breast cancer risk” [2-4]. According to the American cancer society,
about two out of every three cases of breast cancer are hormone
receptor positive. Estrogen receptor-positive (ER+) breast cancer is
the most common type in which the level of estrogen is respon-
sible for the initiation and progression of breast cancer [5-8]. In
order to function in other tissues, estrogen binds to its receptors,
ERα and ERβ. The two ERs serve distinct actions due to differences
in their structures [9]. ERα is the major one involved in breast can-
cer and chosen as an important target for endocrine therapy in
clinic [10].
regioisomer of paracetamol with non-narcotic analgesic properties.
Metacetamol continue to attract considerable scientific attention
because of its advantages over paracetamol due to lower toxic-
ity [16-19], does not cause depletion of GSH in vivo and does not
cause hepatotoxicity. It is evident from literature that metacetamol
derivatives exhibit Antimicrobial and Anthelmintic activities [20].
1,2,3-Triazoles are considered more than just passive linkers
and offer properties such as medium dipole properties, hydro-
gen bonding ability, rigidity and stability [21]. SAR studies re-
vealed that greatest difference in structure and properties of tri-
azole derivatives is due to the groups attached to nitrogen atom
at the first position [22] (Fig 1). “Hybrid molecules occupy an im-
portant position in drug development and hybridization of 1,2,3-
triazole framework with other pharmacophores resulting in wide
variety of applications [23-34]. Recently, we synthesized chromone
linked [1,2,3]-triazole derivatives which inhibited the rapid multi-
plication of breast cancer cells [35].
Paracetamol is one of the most widely used analgesics and an-
tipyretics. It has many pharmacological activities but shows severe
hepatotoxicity [11-14]. Recently, we have synthesized paracetamol
derivatives which inhibited the proliferation of breast cancer cells
[15]. As a follow-up to this study, we are interested in further
The applications of metacetamol and 1,2,3-triazole deriva-
tives, motivated us to synthesize a new series of “N-(3-((1H-
1,2,3-triazol-4-yl)methoxy)phenyl)acetamide” derivatives by apply-
ing click dipolar cycloaddition. A diverse series of twelve hybrid
compounds were synthesized and tested for cytotoxicity, antibac-
terial and antioxidant activities.
∗
Corresponding author.
E-mail address: satyambchem@yahoo.co.in (S. Battu).
https://doi.org/10.1016/j.molstruc.2021.130786
0022-2860/© 2021 Elsevier B.V. All rights reserved.

H.B. Joolakanti, R. Kamepalli, J. Miryala et al.
Journal of Molecular Structure 1242 (2021) 130786
F
F
F
N
O
N
OH
O
N
O
N
N
O
S
O
N
N
O
N
Mubritinib
Tazobactam
NH2
H
H2N
O
Cl
O
N
S
H2N
HO
O
N
N
N
N
N
Cl
Cl
O
N
COOH
NH
Carboxyamidotriazole
Cefatrizine
N
N
N
O
TBSO
NH2
O
O
OTBS
S
O
O
TSAO
Fig 1. Drugs containing 1,2,3-triazole moiety.
2. Materials and methods
was quenched by adding cold water or ammonium chloride solu-
tion. Methanol was evaporated; the residue was dissolved in EtOAc
(100 mL) and washed with water (2 × 100 mL). The organic layer
was dried over anhydrous sodium sulfate and the product was pu-
rified by passing through a column chromatography.
2.1. General
Thin layer chromatography (TLC) was performed on E. Merck
silica gel plates (60 F254) and components were seen by observ-
ing in UV light or phosphomolybdic acid reagent. Column chro-
matography was performed using Avra synthesis private ltd. Silica
gel 60, 0.140–0.25 mm (60–120 mesh). All the melting points were
measured in digital melting point apparatus (Jain scientific glass
works) by open capillary method. The melting points were uncor-
rected and reported in degrees centigrade. “1H NMR and 13C NMR”
spectra were recorded on Varian 400 MHz NMR spectrometer by
using DMSO-d6 or CDCl3. Multiplicities are indicated by multiplet
(m), triplet (t), doublet (d), singlet (s), and coupling constant (J)
was reported in hertz (Hz). The mass spectra were performed on
LCMS 2010A, SHIMADZU, JAPAN. The IR spectra were recorded on
BRUKER FTIR.
2.4. Synthesis of alkyl bromides (3a-l)
To a solution of aryl alcohol (2a-l) (1 g) in ether (10 mL) was
added phosphorus tribromide (0.5 equiv) and stirred for 0.5 h at
0 °C. After completion of reaction, excess phosphorus tribromide
was quenched by adding sodium carbonate solution and then the
residue was dissolved in EtOAc (100 mL) and washed with water
(2 × 100 mL). The product containing organic layer was dried over
anhydrous sodium sulfate and the product was purified by passing
through a column chromatography.
2.5. Synthesis of alkyl azides (4a-l)
Under nitrogen atmosphere, sodium azide (2 equiv) and cat-
alytic amount of TBAB was added to a solution of alkyl halide
(3a-l) (1 g) in 4:8 aqueous dichloromethane and the solution was
stirred at room temperature for 12 h. After completion, the re-
action mixture was dissolved in equal amount of EtOAc and wa-
ter. The product containing organic layer was dried by anhydrous
sodium sulfate and the product was purified using a column chro-
matography.
2.2. Synthesis of (N-(3-(prop-2-ynyloxy)phenyl) acetamide (6a)
Under nitrogen atmosphere, propargyl bromide (5 mmol) was
added to a solution of Metacetamol (5a) (5 mmol) and K2CO3
(10 mmol) in DMF (6 mL) and stirred at room temperature for
12 h and diluted slowly by adding crushed ice, citric acid and again
stirred for 1 h. The crystals were collected, dried and purified by
a column chromatography using eluent “ethyl acetate and hexane
(3:7)”.
2.6. General procedure for the synthesis of metacetamol embedded
2.3. Synthesis of aryl alcohols (2a-l)
[1,2,3]-triazoles by using click chemistry approach (7a-l)
Sodium borohydride (3.41 g, 24 mmol) was added to a solu-
tion of aryl aldehydes (1a-l) (1.5 g, 5.9 mmol) in methanol (30 ml)
and the mixture was stirred for 2 h at 0 °C. Completion of reac-
tion was monitored by TLC and then, excess sodium borohydride
A
mixture of azide (4a-l) (1.1 equiv), (N-(3-(prop–2-
ynyloxy)phenyl) acetamide (6a) (1 g), copper sulfate pentahydrate
(0.25 mmol) and sodium ascorbate (200 mg) in 7:8 aqueous
THF was stirred vigorously at room temparature for 8 h. After
2

H.B. Joolakanti, R. Kamepalli, J. Miryala et al.
Journal of Molecular Structure 1242 (2021) 130786
completion of the reaction, the reaction mixture was dissolved in
EtOAc (100 mL) and washed with water (2 × 100 mL). The organic
layer was dried over anhydrous sodium sulfate. Then, the product
was purified by passing through a column chromatography on
silica gel using ethyl acetate/hexane to give the desired product.
2.6.6. “N-(3-((1-(3-chlorobenzyl)−1H-1,2,3-triazol-4-yl)
methoxy)phenyl)acetamide” (7f)
“White solid, 98% yield. mp: 208–210 °C. 1H NMR (400 MHz,
CDCl3) δ: 2.15 (s, 3H, NH-CO-CH3), 5.17 (s, 2H, C6H5-CH2), 5.49 (s,
2H, O-CH2), 6.69 (d, J=7.8 Hz, 1H, Ar-H), 7.00 (d, J=7.4 Hz, 1H,
Ar-H), 7.13–7.20 (m, 2H, Ar-H), 7.27–7–34 (m, 4H, Ar-H), 7.42 (s,
1H, Ar-H), 7.61 (s, 1H, N-H-CO-CH3). 13C NMR (400 MHz, CDCl3) δ:
24.5, 53.4, 61.7, 106.5, 110.7, 112.6, 123.0, 126.1, 128.0, 128.9, 129.7,
130.3, 134.9, 136.3, 139.2, 144.5, 158.4, 168.6. IR (ATR) cm−1, ν:
731, 968, 1180, 1226, 1361, 1517, 1656, 3061, 3261. MS (APCI) m/z:
358.75 [M+2], C18 H17 ClN4O2 ”.
2.6.1. “N-(3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)
acetamide” (7a)
“White solid, 90% yield. mp: 198–200 °C. 1H NMR (400 MHz,
DMSO–d6) δ: 2.03 (s, 3H, NH-CO-CH3), 5.09 (s, 2H, C6H5-CH2), 5.60
(s, 2H, O-CH2), 6.71 (dd, J=3.5, 2.6 Hz, 1H, Ar-H), 7.11 (d, J=9.2 Hz,
1H, Ar-H), 7.18 (t, J=8.3 Hz, 1H, Ar-H), 7.30–7.40 (m, 6H, Ar-H),
8.27 (s, 1H, Ar-H), 9.89 (s, 1H, N-H-CO-CH3). 13C NMR (400 MHz,
DMSO–d6) δ: 24.0, 52.8, 61.0, 105.8, 108.9, 111.6, 124.5, 127.9, 128.1,
128.7, 129.4, 135.9, 140.4, 142.9, 158.1, 168.3. IR (ATR) cm−1, ν:
777, 983, 1193, 1232, 1369, 1544, 1676, 3068. MS (ESI) m/z: 323.30
[M+1], C18 H18 N4O2 ”.
2.6.7. “N-(3-((1-(4-chlorobenzyl)−1H-1,2,3-triazol-4-yl)
methoxy)phenyl)acetamide” (7g)
“White solid, 88% yield. mp: 192–194 °C. 1H NMR (400 MHz,
CDCl3) δ: 2.16 (s, 3H, NH-CO-CH3), 5.17 (s, 2H, C6H5-CH2), 5.49 (s,
2H, O-CH2), 6.70 (d, J=8.3 Hz, 1H, Ar-H), 6.97 (d, J=7.8 Hz, 1H, Ar-
H), 7.17–7.22 (m, 3H, Ar-H), 7.28–7–36 (m, 4H, Ar-H), 7.58 (s, 1H,
N-H-CO-CH3). 13C NMR (400 MHz, CDCl3) δ: 24.5, 53.4, 61.8, 106.5,
110.7, 112.5, 122.9, 129.3, 129.4, 129.7, 132.9, 134.8, 139.1, 144.5,
158.5, 168.5. IR (ATR) cm−1, ν: 731, 968, 1045, 1209, 1487, 1595,
1653, 3028, 3263. MS (ESI) m/z: 354.95 [M − 1], C18 H17 ClN4O2 ”.
2.6.2. “N-(3-((1-(2-fluorobenzyl)−1H-1,2,3-triazol-4-yl)
methoxy)phenyl)acetamide” (7b)
“White solid, 92% yield. mp: 200–202 °C. 1H NMR (400 MHz,
CDCl3) δ: 2.16 (s, 3H, NH-CO-CH3), 5.18 (s, 2H, C6H5-CH2), 5.59
(s, 2H, O-CH2), 6.71 (d, J=7.8 Hz, 1H, Ar-H), 7.02 (d, J=7.4 Hz,
1H, Ar-H), 7.10–7.39 (m, 8H, Ar-H), 7.66 (s, 1H, N-H-CO-CH3). 13C
NMR (400 MHz, CDCl3) δ: 23.7, 52.0, 61.2, 114.7, 115.5, 115.7, 120.5,
124.5, 130.2, 130.3, 132.2, 132.2, 132.8, 143.1, 153.7, 160.9, 167.9. IR
(ATR) cm−1, ν: 1192, 1232, 1367, 1539, 1743, 2370, 2918. MS (ESI)
m/z: 341.10 [M+1], C18 H17 FN4O2 ”.
2.6.8. “N-(3-((1-(2,4-dichlorobenzyl)−1H-1,2,3-triazol-4-yl)
methoxy)phenyl)acetamide” (7h)
“White solid, 97% yield. mp: 198–200 °C. 1H NMR (400 MHz,
CDCl3) δ: 2.16 (s, 3H, NH-CO-CH3), 5.20 (s, 2H, C6H5-CH2), 5.62 (s,
2H, O-CH2), 6.71 (d, J=6.1 Hz, 1H, Ar-H), 6.98 (d, J=8.3 Hz, 1H, Ar-
H), 7.12 (d, J=8.3 Hz, 1H, Ar-H), 7.18–7.25 (m, 4H, Ar-H), 7.35 (s,
1H, Ar-H), 7.46 (d, J = 2.1 Hz, 1H, Ar-H), 7.68 (s, 1H, N-H-CO-CH3).
13C NMR (400 MHz, CDCl3) δ: 24.4, 50.8, 61.6, 106.5, 110.5, 112.6,
123.3, 127.8, 129.6, 129.6, 130.8, 131.0, 134.1, 135.5, 139.3, 144.2,
158.3, 168.7. IR (ATR) cm−1, ν: 694, 794, 867, 1193, 1247, 1413,
1546, 1676, 3066, 3331. MS (ESI) m/z: 391.40 [M+], 392 [M + 1],
C18 H16 Cl2 N4O2 ”.
2.6.3. “N-(3-((1-(3-fluorobenzyl)−1H-1,2,3-triazol-4-yl)
methoxy)phenyl)acetamide” (7c)
“White solid, 85% yield. mp: 195–197 °C. 1H NMR (400 MHz,
CDCl3) δ: 2.16 (s, 3H, NH-CO-CH3), 5.19 (s, 2H, C6H5-CH2), 5.52
(s, 2H, O-CH2), 6.70 (d, J=8.3 Hz, 1H, Ar-H), 6.97 (t, J=8.7 Hz, 2H,
Ar-H), 7.03–7–07 (m, 2H, Ar-H), 7.19 (t, J=8.3 Hz, 2H, Ar-H), 7.32–
7.37 (m, 2H, Ar-H), 7.61 (s, 1H, N-H-CO-CH3). 13C NMR (400 MHz,
CDCl3) δ: 24.4, 53.4, 61.7, 106.5, 110.6, 112.6, 114.8, 115.6, 123.0,
123.5, 129.6, 130.6, 136.7, 139.2, 144.4, 158.4, 161.6, 164.1. IR (ATR)
cm−1, ν: 721, 777, 1047, 1180, 1253, 1357, 1525, 1656, 3059, 3261.
MS (ESI) m/z: 341.30 [M+1], C18 H17 FN4O2 ”.
2.6.9. “N-(3-((1-(3,4-dichlorobenzyl)−1H-1,2,3-triazol-4-yl)
methoxy)phenyl)acetamide” (7i)
“White solid, 96% yield. mp: 210–212 °C. 1H NMR (400 MHz,
CDCl3) δ: 2.15 (s, 3H, NH-CO-CH3), 5.18 (s, 2H, C6H5-CH2), 5.47 (s,
2H, O-CH2), 6.69 (d, J=7.8 Hz, 1H, Ar-H), 6.95 (d, J=8.7 Hz, 1H,
Ar-H), 7.10 (dd, J=1.7, 2.1 Hz, 1H, Ar-H), 7.18 (t, J=8.3 Hz, 1H, Ar-
H), 7.35–7.45 (m, 4H, Ar-H), 7.64 (s, 1H, N-H-CO-CH3). 13C NMR
(400 MHz, CDCl3) δ: 24.4, 52.8, 61.6, 106.5, 110.7, 112.6, 123.1,
127.2, 129.6, 129.9, 131.0, 133.0, 133.2, 134.5, 139.2, 144.5, 158.3,
168.7. IR (ATR) cm−1, ν: 775, 1176, 1276, 1597, 1662, 3026, 3290.
MS (ESI) m/z: 391.25 [M+], 393 [M + 2], C18 H16 Cl2 N4O2 ”.
2.6.4. “N-(3-((1-(4-fluorobenzyl)−1H-1,2,3-triazol-4-yl)
methoxy)phenyl)acetamide” (7d)
“White solid, 95% yield. mp: 205–207 °C. 1H NMR (400 MHz,
CDCl3) δ: 2.15 (s, 3H, NH-CO-CH3), 5.15 (s, 2H, C6H5-CH2), 5.49 (s,
2H, O-CH2), 6.68 (d, J=7.8 Hz, 1H, Ar-H), 6.99 (d, J=8.3 Hz, 1H, Ar-
H), 7.02–7–08 (m, 2H, Ar-H), 7.17 (t, J=8.3 Hz, 1H, Ar-H), 7.24–7.28
(m, 2H, Ar-H), 7.33 (s, 1H, Ar-H), 7.48 (s, 1H, Ar-H), 7.57 (s, 1H, N-
H-CO-CH3). 13C NMR (400 MHz, CDCl3) δ: 24.5, 53.4, 61.8, 106.5,
110.7, 112.5, 116.0, 116.2, 122.8, 129.7, 129.9, 130.0, 130.2, 139.1,
144.4, 158.5, 164.0, 168.5. IR (ATR) cm−1, ν: 672, 744, 1021, 1171,
1374, 1553, 1662, 2925, 3088, 3421. MS (ESI) m/z: 341.25 [M+1],
C18 H17 FN4O2 ”.
2.6.10. “N-(3-((1-(2-methylbenzyl)−1H-1,2,3-triazol-4-yl)
methoxy)phenyl)acetamide” (7j)
“White solid, 85% yield. mp: 206–208 °C. 1H NMR (400 MHz,
DMSO–d6) δ: 2.02 (s, 3H, NH-CO-CH3), 2.31 (s, 3H, C6H4-CH3), 5.09
(s 2H, C6H5-CH2), 5.62 (s, 2H, O-CH2), 6.71 (d, J=7.8 Hz, 1H, Ar-
H), 7.06–7.27 (m, 6H, Ar-H), 7.33 (s, 1H, Ar-H), 8.16 (s, 1H, Ar-H),
9.89 (s, 1H, N-H-CO-CH3). 13C NMR (400 MHz, DMSO–d6) δ: 18.5,
24.0, 50.9, 60.9, 105.8, 108.9, 111.6, 124.6, 126.2, 128.2, 128.6, 129.4,
130.3, 134.0, 136.2, 140.4, 142.8, 158.1, 168.2. IR (ATR) cm−1, ν: 724,
780, 1014, 1130, 1515, 1662, 2874, 3091, 3289. MS (ESI) m/z: 337.25
[M+1], C19 H20N4O2 ”.
2.6.5. “N-(3-((1-(2-chlorobenzyl)−1H-1,2,3-triazol-4-yl)
methoxy)phenyl)acetamide” (7e)
“White solid, 92% yield. mp: 192–194 °C. 1H NMR (400 MHz,
CDCl3) δ: 2.15 (s, 3H, NH-CO-CH3), 5.18 (s, 2H, C6H5-CH2), 5.66
(s, 2H, O-CH2), 6.71 (d, J=7.8 Hz, 1H, Ar-H), 7.02 (d, J=7.8 Hz, 1H,
Ar-H), 7.17–7–22 (m, 2H, Ar-H), 7.24–7–35 (m, 4H, Ar-H), 7.43 (d,
J=1.3 Hz, 1H, Ar-H), 7.67 (s, 1H, N-H-CO-CH3). 13C NMR (400 MHz,
CDCl3) δ: 24.5, 51.4, 61.8, 106.4, 110.7, 112.6, 123.2, 127.5, 129.7,
129.9, 130.2, 130.3, 132.2, 133.4, 139.2, 144.2, 158.5, 168.5. IR (ATR)
cm−1, ν: 593, 714, 840, 1016, 1178, 1506, 1683, 2981, 3260, 3289.
MS (APCI) m/z: 359.00 [M+2], C18 H17 ClN4O2 ”.
2.6.11. “N-(3-((1-(3-methylbenzyl)−1H-1,2,3-triazol-4-yl)
methoxy)phenyl)acetamide” (7k)
“White solid, 80% yield. mp: 212–214 °C. 1H NMR (400 MHz,
CDCl3) δ: 2.15 (s, 3H, NH-CO-CH3), 2.34 (s, 3H, C6H4-CH3), 5.17 (s,
2H, C6H5-CH2), 5.48 (s, 2H, O-CH2), 6.70 (d, J=6.5 Hz, 1H, Ar-H),
3

H.B. Joolakanti, R. Kamepalli, J. Miryala et al.
Journal of Molecular Structure 1242 (2021) 130786
7.01 (d, J=8.3 Hz, 1H, Ar-H), 7.07 (d, J=8.3 Hz, 2H, Ar-H), 7.15–
7.30 (m, 5H, Ar-H), 7.56 (s, 1H, N-H-CO-CH3). 13C NMR (400 MHz,
CDCl3) δ: 21.2, 24.4, 54.1, 61.7, 106.5, 110.5, 112.6, 122.9, 125.1,
128.7, 128.9, 129.4, 129.6, 134.2, 138.9, 139.3, 144.2, 158.5, 168.7.
IR (ATR) cm−1, ν: 734, 1180, 1273, 1433, 1598, 1653, 3028, 3250.
MS (ESI) m/z: 337.25 [M+1], C19 H20N4O2 ”.
H), 7.02 (d, J = 7.8 Hz, 1H, Ar-H), 7.16–7.21 (m, 5H, Ar-H), 7.29 (s,
2H, Ar-H), 7.53 (s, 1H, N-H-CO-CH3). 13C NMR (400 MHz, CDCl3) δ:
21.0, 24.4, 53.9, 61.7, 106.4, 110.5, 112.6, 122.8, 128.1, 129.6, 129.7,
131.3, 138.6, 139.2, 144.1, 158.5, 168.7. IR (ATR) cm−1, ν: 725, 804,
1045, 1278, 1435, 1598, 1653, 2916, 3072, 3277. MS (APCI) m/z:
336.90 [M + 1], C19 H20N4O2 ”.
2.6.12. “N-(3-((1-(4-methylbenzyl)−1H-1,2,3-triazol-4-yl)
methoxy)phenyl)acetamide” (7l)
2.7. Docking
“White solid, 90% yield. mp: 196–198 °C. 1H NMR (400 MHz,
CDCl3) δ: 2.15 (s, 3H, NH-CO-CH3), 2.35 (s, 3H, C6H4-CH3), 5.15 (s,
2H, C6H5-CH2), 5.48 (s, 2H, O-CH2), 6.70 (d, J = 8.3 Hz, 1H, Ar-
Molecular docking was performed using Schrodinger 2015
(maestro 10.1) version software on HP Compaq 6200 Pro-MT PC
workstation (Intel(R) Core(TM) i7 CPU 2600 @ 3.40 GHz; 8 GB
H
N
H
N
CH3
CH3
Propargyl Bromide
DMF, K2CO3, rt, 12 h
O
O
O
OH
5a
6a
+
H2
H2
C
H
C
H2
NaBH4, Methanol
0 oC, 2 h
PBr3, Ether
NaN3, DCM, H2O
C
C
R
R
Br
O
R
OH
R
0 oC, 0.5 h
N3
TBAB, rt, 12 h
3a-l
1a-l
2a-l
4a-l
THF, H2O
Na Ascorbate, CuSo4
rt, 8 h
H
N
CH3
O
O
N
N N
R
7a-l
F
Cl
R =
Cl
F
F
7b
7f
7a
7c
7d
7e
Cl
CH3
Cl
Cl
Cl
Cl
7i
CH3
CH3
7l
7g
7j
7h
7k
Scheme 1. Synthesis of N-(3-((1R-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide derivatives (7a-7l).
4

H.B. Joolakanti, R. Kamepalli, J. Miryala et al.
Journal of Molecular Structure 1242 (2021) 130786
Table 2
Ram, 500 GB Hard disk). Human Estrogen Receptor Alpha Ligand-
Binding Domain (PDB Code: 1XP6) was selected as the Target.
a
CTC50
/
μg/mL values of test compounds against
MCF-7 cell line obtained by MTT assay.
Comp.
MCF-7
2.8. Cytotoxic activity by MTT assay
7a
22.83 0.4
>100
7b
The Cytotoxic activity was carried out as per procedure avail-
able in the literature [36].
7c
62.91 0.15
30.10 0.6
50.10 0.2
>100
7d
7e
7f
2.9. Anti bacterial activity
7g
18.61 0.7
17.93 0.76
15.84 0.17
>100
7h
The antibacterial activity was tested by determining “the Mini-
mum inhibitory concentration (MIC) for each compound using Disk
diffusion technique” [37]. “Gram positive bacteria (Staphylococcus
aureus(MTCC-96), Gram negative bacteria (Escherichia coli (MTCC-
443), Proteus vulgaris (MTCC-736), Pseudomonas aeruginosa (MTCC-
424)” were used as a test organisms.
7i
7j
7k
>100
7l
>100
Tamoxifenb
9.15
a
CTC50: Concentration of test drug needed to in-
hibit cell growth by 50%.
b
Positive-control.
2.10. Anti oxidant activity
The 1H NMR spectra showed the characteristic peaks in be-
tween δ 2.02 and 9.89 ppm. The spectra also showed the peaks of
aliphatic methyl protons of metacetamol and benzyl ring at δ 2.02–
2.35 ppm, methylene protons were observed at δ 5.09–5.62 ppm,
triazole proton at δ 7.10–8.27 ppm and aromatic protons at δ 6.68–
7.45 ppm. The 13C NMR spectra exhibited the characteristic peaks
of the carbonyl carbons in between δ 164–168 ppm, methyl car-
bons in between δ 18–24 ppm, methylene carbons in between
δ 50–61 ppm, triazole carbons in between δ 120–144 ppm and
aromatic carbons in between δ 105–164 ppm. The mass spectra
showed M+, [M+1], [M+2], [M-1] ions.
Free radical scavenging activity for each sample was evalu-
ated using “1, 1-diphenyl-2-picryl-hydrazyl (DPPH) method” as de-
scribed by Shen et al., 2010. The DPPH radical scavenging ability of
sample was calculated using the following formula.
“DPPH scavenging effect (% inhibition) = {(A0 –A1)/A0)∗100}
Where,
A0 is the absorbance of the control reaction
A1 is the absorbance in presence of all of the extract samples
and reference.
All the tests were performed in triplicates and the results were
averaged [38].
3. Results and discussion
3.2. Docking
3.1. Chemistry
Docking studies were conducted to understand the nature of
the interactions of these hybrid compounds. The Docking stud-
ies suggested that designed compounds (7a-7l) have good bind-
ing ability with 1XP6. Docking scores of compounds were in the
range of −8.211 to −10.438 representing their potential for bind-
ing at 1XP6 (Table 1). The highest docking scores (>−9.00) were
reported for compounds “7a, 7b, 7c, 7d, 7f, 7g, 7h, 7j and 7k”. All
the molecules has shown strong H-bond interaction with LYS 531
except 7i and therefore this could be the reason for the good bind-
ing affinities observed with this class of compounds. Compounds
“7b, 7d, 7e, 7i and 7l” have shown strong hydrophobic interactions
with TRP 383, PHE 404. Compounds “7g, 7h, 7a” have shown high
docking score and 7i has shown additional strong hydrophobic in-
teractions. This could be the reason for their high cytotoxic activity
(Fig 2&3).
The target compounds “N-(3-((1H-1,2,3-triazol-4-yl)methoxy)
phenyl)acetamide derivatives” (7a-7l) were synthesized by a multi-
step sequence as per Scheme 1. “The copper-catalyzed azide-
alkyne cycloaddition (CuAAC)” was used in our synthesis in which
“CuSO4•5H2O and sodium ascorbate” mixture was used as
a
precatalyst system to generate the Cu (I) species in situ. The
alkyne ((N-(3-(prop–2-ynyloxy)phenyl) acetamide (6a)) was pre-
pared from metacetamol (5a), propargyl bromide and potassium
carbonate in DMF medium. The alkyne (6a) was then coupled with
a number of azides (4a-l) in the presence of CuSO4•5H2O and
sodium ascorbate in THF-water media to obtain the desired com-
pounds (7a-7l) in 90–98% yield (Scheme 1). The structures of the
derivatives (7a-7l) are confirmed by using different spectral data.
Table 1
Extra precision (Xp) Docking Results of Schrodinger: “(PDB ID: 1XP6-Human Estrogen Receptor Alpha Ligand-Binding Domain in Complex with
ꢀꢀ
Compound 16 ).
˚
COMP.
DOCK SCORE
NO OF H-BONDS
INTERACTING AMINO ACIDS
H-BOND DISTANCE (A)
Glide energy
EMODEL ENERGY
7a
7b
7c
7d
7e
7f
−9.549
−9.477
−10.123
−9.482
−8.988
−10.031
−10.438
−10.436
−8.211
−10.187
−9.733
−8.44
1
1
1
1
1
1
1
1
0
1
1
1
LYS 531
1.94
1.81
1.95
1.92
1.97
187
1.88
1.88
–
−35.999
−42.335
−42.127
−46.915
−51.619
−49.608
−45.961
−44.101
−48.987
−48.717
−47.205
−50.721
−60.154
−63.11
LYS 531, TRP 383
LYS 531
−66
LYS 531, PHE 404
LYS 531, PHE 404
LYS 531
−69.581
−75.296
−73.005
−70.008
−72.155
−77.413
−72.685
−72.738
−74.837
7g
7h
7i
LYS 531
LYS 531
LYS 531, TRP 383
LYS 531
7j
1.86
1.77
2.15
7k
7l
LYS 531
LYS 531, PHE 404
5

H.B. Joolakanti, R. Kamepalli, J. Miryala et al.
Journal of Molecular Structure 1242 (2021) 130786
Fig 2. Interactions of 7g at active site of “1XP6- Human Estrogen Receptor Alpha Ligand-Binding Domain”.
3.3. Biological activity
with 3-fluoro benzyl, 7d with 4-fluoro benzyl, 7e with 2-chloro
benzyl groups on triazole ring have good cytotoxic activity with
IC50 value of <62 μg/ml whereas compounds 7b with 2-fluoro
benzyl, 7f with 2–chloro benzyl group and methylated compounds
7j, 7k, 7l were least active ones with IC50 value of >100 μg/mL.
Compounds 7a, 7h and 7i have shown to be the most promising
for anticancer and antioxidant activity among all synthetic com-
pounds. SAR studies revealed that Di chloro substitution on benzyl
group at 2,3,4 position increases the activity, Mono chloro substitu-
tion at 4 position increases the activity but 2, 3 position decreases.
Fluoro substitution on benzyl group at 4 position increases the ac-
tivity but 2, 3 position decreases and Methyl substitution on benzyl
group at 2, 3 and 4 position destroys the activity.
3.3.1. Cytotoxic activity by MTT assay
The in vitro cytotoxic activities of the designed compounds (7a-
l) were evaluated against human cancer cell line MCF-7 (breast)
and the test results are shown (Table 2). It is evident from Table 2,
the synthesized compounds (7a-l) showed significant to moder-
ate cancer cell growth inhibition with CTC50 values ranging from
15.84 to >100 μg/mL. Compounds 7i with 3,4-Di chloro benzyl, 7h
with 2,4-Di chloro benzyl, 7g with 4-chloro benzyl, and 7a with
1-benzyl groups on the triazole ring at N-1 were most active with
IC50 value of 15.84, 17.93, 18.61, 22.83 μg/mL respectively and two
fold less active than the positive control Tamoxifen. Compounds 7c
6

H.B. Joolakanti, R. Kamepalli, J. Miryala et al.
Journal of Molecular Structure 1242 (2021) 130786
Fig 3. Interactions of 7h at active site of “1XP6- Human Estrogen Receptor Alpha Ligand-Binding Domain”.
3.3.2. Antioxidant activity
3.3.3. Antibacterial activity
The synthesized triazoles (7a-l) were tested for their capaci-
ties to scavenge DPPH. The antioxidant activities of the derivatives
ranged from 14.01 to 44.07 μM (Table 3). The Compounds 7e, 7i,
7f, 7h, 7d, 7l, 7a, 7j and 7k were found to be the most potent an-
tioxidants and having IC50 value of < 30 μM and more than that
of positive control. SAR studies revealed that Chloro substitution
on benzyl group at 2, 3 position increases the anti oxidant activ-
ity but at 4 position decreases, Fluoro substitution on benzyl group
at 4 position increases the activity but 2, 3 position decreases and
Methyl substitution on benzyl group at 2, 3 and 4 position main-
tains good anti oxidant activity.
The synthesized triazoles (7a-l) were checked for in-vitro an-
tibacterial activity against four bacterial strains, one Gram-positive
(Staphylococcus aureus) and three Gram-negative (E. coli, Proteus
vulgaris and Pseudomonas aeruginosa) by Disk diffusion technique
using Gentamicin as standard drug. Detailed examination of the
results showed that compound 7a was most active against Staphy-
lococcus aureus, Compounds 7a, 7b, 7c and 7d were most active
against E.coli, Compounds 7a, 7b, 7c, 7d and 7g were most active
against Pseudomonas aeruginosa, whereas compounds 7j, 7k and
7l were most active against Proteus vulgaris with a MIC value of
<300 μM (Table 4).
7

H.B. Joolakanti, R. Kamepalli, J. Miryala et al.
Journal of Molecular Structure 1242 (2021) 130786
Table 3
showed good docking score and Hydrogen bonding interactions
with 1XP6. Among the tested compounds “7i, 7h, 7g and 7a”
exhibited promising cytotoxicity with IC50 value of 15.84, 17.93,
18.61, 22.83 μg/mL respectively and docking results also suggested
that these compounds could bind well with the active site of
1XP6, while compounds “7c, 7d and 7e” showed cytotoxicity with
IC50 value <60 μg/ml. Compounds “7a, 7d, 7e, 7f, 7h, 7i, 7j, 7k
and 7l” exhibited most potent anti oxidant activity with IC50 value
of < 30 μM i.e. DPPH scavenging activity levels more than that of
Positive control. Compounds “7a, 7b, 7c, 7d, 7d, 7g, 7j, 7k and 7l”
exhibited moderate antibacterial activities with the MIC value of
<300 μM.
a
IC50 / μM values of test compounds obtained by
DPPH method.
Comp.
DPPH Scavenging
7a
21.71 0.8
44.07 2.8
35.25 0.4
20.56 0.3
14.01 0.8
19.61 0.5
36.43 3.5
20.44 1.0
17.89 0.6
26.75 1.2
26.75 1.1
20.80 0.4
30.81 1.01
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
Declaration of Competing Interest
Ascorbic acidb
a
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
IC50
: Concentration of test drug required to
scavenge 50% of DPPH free radicals.
b
Positive-control.
Table 4
a
MIC / μM values of tested compounds against four pathogenic bacteria.
Supplementary materials
Comp.
S.aureus
E.coli
P.aeruginosa
P.vulgaris
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.130786.
7a
155.10 0.8
155.10 0.2
155.10 0.4
155.10 0.8
293.81 0.5
146.90 1.1
146.90 1.0
–
7b
2938.15 1.7
146.90 0.3
293.81 0.2
7c
2938.15 1.2
293.81 1.0
146.90 1.2
7d
2938.15 1.9
293.81 0.2
146.90 0.3
CRediT authorship contribution statement
7e
–
–
–
7f
–
–
–
–
Hima Bindhu Joolakanti: Investigation, Data curation, Writing
- original draft, Project administration. Ramanjaneyulu Kamepalli:
Methodology, Resources. Jeevanreddy Miryala: Software, Formal
analysis. Satyanarayana Battu: Validation, Conceptualization, Writ-
ing - review & editing, Supervision.
7g
–
–
140.13 1.2
140.13 0.3
2555.91 1.9
1277.95 0.6
148.63 0.2
297.27 1.1
155.10 0.4
<4.18
7h
2555.91 2.5
2555.91 0.5
2555.91 1.6
7i
2555.91 1.8
1277.95 0.3
1277.95 0.8
7j
–
–
–
7k
–
–
–
7l
–
–
–
Gentamicinb
<2.09
>67.00
<4.18
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