Design, synthesis, anticancer and antioxidant activities of amide linked 1,4-disubstituted 1,2,3-triazoles

Article abstract of DOI:10.1016/j.molstruc.2020.129255

To explore anticancer and antioxidant agents with improved potency, we synthesized a series of amide linked 1,4-disubstituted 1,2,3-triazoles through click chemistry approach. The structure of synthesized triazoles were characterized by- FTIR, ¹H NMR, ¹³C NMR spectroscopy and HRMS. All the synthesized compounds were screened for their anticancer activity against four different cell lines- PC3 (prostate cancer), A549 (lung cancer), MIAPACA (liver cancer), Fr2 (Breast epithelial), reflecting compounds 7e and 7f to possess good activity. The antioxidant activity was evaluated by using stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay and compound 7d showed promising activity having IC₅₀ value 1.61 μg/ml. Molecular docking studies of compounds 7e and 7f was carried out in active site of human epidermal growth factor receptor 2 revealed high binding affinities and within toxicity limits. The experimental results were in good agreement with docking studies. In-silico ADME studies of synthesized compounds also have good dispositional profile and are patient compliant, may be potential future candidates for anticancer treatment.

Full text of DOI:10.1016/j.molstruc.2020.129255

Journal of Molecular Structure 1226 (2021) 129255
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Design, synthesis, anticancer and antioxidant activities of amide
linked 1,4-disubstituted 1,2,3-triazoles
a,∗
b
a
a
a
b
C.P. Kaushik , Jyoti Sangwan , Raj Luxmi , Devinder Kumar , Deepak Kumar ,
c
d
Ashutosh Das , Ashwani Kumar , Dharmendra Singh
a
Department of Chemistry, Guru Jambheshwar University of Science & Technology, Hisar, Haryana, India
School of Pharmaceutical Sciences, Shoolini University, Bajhol, Solan, Himachal Pradesh, India
Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science & Technology, Hisar, India
Centre for Research & Development, IPCA Lab Ltd., Kandivali, Mumbai, Maharashtra, India
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
To explore anticancer and antioxidant agents with improved potency, we synthesized a series of amide
linked 1,4-disubstituted 1,2,3-triazoles through click chemistry approach. The structure of synthesized tri-
azoles were characterized by- FTIR, 1H NMR, 13 C NMR spectroscopy and HRMS. All the synthesized com-
pounds were screened for their anticancer activity against four different cell lines- PC3 (prostate cancer),
A549 (lung cancer), MIAPACA (liver cancer), Fr2 (Breast epithelial), reflecting compounds 7e and 7f to
possess good activity. The antioxidant activity was evaluated by using stable free radical 1,1-diphenyl-2-
picrylhydrazyl (DPPH) assay and compound 7d showed promising activity having IC50 value 1.61 μg/ml.
Molecular docking studies of compounds 7e and 7f was carried out in active site of human epidermal
growth factor receptor 2 revealed high binding affinities and within toxicity limits. The experimental re-
sults were in good agreement with docking studies. In-silico ADME studies of synthesized compounds
also have good dispositional profile and are patient compliant, may be potential future candidates for
anticancer treatment.
Received 28 June 2020
Revised 10 September 2020
Accepted 10 September 2020
Available online 19 September 2020
©
2020 Elsevier B.V. All rights reserved.
1
. Introduction
i.e., pollution, cigarette smoke, radiation, medication etc. Oxidative
damage to DNA is considered a critical step in cancer development
[6]. Free radicals play a significant role in causation of oxidative
stress related diseases such as Carcinogenesis, Alzheimer, Parkin-
son, Inflammatory disorder and Cataract [7]. Antioxidants are our
first line to slow down or prevent the free radical damage. The
need for antioxidants becomes even more critical with increased
exposure to free radicals. 1,1-diphenyl-2-picryl-hydrazyl (DPPH) is
a stable free radical which has an unpaired valence electron at one
atom of nitrogen bridge which produce a violet solution, scaveng-
ing of DPPH radical is the basis of the popular DPPH antioxidant
assay. This free radical is stable at room temperature and reduced
in the presence of an antioxidant molecule, giving rise to violet to
colorless solution. The use of the DPPH assay offers an easy and
fast method to estimate antioxidants by spectrophotometry.
Cancer, a major health concern, being the second most lethal
disease after heart ailments responsible for 21% of annual deaths
globally. The World Health Organization’s cancer agency warns that
there will be 22 million new cases of cancer every year within the
next two decades [1]. Hence, cancer treatment is the primary task
of today’s medical research [2]. Despite the invention of several
therapeutic approaches, still treatment of cancer is a major chal-
lenge, because of multi-drug resistance, toxicity or poor bioavail-
ability. The effectiveness of many anticancer drugs is limited by ac-
quired resistance to drugs, side effects due to their toxicity to nor-
mal cells because of their inability to differentiate between normal
and cancerous cells. In this context, there is need to design and
synthesize new, effective and less toxic anticancer agents throwing
a challenge to medicinal chemists all over the world [3,4].
Triazole includes two carbon and three nitrogen atoms compris-
ing a five membered heterocyclic ring. 1,2,3-Triazoles are of key
importance in medicinal chemistry owing to its broad biological
spectrum such as antimicrobial [8–11], antioxidant [12–14], anti-
diabetic [15,16], anticancer [17–20], anti-inflammatory [21], antitu-
bercular [22,23], antiviral [24,25], antimalarial [26,27] agents.
The accumulation of free radicals plays multiple roles in tis-
sue damage and loss of function in organs [5]. They are produced
either from normal cell metabolisms or from external sources
∗
Corresponding author.
E-mail address: kaushikcp@gmail.com (C.P. Kaushik).
https://doi.org/10.1016/j.molstruc.2020.129255
0
022-2860/© 2020 Elsevier B.V. All rights reserved.

C.P. Kaushik, J. Sangwan, R. Luxmi et al.
Journal of Molecular Structure 1226 (2021) 129255
Fig. 1. Biologically active 1,4-disubstituted 1,2,3-triazoles having amide/hydroxyalkyl group.
In past various methods have been developed for the synthe-
sis of 1,2,3-triazoles, however the method put forward by Sharp-
less [28] and Meldal [29] gives the selective synthesis of 1,4-
disubstituted 1,2,3-triazoles via 1,3-dipolar cycloaddition between
terminal alkynes and azides using copper(I) as a catalyst. This
methodology, click synthesis possess a significant importance over
thermally induced Huisgen classical approach which leads to the
mixture of isomers [30]. Moreover, importance of click reaction
has also been recognized in the synthesis of nanotubes [31], den-
drimers [32], enzymes [33], peptide conjugation [34], cyclic pep-
tides [35], liquid crystals [36] etc.
recorded on Waters Micromass Q-Tof Micro (ESI) spectrophotome-
ter.
2
.1.2. Synthesis of amide linked 1,4-disubstituted 1,2,3-triazoles
The starting reactants i.e., 2/3/4-(prop-2-yn-1-yloxy)phenyl)
methanol (3a-3c) were synthesized by dropwise addition of
propargyl bromide (2) (1.2 mmol) into stirred solution of
/3/4-hydroxy benzyl alcohols (1a-1c) (1.0 mmol) in the pres-
a
2
ence of potassium carbonate (2 mmol) in dimethylformamide with
continuous stirring at 0-10 °C for 4-5 h. After the completion
of reaction as indicated by TLC, water (20 mL) was added in
the reaction mixture and product was extracted using ethyl ac-
etate (3 × 25 mL) from the reaction mixture. The separated or-
ganic layer was evaporated under reduced pressure to get termi-
nal alkynes (3a-3c). Further, for the synthesis of 4-(prop-2-yn-1-
yloxy)benzyl acetate (3d), (4-(prop-2-yn-1-yloxy)phenyl)methanol
Keeping in view the potential significance of 1,2,3-triazole and
amide group in anticancer activity [37–41] and 1,2,3-triazole-
hydroxyl alkyl in antioxidant activity [42], (Fig 1).
It has been thought to design and synthesize chemical enti-
ties by combination of both amide as well as hydroxyl alkyl group
with 1,2,3-triazole for exploring anticancer and antioxidant activ-
ities. Owing to this aspect, twenty 1,2,3-triazole derivatives have
been synthesized and evaluated for anticancer and antioxidant ac-
tivities. Molecular docking studies of compounds 7e and 7f was
carried out in active site of human epidermal growth factor recep-
tor 2.
(
3c) (1.0 mmol) was reacted with acetyl chloride (1.2 mmol) using
N,N-dimethylaminopyridine (2.0 mmol) as base at 0-5 °C for 2-3 h.
Upon completion of the reaction, neutralized the reaction content
with dilute HCl and product was extracted with dichloromethane
(
(
3 × 25 mL). Organic layer was distilled under vacuum to get 4-
prop-2-yn-1-yloxy)benzyl acetate.
Synthesis of 2-Bromo-N-aryl acetamides (6a–6e) were carried
out by drop wise addition of bromoacetylbromide (5) (1.2 mmol)
into a stirred solution of aromatic amines (4a–4e) (1.0 mmol) in
dichloromethane using potassium carbonate (2.0 mmol) as a base
at 0–5 °C, further continue stirring for 20–25 min. When reaction
was completed, ice cold water was added, precipitated solid prod-
uct was filtered and dried to get 2-bromo-N-aryl acetamides.
In the final step, synthesis of amide & ester-amide linked 1,4-
disubstituted 1,2,3-triazoles (7a-7t), aqueous solution of sodium
azide (3.0 mmol) was added to 2-bromo-N-arylacetamides (6a–6e)
2
. Materials and methods
2
.1. Experimental section
2.1.1. General
All chemicals used in the synthesis were purchased from Sigma
Aldrich, Hi-Media, Alfa-Aesar and were used without purification.
Thin layer chromatography was used to monitor the progress of
the reactions and purity of compounds. Melting points of the
synthesized compounds were determined by open capillary us-
ing an electrothermal apparatus and were uncorrected. IR spec-
tra were recorded on Shimazdu IR Affinity-I FT-IR spectrophotome-
ter using potassium bromide (KBr) powder and absorption fre-
(
1.0 mmol) in DMF (8 ml) at 30-40 °C under stirring. After half an
hour, terminal alkynes (3a-3d) (1.0 mmol), copper sulfate pentahy-
drate (0.1 mmol) and sodium ascorbate (0.4 mmol) were added
and stirred the reaction contents for 4-6 h. After completion of
reaction, in the reaction mixture added 25 ml ice cold water, pre-
cipitated product was, filtered and washed with ammonia solution.
Crude product was dissolved in mixture of ethyl acetate:methanol
quencies were stated in cm−1. The 1H and 13C NMR spectra of
the synthesized compounds were recorded at 400 MHz and 100
MHz, respectively, using Bruker Avance II 400 MHz, in deuterated
dimethylsulphoxide-d6 using tetramethylsilane (TMS) as an inter-
nal standard. The chemical shifts were expressed in δ relative to
TMS and coupling constants (J) in Hz and abbreviation in NMR
spectra were s: singlet, d: doublet, t: triplet, q: quartet, m: mul-
tiplet, dd: doublet of doublet. High resolution mass spectra were
(
1:1) and precipitated out by hexane, which was filtered and dried
to get 1,4-disubstituted 1,2,3-triazoles (7a-7t).
Characterization of the synthesized compounds (7a-7t)
2.1.2.1. 2-(4-((2-(hydroxymethyl)phenoxy)methyl)-1H-1,2,3-triazol-1-
yl)-N-phenylacetamide (7a). White solid; Yield: 87 %; m.p. 168-172
2

C.P. Kaushik, J. Sangwan, R. Luxmi et al.
Journal of Molecular Structure 1226 (2021) 129255
1
3
°
C; FTIR (KBr, υmax): 3264 (N-H amide str.), 3146 (C-H str., triazole
1H), 4.50 (d, J = 5.6 Hz, 2H); C NMR (100 MHz, CDCl ): δ 165.6,
3
ring), 3065 (C-H str., aromatic ring), 2945 (C-H str., aliphatic), 1668
155.3, 143.3 (C4 triazole), 134.2, 133.2, 131.2, 128.7, 128.0, 127.5,
126.7, 126.5 (C5 triazole), 126.2, 126.1, 123.1, 122.0, 121.0, 112.1,
61.9, 58.3, 52.6; HRMS (m/z) calculated for C22H20N O [M+H]+:
(
C=O str., amide) cm−1; 1H NMR (400 MHz, CDCl ): δ 10.49 (s,
3
1
9
H, N-H amide), 8.25 (s, 1H, C–H triazole), 7.27 (dd, J = 153.30,
4
3
0.6 Hz, 9H, ArH), 5.36 (s, 2H), 5.19 (s, 2H), 4.98 (s, 1H), 4.51
389.1535. Found: 389.1546
(
s, 2H); 13C NMR (100 MHz, CDCl ): δ 164.7, 155.3, 143.3 (C4
3
triazole), 138.9, 131.3, 129.4, 128.0, 127.5, 126.5 (C5 triazole), 124.3,
21.0, 119.7, 112.2, 61.9, 58.3, 52.7; HRMS (m/z) calculated for
2
.1.2.6. 2-(4-((3-(hydroxymethyl)phenoxy)methyl)-1H-1,2,3-triazol-1-
yl)-N-phenylacetamide (7f). White solid; Yield: 91 %; m.p. 158-162
C; FTIR (KBr, υmax): 3273 (N-H amide str.), 3144 (C-H str., triazole
1
+
C18 H18 N O [M+H] : 339.1379. Found: 339.1389
4
3
°
ring), 3092 (C-H str., aromatic ring), 2945 (C-H str., aliphatic), 1672
2
1
.1.2.2. 2-(4-((2-(hydroxymethyl)phenoxy)methyl)-1H-1,2,3-triazol-
-yl)-N-(p-tolyl)acetamide (7b). White solid; Yield: 83 %; m.p.
(
C=O str., amide) cm 1; 1H NMR (400 MHz, CDCl ): δ 10.49 (s,
−
3
1
H, N-H amide), 8.26 (s, 1H, C–H triazole), 7.59 (d, J = 8.0 Hz, 2H,
188-192 °C; FTIR (KBr, υmax): 3264 (N-H amide str.), 3140 (C-H
ArH), 7.34 (t, J = 8.0 Hz, 2H, ArH), 7.26 (t, J = 8.0 Hz, 1H, ArH),
7.10 (t, J = 8.0 Hz, 1H, ArH), 7.01 (s, 1H, ArH), 6.94 (d, J = 8.0
Hz, 1H, ArH), 6.92 (d, J = 8.0 Hz, 1H, ArH), 5.36 (s, 2H), 5.20 (t,
str., triazole ring), 3044 (C-H str., aromatic ring), 2947 (C-H str.,
aliphatic), 1665 (C=O str., amide) cm−1; 1H NMR (400 MHz,
CDCl ): δ 10.40 (s, 1H, N-H amide), 8.24 (s, 1H, C–H triazole),
3
13
J = 5.8 Hz, 1H), 5.17 (s, 2H), 4.49 (d, J = 5.8 Hz, 2H); C NMR
7
.47 (d, J = 8.0 Hz, 2H, ArH), 7.40 (d, J = 8.0 Hz, 1H, ArH), 7.23
(
100 MHz, CDCl ): δ 164.6, 158.5, 144.8, 143.1 (C triazole), 138.9,
3 4
(
t, J = 8.0 Hz, 1H, ArH), 7.15 (t, J = 8.0 Hz, 3H, ArH), 6.97 (t,
1
29.6, 129.4, 126.6 (C5 triazole), 124.3, 119.7, 119.4, 113.3, 113.1,
J = 8.0 Hz, 1H, ArH), 5.34 (s, 2H), 5.20 (s, 2H), 4.97 (t, J = 5.4
63.2, 61.4, 52.7; HRMS (m/z) calculated for C18 H18 N O [M+H]+:
13
Hz, 1H), 4.50 (d, J = 5.4 Hz, 2H), 2.26 (s, 3H, CH ); C NMR (100
4
3
3
339.1379. Found: 339.1389
MHz, CDCl ): δ 164.4, 155.3, 143.3 (C triazole), 136.4, 133.2, 131.2,
3
4
1
29.8, 128.0, 127.5, 126.5 (C5 triazole), 121.0, 119.7, 112.1, 61.9, 58.3,
5
3
2.7, 20.9 (CH ); HRMS (m/z) calculated for C19 H20N O [M+H]+:
3
4
3
2
1
.1.2.7. 2-(4-((3-(hydroxymethyl)phenoxy)methyl)-1H-1,2,3-triazol-
-yl)-N-(p-tolyl)acetamide (7g). White solid; Yield: 85 %; m.p.
53.1535. Found: 353.1545
1
64-168 °C; FTIR (KBr, υmax): 3269 (N-H amide str.), 3136 (C-H
2
1
.1.2.3. N-(4-ethylphenyl)-2-(4-((2-(hydroxymethyl)phenoxy)methyl)-
H-1,2,3-triazol-1- yl)acetamide (7c). White solid; Yield: 87 %;
str., triazole ring), 3099 (C-H str., aromatic ring), 2941 (C-H str.,
aliphatic), 1662 (C=O str., amide) cm 1; 1H NMR (400 MHz,
−
m.p. 178-182 °C; FTIR (KBr, υmax): 3271 (N-H amide str.), 3146
CDCl ): δ 10.40 (s, 1H, N-H amide), 8.25 (s, 1H, C–H triazole), 7.47
3
(
C-H str., triazole ring), 3044 (C-H str., aromatic ring), 2968 (C-H
(
d, J = 12 Hz, 2H, ArH), 7.25 (t, J = 8.0 Hz, 1H, ArH), 7.14 (d, J = 8.0
str., aliphatic), 1668 (C=O str., amide) cm 1; 1H NMR (400 MHz,
−
Hz, 2H, ArH), 7.01 (s, 1H, ArH), 6.92 (d, J = 8.0 Hz, 2H, ArH), 5.34
CDCl ): δ 10.44 (s, 1H, N-H amide), 8.21 (s, 1H, C–H triazole),
3
(
(
(
s, 2H), 5.18 (t, J = 5.8 Hz, 2H & OH), 4.49 (d, J = 5.8 Hz, 2H), 2.26
7
.45 (d, J = 8.0 Hz, 2H, ArH), 7.37 (d, J = 8.0 Hz, 1H, ArH), 7.23
t, J = 8.0 Hz, 1H, ArH), 7.15 (t, J = 8.0 Hz, 3H, ArH), 6.96 (t,
J = 8.0 Hz, 1H, ArH), 5.30 (s, 2H), 5.17 (t, J = 5.5 Hz, 2H & OH),
.48 (d, J = 5.5 Hz, 2H), 2.54 (q, J = 8 Hz, 4H, CH CH & H O),
s, 3H); 13C NMR (100 MHz, CDCl ): δ 164.4, 158.5, 144.8, 143.0
3
(
C4 triazole), 136.4, 133.2, 129.8, 129.6, 126.7 (C5 triazole), 119.7,
119.3, 113.3, 113.1, 63.2, 61.4, 52.6, 20.9; HRMS (m/z) calculated for
4
2
3
2
+
C19 H20N O [M+H] : 353.1535. Found: 353.1545
13
4
3
1
.13 (t, J = 8.0 Hz, 3H); C NMR (100 MHz, CDCl ): δ 164.3,
3
155.2, 143.3 (C4 triazole), 140.0, 136.3, 130.9, 128.6, 128.2, 127.6,
1
26.5 (C5 triazole), 121.2, 120.0, 112.2, 61.7, 58.3, 52.6, 28.0, 16.0;
2.1.2.8. N-(4-ethylphenyl)-2-(4-((3-(hydroxymethyl)phenoxy)methyl)-
1H-1,2,3-triazol-1- yl)acetamide (7h). White solid; Yield: 89 %;
m.p. 178-182 °C; FTIR (KBr, υmax): 3300 (N-H amide str.), 3196
+
HRMS (m/z) calculated for C20H22N O [M+H] : 367.1692. Found:
4
3
3
67.1699
(
C-H str., triazole ring), 3105 (C-H str., aromatic ring), 2940 (C-H
2
1
.1.2.4. 2-(4-((2-(hydroxymethyl)phenoxy)methyl)-1H-1,2,3-triazol-
-yl)-N-(4-nitrophenyl)acetamide (7d). Orange solid; Yield: 85 %;
str., aliphatic), 1665 (C=O str., amide) cm ; 1H NMR (400 MHz,
−1
CDCl ): δ 10.42 (s, 1H, N-H amide), 8.25 (s, 1H, C–H triazole),
3
m.p. 142-146 °C; FTIR (KBr, υmax): 3213 (N-H amide str.), 3157
7
.50 (d, J = 8.0 Hz, 2H, ArH), 7.25 (t, J = 8.0 Hz, 1H, ArH), 7.17
(
C-H str., triazole ring), 3048 (C-H str., aromatic ring), 2951 (C-H
(
d, J = 8.0 Hz, 2H, ArH), 7.01 (s, 1H, ArH), 6.92 (d, J = 8.0 Hz, 2H,
str., aliphatic), 1719 (C=O str., amide) cm 1; 1H NMR (400 MHz,
−
ArH), 5.34 (s, 2H), 5.18 (t, J = 5.7 Hz, 2H & OH), 4.49 (d, J = 5.7
CDCl ): δ 11.50 (s, 1H, N-H amide), 8.28 (s, 1H, C-H triazole), 8.25
13
3
Hz, 2H), 2.56 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H); C NMR
(
d, J = 8.0 Hz, 2H, ArH), 7.90 (d, J = 8.0 Hz, 2H, ArH), 7.40 (d,
(
100 MHz, CDCl ): δ 164.4, 158.5, 144.8, 143.1 (C triazole), 139.7,
3 4
J = 8.0 Hz, 1H, ArH), 7.23 (t, J = 8.0 Hz, 1H, ArH), 7.16 (d, J = 8.0
Hz, 1H, ArH), 6.97 (t, J = 8.0 Hz, 1H, ArH), 5.50 (s, 2H), 5.20 (s,
1
36.6, 129.6, 128.6, 126.6 (C5 triazole), 119.8, 119.3, 113.3, 113.1,
6
3.2, 61.4, 52.7, 28.1, 16.1; HRMS (m/z) calculated for C20H22N O
4
3
2
H), 5.01 (s, 1H), 4.49 (s, 2H); 13C NMR (100 MHz, CDCl ): δ 165.8,
+
3
[M+H] : 367.1692. Found: 367.1699
155.3, 145.1, 143.4 (C4 triazole), 143.0, 131.3, 128.0, 127.5, 126.5 (C5
triazole), 125.5, 121.0, 119.5, 112.1, 61.9, 58.2, 52.8; HRMS (m/z)
+
calculated for C18 H17 N O [M+H] : 384.1230. Found: 384.1234
2.1.2.9. 2-(4-((3-(hydroxymethyl)phenoxy)methyl)-1H-1,2,3-triazol-
5
5
1
-yl)-N-(4-nitrophenyl)acetamide (7i). White solid; Yield: 81 %;
2
.1.2.5. 2-(4-((2-(hydroxymethyl)phenoxy)methyl)-1H-1,2,3-triazol-1-
m.p. 182-186 °C; FTIR (KBr, υmax): 3260 (N-H amide str.), 3167
(C-H str., triazole ring), 3089 (C-H str., aromatic ring), 2945 (C-H
str., aliphatic), 1703 (C=O str., amide) cm 1; 1H NMR (400 MHz,
yl)-N-(naphthalen-1-yl)acetamide (7e). Brown solid; Yield: 89 %;
m.p. 190-194 °C; FTIR (KBr, υmax): 3250 (N-H amide str.), 3142
−
(
C-H str., triazole ring), 3088 (C-H str., aromatic ring), 2945 (C-H
CDCl ): δ 11.10 (s, 1H, N-H amide), 8.26 (d, J = 8.0 Hz, C–H triazole
3
str., aliphatic), 1665 (C=O str., amide) cm 1; 1H NMR (400 MHz,
−
& 2 ArH), 7.84 (d, J = 8.0 Hz, 2H, ArH), 7.26 (t, J = 8.0 Hz, 1H,
ArH), 7.00 (s, 1H, ArH), 6.92 (d, J = 8.0 Hz, 2H, ArH), 5.45 (s, 2H),
CDCl ): δ 10.47 (s, 1H, N-H amide), 8.31 (s, 1H, C–H triazole), 8.18
3
13
(
d, J = 12.0 Hz, 1H, ArH), 7.97 (d, J = 8.0 Hz, 1H, ArH), 7.81 (d,
J = 8.0 Hz, 1H, ArH), 7.73 (d, J = 8.0 Hz, 1H, ArH), 7.63-7.56 (m,
H, ArH), 7.52 (t, J = 8.0 Hz, 1H, ArH), 7.40 (d, J = 8.0 Hz, 1H, ArH),
.23 (t, J = 8.0 Hz, 1H, ArH), 7.17 (d, J = 8.0 Hz, 1H, ArH), 6.97 (t,
J = 8.0 Hz, 1H, ArH), 5.57 (s, 2H), 5.21 (s, 2H), 5.01 (t, J = 5.6 Hz,
5.19 (t, J = 4 Hz, 2H & OH), 4.49 (d, J = 4.0 Hz, 2H); C NMR
(100 MHz, CDCl ): δ 165.8, 158.5, 145.0, 144.8, 143.2, 143.1 (C
3
4
2
triazole), 129.6, 126.7 (C5 triazole), 125.6, 119.5, 119.4, 113.3, 113.1,
7
63.2, 61.4, 52.8; HRMS (m/z) calculated for C18 H17 N O [M+H]+:
5
5
384.1230. Found: 384.1234
3

C.P. Kaushik, J. Sangwan, R. Luxmi et al.
Journal of Molecular Structure 1226 (2021) 129255
2
1
.1.2.10. 2-(4-((3-(hydroxymethyl)phenoxy)methyl)-1H-1,2,3-triazol-
-yl)-N-(naphthalen-1-yl)acetamide (7j). Brown solid; Yield: 87 %;
135.4, 128.4, 126.7 (C5 triazole), 125.6, 119.5, 114.8, 63.0, 61.5, 52.8;
+
HRMS (m/z) calculated for C18 H17 N O [M+H] : 384.1230. Found:
5
5
m.p. 144-148 °C; FTIR (KBr, υmax): 3264 (N-H amide str.), 3132
384.1234
(
C-H str., triazole ring), 3084 (C-H str., aromatic ring), 2943 (C-H
str., aliphatic), 1676 (C=O str., amide) cm 1; 1H NMR (400 MHz,
−
2.1.2.15. 2-(4-((4-(hydroxymethyl)phenoxy)methyl)-1H-1,2,3-triazol-1-
yl)-N-(naphthalen-1-yl)acetamide (7o). Brown solid; Yield: 85 %;
m.p. 184-188 °C; FTIR (KBr, υmax): 3260 (N-H amide str.), 3130
(C-H str., triazole ring), 3088 (C-H str., aromatic ring), 2945 (C-H
str., aliphatic), 1678 (C=O str., amide) cm 1; 1H NMR (400 MHz,
CDCl ): δ 10.44 (s, 1H, N-H amide), 8.30 (s, 1H, C–H triazole), 8.17
3
(
d, J = 8.0 Hz, 1H, ArH), 7.97 (d, J = 8.0 Hz, 1H, ArH), 7.81 (d,
J = 8.0 Hz, 1H, ArH), 7.73 (d, J = 4 Hz, 1H, ArH), 7.61–7.52 (m, 4H,
ArH), 7.25 (t, J = 8.0 Hz, 1H, ArH), 7.01 (s, 1H, ArH), 6.93 (s, 2H,
−
13
ArH), 5.56 (s, 2H), 5.18 (s, 2H & OH), 4.49 (s, 2H); C NMR (100
CDCl ): δ 10.45 (s, 1H, N-H amide), 8.31 (s, 1H, C–H triazole), 8.17
3
MHz, CDCl ): δ 165.6, 158.5, 144.8, 143.1 (C triazole), 134.2, 133.2,
(d, J = 8.0 Hz, 1H, ArH), 7.97 (d, J = 8.0 Hz, 1H, ArH), 7.81 (d,
J = 8.0 Hz, 1H, ArH), 7.73 (d, J = 8.0 Hz, 1H, ArH), 7.63–7.56 (m,
2H, ArH), 7.52 (t, J = 8.0 Hz, 1H, ArH), 7.25 (d, J = 8.0 Hz, 2H,
ArH), 7.02 (d, J = 8.0 Hz, 2H, ArH), 5.57 (s, 2H), 5.18 (s, 2H), 5.05
3
4
129.6, 128.7, 128.0, 126.7, 126.5 (C5 triazole), 126.2, 126.1, 123.1,
1
22.1, 119.4, 113.3, 113.1, 63.2, 61.4, 52.6; HRMS (m/z) calculated
+
for C22H20N O [M+H] : 389.1535. Found: 389.1546
4
3
13
(
t, J = 5.4 Hz, 1H), 4.43 (d, J = 5.4 Hz, 2H); C NMR (100 MHz,
2
.1.2.11. 2-(4-((4-(hydroxymethyl)phenoxy)methyl)-1H-1,2,3-triazol-1-
yl)-N-phenylacetamide (7k). White solid; Yield: 93 %; m.p. 184-188
C; FTIR (KBr, υmax): 3275 (N-H amide str.), 3140 (C-H str., triazole
ring), 3094 (C-H str., aromatic ring), 2941 (C-H str., aliphatic), 1695
CDCl ): δ 165.6, 157.4, 143.1 (C triazole), 135.4, 134.2, 133.2, 128.7,
3 4
128.4, 128.0, 126.7 (C5 triazole), 126.5, 126.2, 126.0, 123.1, 122.0,
°
114.8, 63.0, 61.5, 52.6; HRMS (m/z) calculated for C22H20N O
4
3
+
[M+H] : 389.1535. Found: 389.1546
(
C=O str., amide) cm−1; 1H NMR (400 MHz, CDCl ): δ 10.49 (s,
3
1
H, N-H amide), 8.25 (s, 1H, C–H triazole), 7.59 (d, J = 8.0 Hz, 2H,
2.1.2.16. 4-((1-(2-oxo-2-(phenylamino)ethyl)-1H-1,2,3-triazol-4-
ArH), 7.34 (t, J = 8.0 Hz, 2H, ArH), 7.25 (d, J = 8.0 Hz, 2H, ArH),
yl)methoxy)benzyl acetate (7p). White solid; Yield: 89 %; m.p.
156-160 °C; FTIR (KBr, υmax): 3275 (N-H amide str.), 3144 (C-H
str., triazole ring), 3099 (C-H str., aromatic ring), 2939 (C-H str.,
7
.10 (t, J = 8.0 Hz, 1H, ArH), 7.01 (d, J = 8.0 Hz, 2H, ArH), 5.35
(
s, 2H), 5.16 (s, 2H), 5.07 (t, J = 5.7 Hz, 1H), 4.43 (d, J = 5.7 Hz,
13
−1
2
H); C NMR (100 MHz, CDCl ): δ 164.6, 157.4, 143.1 (C triazole),
aliphatic), 1746 (C=O str., ester), 1687 (C=O str., amide) cm
;
3
4
1
1
38.9, 135.4, 129.4, 128.4, 126.7 (C5 triazole), 124.3, 119.7, 114.7,
H NMR (400 MHz, CDCl ): δ 10.49 (s, 1H, N-H amide), 8.27 (s,
3
6
3
3.0, 61.5, 52.7; HRMS (m/z) calculated for C18 H18 N O [M+H]+:
1H, C–H triazole), 7.59 (d, J = 8.0 Hz, 2H, ArH), 7.36–7.31 (m, 4H,
ArH), 7.10 (d, J = 4.0 Hz, 1H, ArH), 7.06 (d, J = 8.0 Hz, 2H, ArH),
4
3
39.1379. Found: 339.1389
5
.36 (s, 2H), 5.19 (s, 2H), 5.00 (s, 2H), 2.04 (s, 3H); 13C NMR (100
2
1
.1.2.12. 2-(4-((4-(hydroxymethyl)phenoxy)methyl)-1H-1,2,3-triazol-
-yl)-N-(p-tolyl)acetamide (7l). White solid; Yield: 81 %; m.p.
MHz, CDCl ): δ 170.8, 164.6, 158.4, 142.9 (C4 triazole), 138.9, 130.5,
129.4, 128.9, 126.7 (C5 triazole), 124.3, 119.7, 115.1, 65.7, 61.5, 52.7,
3
+
1
90-194 °C; FTIR (KBr, υmax): 3277 (N-H amide str.), 3138 (C-H
21.2; HRMS (m/z) calculated for C20H20N O [M+H] : 381.1485.
4
4
str., triazole ring), 3096 (C-H str., aromatic ring), 2941 (C-H str.,
Found: 381.1489
aliphatic), 1678 (C=O str., amide) cm 1; 1H NMR (400 MHz,
−
CDCl ): δ 10.52 (s, 1H, N-H amide), 8.25 (s, 1H, C–H triazole),
2.1.2.17. 4-((1-(2-oxo-2-(p-tolylamino)ethyl)-1H-1,2,3-triazol-4-
yl)methoxy)benzyl acetate (7q). White solid; Yield: 79 %; m.p.
178-182 °C; FTIR (KBr, υmax): 3271 (N-H amide str.), 3134 (C-H
3
7
.49 (d, J = 8.0 Hz, 2H, ArH), 7.25 (d, J = 8.0 Hz, 2H, ArH), 7.14
(
d, J = 8.0 Hz, 2H, ArH), 7.01 (d, J = 8.0 Hz, 2H, ArH), 5.35 (s,
2
2
H), 5.15 (s, 2H), 5.07 (t, J = 4.0 Hz, 1H), 4.43 (d, J = 4.0 Hz, 2H),
str., triazole ring), 3086 (C-H str., aromatic ring), 2943 (C-H str.,
.26 (s, 3H); 13C NMR (100 MHz, CDCl ): δ 164.4, 157.4, 143.0 (C
aliphatic), 1734 (C=O str., ester), 1668 (C=O str., amide) cm ; 1
−1
H
3
4
triazole), 136.4, 135.4, 133.2, 129.7, 128.4, 126.6 (C5 triazole), 119.7,
14.7, 63.0, 61.5, 52.7, 20.9; HRMS (m/z) calculated for C19 H20N O3
NMR (400 MHz, CDCl ): δ 10.39 (s, 1H, N-H amide), 8.25 (s, 1H,
3
1
C–H triazole), 7.47 (d, J = 8.0 Hz, 2H, ArH), 7.32 (d, J = 8.0 Hz, 2H,
ArH), 7.14 (d, J = 8.0 Hz, 2H, ArH), 7.06 (d, J = 8.0 Hz, 2H, ArH),
4
+
[
M+H] : 353.1535. Found: 353.1545
13
5
.33 (s, 2H), 5.18 (s, 2H), 5.00 (s, 2H), 2.26 (s, 3H), 2.04 (s, 3H);
C
2
1
.1.2.13. N-(4-ethylphenyl)-2-(4-((4-(hydroxymethyl)phenoxy)methyl)-
H-1,2,3-triazol-1 yl)acetamide (7m). White solid; Yield: 87 %;
NMR (100 MHz, CDCl ): δ 170.8, 164.4, 158.4, 142.9 (C triazole),
3 4
136.3, 133.3, 130.4, 129.8, 128.9, 126.7 (C5 triazole), 119.7, 115.1,
65.7, 61.5, 52.6, 21.2, 20.9; HRMS (m/z) calculated for C21H22N O
m.p. 176-180 °C; FTIR (KBr, υmax): 3268 (N-H amide str.), 3145
4
4
+
(
C-H str., triazole ring), 3088 (C-H str., aromatic ring), 2956 (C-H
[M+H] : 395.1641. Found: 395.1645
str., aliphatic), 1687 (C=O str., amide) cm 1; 1H NMR (400 MHz,
−
CDCl ): δ 10.47 (s, 1H, N-H amide), 8.25 (s, 1H, C–H triazole),
2.1.2.18. 4-((1-(2-((4-ethylphenyl)amino)-2-oxoethyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzyl acetate (7r). White solid; Yield: 85 %; m.p.
192-196 °C; FTIR (KBr, υmax): 3275 (N-H amide str.), 3149 (C-H
3
7
.47 (d, J = 8.0 Hz, 2H, ArH), 7.22 (t, J = 8.0 Hz, 2H, ArH), 7.14
(
d, J = 8.0 Hz, 2H, ArH), 6.98 (d, J = 8.0 Hz, 2H, ArH), 5.32 (s,
2
2
H), 5.13 (s, 2H), 5.07 (s, 1H), 4.40 (s, 2H), 2.54 (q, J = 8.0 Hz,
str., triazole ring), 3097 (C-H str., aromatic ring), 2945 (C-H str.,
13
aliphatic), 1739 (C=O str., ester), 1675 (C=O str., amide) cm ; 1
−1
H), 1.13 (t, J = 8.0 Hz, 3H); C NMR (100 MHz, CDCl ): δ 164.4,
H
3
157.4, 143.1 (C4 triazole), 139.7, 136.5, 135.3, 128.5, 128.4, 126.4
NMR (400 MHz, CDCl ): δ 10.40 (s, 1H, N-H amide), 8.25 (s, 1H,
3
(
C5 triazole), 119.9, 114.8, 63.0, 61.5, 52.7, 28.0, 16.1; HRMS (m/z)
C–H triazole), 7.49 (d, J = 8.0 Hz, 2H, ArH), 7.32 (d, J = 8.0 Hz, 2H,
ArH), 7.17 (d, J = 8.0 Hz, 2H, ArH), 7.06 (d, J = 8.0 Hz, 2H, ArH),
+
calculated for C20H22N O [M+H] : 367.1692. Found: 367.1699
4
3
5
.33 (s, 2H), 5.19 (s, 2H), 5.00 (s, 2H), 2.56 (q, J = 5.8 Hz, 2H),
13
2
1
.1.2.14. 2-(4-((4-(hydroxymethyl)phenoxy)methyl)-1H-1,2,3-triazol-
-yl)-N-(4-nitrophenyl)acetamide (7n). White solid; Yield: 91 %;
2.04 (s, 3H), 1.17 (t, J = 5.8 Hz, 3H); C NMR (100 MHz, CDCl ):
3
δ 170.8, 164.4, 158.4, 142.9 (C4 triazole), 139.7, 136.5, 130.4, 128.9,
m.p. 178-182 °C; FTIR (KBr, υmax): 3289 (N-H amide str.), 3159
128.6, 126.7 (C5 triazole), 119.8, 115.1, 65.7, 61.5, 52.6, 28.0, 21.2,
+
(
C-H str., triazole ring), 3102 (C-H str., aromatic ring), 2945 (C-H
16.1; HRMS (m/z) calculated for C22H24N O [M+H] : 409.1798.
4
4
str., aliphatic), 1709 (C=O str., amide) cm 1; 1H NMR (400 MHz,
−
Found: 409.1807
CDCl ): δ 8.26 (d, J = 12.0 Hz, 3H, C–H triazole & 2 ArH), 7.86 (d,
3
J = 8.0 Hz, 2H, ArH), 7.25 (d, J = 8.0 Hz, 2H, ArH), 7.01 (d, J = 8.0
2.1.2.19. 4-((1-(2-((4-nitrophenyl)amino)-2-oxoethyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzyl acetate (7s). Orange solid; Yield: 93 %; m.p.
182-186 °C; FTIR (KBr, υmax): 3304 (N-H amide str.), 3159 (C-H
13
Hz, 2H, ArH), 5.47 (s, 2H), 5.17 (s, 2H), 4.43 (s, 2H); C NMR
(
100 MHz, CDCl ): δ 165.8, 157.4, 145.0, 143.2, 143.1 (C4 triazole),
3
4

C.P. Kaushik, J. Sangwan, R. Luxmi et al.
Journal of Molecular Structure 1226 (2021) 129255
str., triazole ring), 3073 (C-H str., aromatic ring), 2945 (C-H str.,
The inhibition ratio (I %) of the tested compounds was calcu-
lated according to the following equation:
I % = (A -A ) / A × 100,
aliphatic), 1736 (C=O str., ester), 1699 (C=O str., amide) cm 1;
−
1
H NMR (400 MHz, CDCl ): δ 11.09 (s, 1H, N-H amide), 8.26 (d,
3
0
1
0
J = 12.0 Hz, C–H triazole & 2 ArH), 7.84 (d, J = 8.0 Hz, 2H, ArH),
Where A0 is the absorbance of the control and A is the ab-
1
7
.32 (d, J = 8.0 Hz, 2H, ArH), 7.06 (d, J = 8.0 Hz, 2H, ArH), 5.45
sorbance of the sample.
13
(
s, 2H), 5.20 (s, 2H), 5.01 (s, 2H), 2.04 (s, 3H); C NMR (100 MHz,
CDCl ): δ 170.7, 165.8, 158.4, 145.0, 143.1, 143.0 (C triazole), 130.4,
2.4. Docking
3
4
1
29.0, 126.7 (C5 triazole), 125.6, 119.5, 115.1, 65.7, 61.5, 52.8, 21.2;
+
HRMS (m/z) calculated for C20H19N O [M+H] : 426.1335. Found:
The target protein HER2 was retrieved from protein data bank
(pdb id: 3PP0). The preparation of protein was accomplished by
Chimera [43] and the 3D structures of the compounds were pre-
pared and standardized by Marvin Sketch [44]. AutoDock vina
[45] was used for docking simulations and docking protocols were
validated by redocking of co-crystallized ligand. The docked poses
were visualized using discovery studio [46] and PyMOL [47].
5
6
4
26.1332
2
.1.2.20. 4-((1-(2-(naphthalen-1-ylamino)-2-oxoethyl)-1H-1,2,3-
triazol-4-yl)methoxy)benzyl acetate (7t). White solid; Yield: 83 %;
m.p. 168-172 °C; FTIR (KBr, υmax): 3258 (N-H amide str.), 3134
(
C-H str., triazole ring), 3088 (C-H str., aromatic ring), 2942 (C-H
str., aliphatic), 1734 (C=O str., ester), 1674 (C=O str., amide) cm 1;
−
1
H NMR (400 MHz, CDCl ): δ 10.85 (s, 1H, N-H amide), 8.33 (s,
3. Result and Discussion
3
1
1
H, C–H triazole), 8.23 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz,
H), 7.79 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 1H, ArH), 7.54 (t,
3.1. Drug design
J = 8.0 Hz, 1H, ArH), 7.41 (d, J = 8.0 Hz, 1H, ArH), 7.32 (d, J = 8.0
Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 5.63 (s, 2H), 5.17 (s, 2H), 4.98 (s,
Based on the aforementioned findings about the potential anti-
cancer activity of amide linked 1,2,3-triazoles and antioxidant ac-
tivity of hydroxyl alkyl linked 1,2,3-triazoles, we designed the am-
bitious scaffold to obtain combined effect of both amide and hy-
droxyl alkyl group in a single molecule. To define a good structure-
activity relationship (SAR), amide linked 1,2,3-triazole with differ-
ent substitution were used. To check the significance of hydroxyl
alkyl group in anticancer activity, we designed some molecules
without free hydroxyl group (Fig 2).
2
H), 2.02 (s, 3H); 13C NMR (100 MHz, CDCl ): δ 170.2, 164.7, 155.5,
3
1
42.8 (C4 triazole), 134.7, 133.5, 128.8, 128.6, 128.4, 128.0, 126.6
(
C5 triazole), 126.4, 126.2, 126.1, 123.2, 122.1, 115.1, 65.1, 61.5, 52.5,
+
2
1.3; HRMS (m/z) calculated for C24H22N O [M+H] : 431.1641.
4
4
Found: 431.1633
2
.2. Anticancer activity
Human cancer cell lines were procured from U.S. National Can-
cer Institute (NCI). Three human cancer cell lines were grown in
tissue culture flasks in complete growth medium (RPMI-1640) sup-
plemented with 10% fetal bovine serum, 100μg/ml streptomycin
and 100 units/ml penicillin and MIAPACA were grown in Dul-
becco’s minimal essential medium supplemented with 10 % FBS,
3.2. Chemistry
The sequence of the reactions employed for the amide
&
ester-amide linked 1,4-disubstituted 1,2,3-triazoles is out-
lined in Scheme 1 & 2. The terminal alkynes i.e., 2/3/4-(prop-
2yn-1yloxy)phenyl)methnol (3a-3c) were synthesized by treat-
ing 2/3/4-hydroxy benzyl alcohols (1a-1c) with propargyl bro-
mide (2) in the presence of potassium carbonate in dimethylfor-
mamide for 4-5 h. Further, for the synthesis of 4-(prop-2-yn-1-
yloxy)benzyl acetate (3d), (4-(prop-2-yn-1-yloxy)phenyl)methanol
(3c) was treated with acetyl chloride in DCM using DMAP as a
base. 2-Bromo-N-arylacetamides (6a–6e) were synthesized from
the reaction of aromatic amines (4a–4e) with bromoacetylbromide
(5) in dichloromethane using potassium carbonate as a base at 0–5
°C for 20-25 min. Finally, for the synthesis of 1,4-disubsituted 1,2,3-
triazoles (7a–7t), terminal alkynes (3a–3d) were reacted with in-
situ generated 2-azido-N-arylacetamides (6a–6e) (which were ob-
tained by the reaction of 2-bromo-N-arylacetamides with sodium
azide) in the presence of copper sulfate pentahydrate and sodium
ascorbate in dimethylformamide:water (Scheme 1 & 2).
2
-mM L-glutamine, 3-mM sodium pyruvate, 100-units/mL peni-
cillin, 100-μg/mL streptomycin in a carbon dioxide incubator (New
Brunswick, Galaxy 170R, Eppendorf) at 37°C, 5% CO2 and 98% RH.
In vitro Cytotoxicity
Cell viability was determined by thiazolyl blue tetrazolium bro-
mide (MTT) and Trypan blue assays. Briefly, 7 × 103 cells were
seeded into 96-well microtitre plate and differentiated for 48 h.
After 48 h treatment with different concentrations, MTT dye (2.5
mg/mL) was added and incubated for 4 h at 37°C; after incuba-
tion, the media was aspirated and 150 μL/well DMSO was added
and read at 570 nm on Mutliskan GO plate reader (Thermo Fisher
Scientific, Waltham, MA, USA)
2
.3. Antioxidant activity
The DPPH radical scavenging activity of the synthesized com-
The structure of all synthesized triazoles were confirmed by
FTIR, 1H NMR, 13C NMR and mass spectral analysis. In IR spec-
tra of all compounds characteristic absorption band at 3304–3213
pounds was studied in vitro by using Dubey assay method [42].
Stock solution of the compounds was prepared for different con-
centrations in the range of 100, 80, 60, 40, 20 μg/mL. 100 μM
DPPH (0.004 g DPPH in 100 ml methanol) solution was prepared
in methanol. 1 ml methanolic solution of DPPH was added into 2
mL solution of the synthesized compounds. Test compounds were
allowed to stand for 30 minutes in dark at room temperature to
react with stable free radical after which the optical density was
measured at 517 nm using UV Visible spectrophotometer and the
percentage of scavenging activity was calculated. Radical scaveng-
ing activity was measured by using Ascorbic acid as standard and
all values were expressed as IC50 (microgram of compound per
milliliter), the concentration of the samples that causes 50% scav-
enging of DPPH radical. The DPPH radical stock solution was pre-
pared fresh.
cm 1 due to N–H stretching of amide linkages, 3167–3130 cm
−
−1
due to C–H stretching of triazole ring, 1719–1662 cm 1 due to C=O
stretching of amide bonds and 1746–1734 cm 1 were due to C=O
stretching of ester bonds. The 1H NMR spectra exhibited a broad
singlet in the range δ 11.51–10.39 corresponding to the NH pro-
ton and a singlet in the range δ 8.31–8.21 was assigned to the
triazole-H. In the 13C NMR spectrum, a characteristic signals of
C=O appeared in range of δ 170.8–170.7 (ester) and δ 165.8–164.4
(amide). Signals due to C–4 and C–5 of triazole ring appeared at
δ 144.8–142.9 and δ 126.7–119.5 respectively. HRMS spectral anal-
ysis of synthesized compounds showed good agreement with ex-
pected values. The structure of compounds 7e and 7f was further
confirmed by 2D-spectral techniques (Fig 3 & 4).
−
−
5

C.P. Kaushik, J. Sangwan, R. Luxmi et al.
Journal of Molecular Structure 1226 (2021) 129255
Fig. 2. Strategy for designing of target disubstituted 1,2,3-triazoles for anticancer activity.
Scheme 1. Synthesis of amide linked 1,4-disubstituted 1,2,3-triazole.
Scheme 2. Synthesis of ester-amide linked 1,4-disubstituted 1,2,3-triazoles.
6

C.P. Kaushik, J. Sangwan, R. Luxmi et al.
Journal of Molecular Structure 1226 (2021) 129255
The structure of compounds 7e & 7f was identified by analyzing
the FTIR, 1D-NMR ( H, 13C and DEPT-135), 2D-NMR (COSY, HSQC
H, C ꢀ -H, C ꢀ -H & C ꢀ -H respectively. Three triplets at δ 7.52, 7.23 &
2
3 ’
5 ’
1
6.97 integrating for one proton each were assigned to C ꢀ -H, C ꢀ -H
3
5 ’
&
HMBC) and HRMS data. FTIR spectrum of 7e displayed absorp-
& C ꢀ -H respectively. One multiplet at δ 7.59 which was integrat-
4 ’
13
tion at 3250 (N-H amide str.), 3142 (C-H str., triazole ring), 3088
ing for two protons attributed to protons (C ꢀ -H & C ꢀ -H). In
C
7
8
(
C-H str., aromatic ring), 2945 (C-H str., aliphatic), 1665 (C=O str.,
NMR spectrum of 7e, peak in the most downfield region at δ 165.6
was assigned to the carbonyl carbon. The peaks at δ 143.3 and
126.5 were assigned to C4 and C5 carbons of triazole ring respec-
tively. 135-DEPT spectrum of compound 7e confirmed the presence
of eleven carbon signals for methine carbons and three carbon sig-
nals for methylene carbons. These assignments were confirmed by
2D NMR spectral techniques like COSY, HSQC and HMBC. The 1H-
−1 1
amide) cm
. H NMR spectrum of compound 7e shows four sin-
glets at δ 10.47 (1H), 8.31 (1H), 5.57 (2H) and 5.21 (2H) were as-
signed to N-H, C -H, N -CH and OCH2 respectively. A one proton
5
1
2
triplet at δ 5.01 and two proton doublet at δ 4.50 were assigned to
O-H and CH OH. Six doublets at δ 8.18, 7.97, 7.81, 7.73, 7.40 & 7.17
2
each integrating for one proton were assigned to C ꢀ -H, C ꢀ -H, C ꢀ -
9
6
4
7

C.P. Kaushik, J. Sangwan, R. Luxmi et al.
Journal of Molecular Structure 1226 (2021) 129255
Fig. 3. 1H & 13 C NMR values of 7e.
Fig. 4. 1H & 13 C NMR values of 7f.
1
H correlation between protons of (C ꢀ -H) with (C ꢀ -H, C ꢀ -H), (C ꢀ -
7.34 (2H), 7.26 (1H) & 7.10 (1H) were assigned to C ꢀ -H, C ꢀ -H
9
7
8
7
3
5 ’
H, C ꢀ -H) with (C ꢀ -H), (C ꢀ -H) with (C ꢀ -H), (C ꢀ -H) with (C ꢀ -H),
& C ꢀ -H respectively. One proton singlet at δ 7.01 was attributed
4
13
8
6
2
3
3
4
(
C ꢀ -H) with (C ꢀ -H) and (C ꢀ -H) with (C ꢀ -H) were established
to (C ꢀ -H). In C NMR spectrum of 7f, peak in the most down-
3
’
4 ’
4 ’
5 ’
2 ’
through COSY spectrum. The HSQC spectrum revealed the assign-
field region at δ 164.6 was assigned to the carbonyl carbon. The
peaks at δ 143.1 and 126.6 were assigned to C4 and C5 carbons
of triazole ring respectively. 135-DEPT spectrum of compound 7f
confirmed the presence of eight carbon signals for methine car-
bons and three carbon signals for methylene carbons. These as-
signments were confirmed by 2D NMR spectral techniques like
COSY, HSQC and HMBC. The 1H- H correlation between protons of
(C ꢀ -H) with (C ꢀ -H), (C ꢀ -H) with (C ꢀ -H) and (C ꢀ -H) with (C ꢀ -H)
ment of carbon signals at δ 52.6 (N -CH ), 58.3 (CH OH), 61.9
1
2
2
(
OCH ), 112.1 (C ꢀ ), 121.0 (C ꢀ ), 122.0 (C ꢀ ), 123.1 (C ꢀ ), 126.1 (C ꢀ ),
6 ’ 4 ’ 2 9 3
2
1
26.2 (C ꢀ ), 126.5 (C ), 126.7 (C ꢀ & C ꢀ ), 127.5 (C ꢀ ), 128.0 (C ꢀ ) and
4
5
7
8
3 ’
13
5 ’
1
1
28.7 (C ꢀ ) and because the key correlation ( H- C) observed was
6
δ 4.50:58.3, 5.57:52.6, 5.21:61.9, 7.17:112.1, 7.73:122.0, 8.18:123.1,
7
1
.52:126.1, 7.81:126.2, 8.31:126.5, 7.59:126.7, 7.40:127.5, 7.23:128.0
and 7.97:128.7 respectively. Heteronuclear Multiple Bond Correla-
tion (HMBC) experiment established the connectivity of hydrogen
with other carbons through multiple bond correlation of signals
at δ 4.50–127.5, 131.2, 155.3 (confirm C2ꢀ’ at 131.2); δ 5.21- 126.5,
2
3
3
4
4 ’
5 ’
were established through COSY spectrum. The HSQC spectrum re-
vealed the assignment of carbon signal at δ 52.7 (N1-CH2), 61.4
(OCH2), 63.2 (CH2OH), 113.1 (C ꢀ ), 113.3 (C ꢀ ), 119.4 (C ꢀ ), 119.7
2 ’
6 ’
4 ’
1
43.3, 155.3 (confirm C1ꢀ’ at 155.3, C-4 at 143.3, C-5 at 126.5) and
(C ꢀ ), 124.3 (C ꢀ ), 126.6 (C5), 129.4 (C ꢀ ) and 129.6 (C ꢀ ) because
2 4 3 5 ’
1 13
5
.57- 126.5, 165.6 (confirm N -CH2 at 5.57, C-5 at 126.5). Further,
the key correlation ( H- C) observed was δ 5.36:52.7, 5.17:61.4,
4.49:63.2, 7.01:113.1, 6.94:113.3, 6.92:119.4, 7.59:119.7, 7.10:124.3,
8.26:126.6, 7.34:129.4 and 7.26:129.6 respectively. Heteronuclear
Multiple Bond Correlation (HMBC) experiment established the con-
nectivity of hydrogen with other carbons through multiple bond
correlation of signals at δ 4.49- 113.1, 119.4, 144.8 (confirm C3ꢀ’ at
144.8), 5.17- 126.6, 143.1, 158.5 (confirm C1ꢀ’ at 158.5, C-4 at 143.1,
C-5 at 126.6), 5.36-126.6, 164.6 (confirm N1-CH2 at 5.36, C-5 at
126.6) and 7.59- 119.7, 124.3, 138.9; 7.34- 119.7, 129.4, 138.9 (fur-
1
the HRMS of compound 7e i.e 389.1546 was found in good agree-
ment with the theoretically predicted molecular mass.
FTIR spectrum of 7e displayed absorption at 3273 (N-H amide
str.), 3144 (C-H str., triazole ring), 3092 (C-H str., aromatic ring),
2
945 (C-H str., aliphatic), 1672 (C=O str., amide) cm−1. 1H NMR
spectrum of compound 7f shows four singlets at δ 10.49 (1H), 8.26
(
1H), 5.36 (2H) and 5.17 (1H) were assigned to N-H, C -H, N -CH
5 1
2
and OCH2 respectively. A one proton triplet at δ 5.20 and two pro-
ton doublet at δ 4.49 were assigned to O-H and CH OH respec-
ther confirm C ꢀ at 138.9). Further, the HRMS of compound 7f i.e.,
2
1
tively. Three doublets at δ 7.59 (2H), 6.94 (1H) and 6.92 (1H) were
assigned to C ꢀ -H, C ꢀ -H & C ꢀ -H respectively. Three triplets at δ
339.1389 were found in good agreement with the theoretically pre-
dicted molecular mass.
2
4 ’
6 ’
8

C.P. Kaushik, J. Sangwan, R. Luxmi et al.
Journal of Molecular Structure 1226 (2021) 129255
Table 1
Anticancer activity data of amide linked 1,4-disubstituted 1,2,3-triazoles on different cancer cell lines.
Compounds
PC3 (prostate cancer)
A549 (lung cancer)
MIAPACA (liver cancer)
Fr2 (Breast epithelial)
IC50 (μM) ± SD
150.58 ± 0.8
108 ± 3.4
155.8 ± 3.5
122.8± 1.3
82 ± 1.9
IC50 (μM) ± SD
96 ± 3.9
IC50 (μM) ± SD
138.70 ± 3.01
165 ± 0.9
IC50 (μM) ± SD
93 ± 5.9
7
a
7
b
196 ± 2.0
100 ± 1.3
92 ± 5.9
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
c
d
e
f
141.1 ± 0.1
164.992 ± 0.3
49 ± 2.0
130.25 ± 3.00
124.09 ± 3.6
45 ± 2.5
95.2 ± 6.5
100.2 ± 0.9
92 ± 3.6
62 ± 8.9
63 ± 2.8
45 ± 2.9
g
h
i
150.08 ± 2.9
130.1 ± 1.4
139.4 ± 3.3
82 ± 0.9
141.24 ± 0.9
125 ± 0.01
102.5 ± 0.6
88.6 ± 2.8
122 ± 2.8
130.70 ± 2.00
152.5± 0.1
156.9 ± 3.7
75.5 ± 1.9
165 ± 2.2
85.6 ± 6.5
99.2 ± 3.5
111.5 ± 5.5
100.6 ± 0.9
102 ± 5.9
102 ± 5.9
100 ± 3.9
98 ± 1.2
j
k
l
112 ± 2.9
69.9 ± 2.9
111 ± 3.2
40.60 ± 2.4
139 ± 6.6
102 ± .09
122.5 ± 1.2
212 ± 8.8
165.6 ± 2.9
156 ± 3.9
m
n
o
p
q
r
63.47± 2.3
160 ± 2.0
94.41± 3.5
145 ± 1.3
71 ± 3.0
111 ± 2.3
168 ± 2.0
106 ± 3.6
135.1 ± 4.9
98 ± 5.0
155.4 ± 3.8
154.99 ± 2.4
112 ± 4.5
145.1 ± 0.6
159.00 ± 1.9
122 ± 6.5
132.5 ± 9.6
106 ± 7.9
s
166 ± 3.6
100 ± 3.0
100 ± 5.9
>100
t
140.2± 2.9
0.6 ± 0.03
132.41 ± 3.8
0.7 ± 0.06
160.44 ± 1.1
0.5± 0.08
Doxorubicin
3
.3. Anticancer activity
The synthesized triazoles were screened against four different
cell lines- PC3 (prostate cancer) A549 (lung cancer), MIAPACA (liver
cancer) and Fr2 (Breast epithelial). IC50 of compounds which shows
%
inhibition at 60 μM was determined by using Prism software
is shown in Table 1. Here doxorubicin was used as a standard.
It has been observed from the data that most of the compounds
were non-toxic against normal cell line Fr2 (Breast epithetical). The
tested compounds 7e and 7f displayed moderate activity against all
cancer cell lines while 7n showed good activity only against PC3
(
prostate cancer). Additionally, the molecular docking studies for
molecules 7e and 7f were also carried out to identifying the prob-
able mechanism of action for anticancer activity.
Fig. 5. IC50 values of synthesized compounds (7a-7t).
3
.4. Antioxidant activity
4
Synthesized triazoles with free 4-CH OH groups are broadly ac-
2
The 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical has been used
tive than 4-CH2OCOCH3 group.
widely to determine the scavenging activities of synthesized com-
pounds [42]. The DPPH method is based on the fact that the free
radical is purple in color, and that the purple color of DPPH de-
cays in the presence of an antioxidant resulting in a decrease of
absorbance at particular wavelength. Hence, the more rapidly the
absorbance decreases, the more potent the radical scavenging ac-
tivity of the compounds. Majority of compounds screened signif-
icantly inhibited DPPH radical level as compared to the standard
antioxidant used. The IC50 values of the compounds (7a–7t) are in
the range of 1.61–6.04 μg/mL as shown in Table 2, Fig. 5. It has
been observed from the antioxidant activity data that compounds
Antioxidant activity:
1 Generally, compounds having phenyl moiety demostrated better
activity than naphthyl group.
2 Incorporation of methyl/ethyl group on the phenyl ring de-
crease the activity.
3 Triazoles having nitro group on phenyl ring increase the activ-
ity.
4 It has been observed that methyl group on phenyl ring showed
better activity than ethyl group.
5 Generally, presence of CH2OH group in the synthesized com-
pounds at p-position shows good activity than o-position while
o-position possess an upper hand than m-position or one can
say that overall trend of activity is p-CH2OH > o-CH2OH > m-
CH2OH.
7a, 7d, 7i, 7n and 7p displayed appreciable scavenging effect on
DPPH radical, having IC50 values 2.65, 1.61, 2.92, 2.26 and 2.62
μg/mL respectively.
Structure activity relationship (SAR):
Anticancer activity:
6 Compounds having free 4-CH2OH group are more active than
4
-CH OCOCH3 group.
2
1
2
3
In most of the cases, compounds having phenyl group exhibited
better activity in comparison to naphthyl moiety.
Substitution on phenyl ring with methyl/ethyl group leads to
decrease in activity as compared to unsubstituted ones.
Compounds having electron withdrawing nitro group on phenyl
ring demonstrated better activity than the electron releasing
methyl/ethyl group.
3.5. Docking Studies
With the purpose of identifying the probable mechanism of ac-
tion for anticancer activity, two most active compounds 7e and 7f
were docked in active site of Human epidermal growth factor re-
ceptor 2.
9

C.P. Kaushik, J. Sangwan, R. Luxmi et al.
Journal of Molecular Structure 1226 (2021) 129255
Table 2
Inhibition of DPPH radical by synthesized compounds.
Compounds
IC50 (µg/mL) ± SD
Compounds
IC50 (µg/mL) ± SD
3.2 ± 0.35
7a
7b
7c
7d
7e
2.65 ± 0.79
3.63 ± 0.98
4.27 ± 0.08
1.61 ± 0.23
3.73 ± 0.59
3.34 ± 0.89
3.83 ± 0.15
5.55 ± 0.71
2.92 ± 0.47
4.3 ± 0.69
7k
7l
3.08 ± 0.88
3.69 ± 0.67
2.26 ± 0.04
3.37 ± 0.53
2.62 ± 0.39
6.04 ± 1.03
5.69 ± 1.21
4.45 ± 0.09
5.52 ± 0.79
1.41 ± 0.06
7m
7n
7o
7
f
7p
7
7
g
h
7q
7r
7
7
i
j
7s
7t
Ascorbic acid
1.41 ± 0.06
Ascorbic acid
IC50 values were determined by linear regression analysis using five different concentrations in triplicate ± SD.
The binding affinity of compound 7e was comparable to that
of co-crystallized ligand (O3Q) binding energy (10.9 kcal/mol and
similar to that of co-crystallized ligand. So, it can be said that
the compounds under study successfully inhibited the HER2 pro-
tein. The interactions of studied compounds 7e and 7f with active
site are shown in Fig 6. Cartoon picture of protein along with co-
crystallized ligand O3Q and both molecules 7e and 7f is shown in
Fig 7.
11.1 kcal/mol respectively). The dock score for compound 7f was
10.2 kcal/mol. This is also in agreement with the experimental re-
sults as 7e is more active than 7f in in-vitro studies against can-
cer cell lines. Substitution of naphthyl group (7e) for phenyl group
(
7f) caused better fit of the former molecule in the active site.
Hydroxy group of 7e made hydrogen bond with Ser783. Triazole
ring created carbon hydrogen bond with Thr862. Pi orbitals of this
nucleus made pi-sigma bond with Thr798 while that of naphthyl
ring showed interactions with Leu726 and 852. Phenoxy ring ex-
hibited T-shaped pi-pi interactions with Phe864. However, in com-
pound 7f, no hydrogen bond was observed. Also, other interac-
tions were less prominent as compare to compound 7e. The in-
teractions displayed by the synthesized compounds were almost
3.6. Bioavailability studies
It has been reported that some physicochemical properties like
lipophilicity, molecular weight, polar descriptors, ionization state,
and free rotatable bonds (RB) control drug bioavailability. To ascer-
tain the drug likeliness of the synthesized molecules, these molec-
ular properties were calculated using ADMET lab [48]. Based upon
these properties, five commonly used rules namely Lipinski’s rule
10

C.P. Kaushik, J. Sangwan, R. Luxmi et al.
Journal of Molecular Structure 1226 (2021) 129255
Fig. 6. Binding interactions of compound (a) 7e and (b) 7f.
(
(
MW<=500; logP<=5; Hacc<=10; Hdon<=5) [49], Ghose’s rule
5.6< MclogP < -0.4; 160 < MW < 480; 40 < MR < 130; 20
<
natoms < 70) [50], Oprea’s rule (nrings≥3; nrigidbond>=18;
nRotbond≥6) [51], Veber’s rule (nRotbond<=10; tPSA<= 140 or
Hacc and Hdon<=12) [52], Varma’s rule (MW<=500; tPSA<=125;
-
5<logD<–2; Hacc+Hdon<=9; nRotbond<=12) [53] were applied
to access the drug likeness of the synthesized molecules. The cal-
culated properties are shown in Table 3. All the compounds exhib-
ited zero violation of Lipinski’s rule, Ghose’s rule and Oprea’s rule.
Only two compounds 7r and 7s slightly violated one criteria of Ve-
ber’s rule (number of rotatable bonds). Four compounds 7d, 7i, 7n,
and 7s has topological polar surface area more than 125 and have
total hydrogen bond acceptor and donors more than nine while all
other molecules passed the criteria of Varma’s rule. These findings
confirm good absorption of the molecules and these compounds
will be orally bioavailable with favorable gut and hepatic elimina-
tion escape. These compounds have good dispositional profile and
are patient compliant.
Fig. 7. Cartoon diagram of HER2 protein along with co-crystallized ligand O3Q
(red), compound 7e (Cyan) and compound 7f (light pink).
Table 3
Calculated physicochemical properties of synthesized molecules.
Sr. no
tpsa
nhac
logP
Nheav bond
MW
Nring count
nhdon
nRot bond
Nheav atom
MR
natom
Nrigid bond
logD
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
a
b
c
d
e
f
89.27
89.27
89.27
132.41
89.27
89.27
89.27
89.27
132.41
89.27
89.27
89.27
89.27
132.41
89.27
95.34
95.34
95.34
138.48
95.34
6
6
6
8
6
6
6
6
8
6
6
6
6
8
6
7
7
7
9
7
1.99
2.30
2.55
1.90
3.14
1.99
2.30
2.55
1.90
3.14
1.99
2.30
2.55
1.90
3.14
2.56
2.87
3.12
2.47
3.71
27
28
29
30
32
27
28
29
30
32
27
28
29
30
32
30
31
32
33
35
338.37
352.39
366.42
383.36
388.43
338.37
352.39
366.42
383.36
388.43
338.37
352.39
366.42
383.36
388.43
380.40
394.43
408.46
425.40
430.46
3
3
3
3
4
3
3
3
3
4
3
3
3
3
4
3
3
3
3
4
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
1
1
8
25
26
27
28
29
25
26
27
28
29
25
26
27
28
29
28
29
30
31
32
91.79
43
46
49
45
49
43
46
49
45
49
43
46
49
45
49
48
51
54
50
54
19
20
20
21
24
19
20
20
21
24
19
20
20
21
24
20
21
21
22
25
0.71
0.84
1.06
0.48
1.40
0.73
0.85
1.06
0.48
1.41
0.70
0.82
1.04
0.44
1.42
0.89
1.02
1.18
0.75
1.18
8
96.53
9
101.17
98.45
9
8
109.30
91.79
8
g
h
i
8
96.53
9
101.17
98.45
9
j
8
109.30
91.79
k
l
8
8
96.53
m
n
o
p
q
r
9
101.17
98.45
9
8
109.30
101.338
106.08
110.72
107.99
118.84
10
10
11
11
10
s
t
11

C.P. Kaushik, J. Sangwan, R. Luxmi et al.
Journal of Molecular Structure 1226 (2021) 129255
4
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Declaration of Competing Interest
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Validation, Investigation, Writing - review & editing. Raj Luxmi:
Formal analysis, Data curation. Devinder Kumar: Formal analysis,
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