Synthesis and biological evaluation of novel triazolyl 4-anilinoquinazolines as anticancer agents

Article abstract of DOI:10.1007/s00044-019-02413-6

The synthesis of novel triazolyl 4-anilinoquinazolines in five sequential synthetic steps via copper-catalyzed click chemistry and their anticancer biological evaluation is described.

Full text of DOI:10.1007/s00044-019-02413-6

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-019-02413-6
ORIGINAL RESEARCH
Synthesis and biological evaluation of novel triazolyl
4-anilinoquinazolines as anticancer agents
Hani Mutlak A. Hassan1 Iuliana Denetiu1 Salman A. Khan2 Mohd Rehan1 Kaltoom Sakkaf3
Kalamegam Gauthaman4
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Received: 15 April 2019 / Accepted: 23 July 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
The synthesis of novel triazolyl 4-anilinoquinazolines in five sequential synthetic steps via copper-catalyzed click chemistry
and their anticancer biological evaluation is described.
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Keywords Quinazolines Triazoles Click chemistry Anticancer
Introduction
2011), quinazolines exhibit a wide spectrum of pharmaco-
logical properties such as anti-inflammatory (Smits et al.
2010) antimalarial (Verhaeghe et al. 2008), antibacterial,
(Van Horn et al. 2014), and antitubercular activities (Odi-
ngo et al. 2014).
Despite advances in chemotherapy, cancer remains one of
the leading causes of morbidity and mortality worldwide
(Bray et al. 2018). The current anticancer drugs have
shortcomings such as lack of efficacy and poor selectively,
the latter of which could lead to adverse side effects. In
addition, the emergence of drug resistance (Holohan et al.
2013) has hampered the effectiveness of these drugs in the
clinic. Thus, there is a necessity to develop efficacious, safe,
and selective anticancer agents with enhanced properties
that could overcome current limitations in chemotherapy
treatment. Quinazolines exert their anticancer activity
through inhibition of various enzymes such as protein
kinases (Zhang et al. 2009), protein lysine methyltransferase
(Liu et al. 2011), DNA topoisomerase (Garofalo et al.
2010), and histone deacetylase (Yang et al. 2015). Besides
their anticancer activity (Giardina et al. 2009; Garofalo et al.
As part of our research program in the use of metal-
catalyzed reactions for the synthesis of molecules of interest
(Hassan et al. 2017, 2018; Hassan and Brown 2010), we
were interested in designing and synthesizing novel 4-
anilinoquinazolines that possess the 1,2,3-triazole motif
(Lauria et al. 2014) embedded in their structure using
copper-catalyzed click chemistry, a highly useful synthetic
tool that has been extensively utilized in medicinal chem-
istry (Thirumurugan et al. 2013; Kolb and Sharpless 2003).
We hypothesized that the incorporation of a second phar-
macophore to the quinazoline nucleus could lead to phar-
macologically potent quinazolines. Herein, we report the
synthesis of a small molecule library of triazolyl 4-
anilinoquinazolines using copper-catalyzed azide-alkyne
cycloaddition (CuAAC) ‘click’ reactions to generate 1,4-
disubstituted triazole products 12a‒i in a regioselective
fashion for anticancer evaluation.
* Hani Mutlak A. Hassan
hmahassan@kau.edu.sa
1
2
3
King Fahd Medical Research Center, King Abdulaziz University,
P. O. Box 80216, Jeddah 21589, Saudi Arabia
Materials and methods
Department of Chemistry, Faculty of Science, King Abdulaziz
University, P. O. Box 80203, Jeddah 21589, Saudi Arabia
General chemistry
Department of Medical Laboratory Technology, Faculty of
Applied Medical Sciences, P. O. Box 80216, Jeddah 21589, Saudi
Arabia
Chemical reactions were carried out under a nitrogen
atmosphere with anhydrous solvents, unless otherwise
noted. Reactions were monitored by thin-layer chromato-
graphy carried out on 0.25 mm silica gel plates with
4
Center of Excellence in Genomic Medicine Research, King
Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi
Arabia

Medicinal Chemistry Research
fluorescent indicator (254 nm) and visualized using ultra-
violet (UV) irradiation and/or staining with aqueous basic
solution of potassium permanganate. Nuclear magnetic
resonance (NMR) spectra were recorded on a Bruker
400 MHz spectrometer using DMSO-d6 as the solvent and
calibrated using residual undeuterated solvent as an internal
reference. Chemical shifts and coupling constants (J-values)
are reported in parts per million (ppm) and Hertz (Hz),
respectively. The following abbreviations were used to
explain multiplicities: s = singlet, d = doublet, triplet = t,
quintet = quin, sext = sextet, and m = multiplet. Elemental
analyses were performed on a 2400 Perkin Elmer Series II
analyzer and high-resolution mass spectrometry (HRMS)
N‐(3‐azidophenyl)‐6,7‐dimethoxyquinazolin‐4‐amine (9)
To a stirred mixture of compound 8 (2.00 g, 6.75 mmol) in
(CH3)2CO (30 mL) was added conc. HCl (5 mL, 6 M) and
the reaction mixture was cooled to −5 °C. A solution of
NaNO2 (932 mg, 13.5 mmol) in H2O (2 mL) was added
dropwise over 10 min and the reaction mixture was then
stirred for a further 30 min. A solution of NaN3 (878 mg,
13.5 mmol) in H2O (3 mL) was then added dropwise over a
period of 20 min and the reaction mixture was stirred for
1 h. After the starting material was consumed, H2O was
added and the resulting precipitate was filtered, washed with
cold EtOH, cold Et2O, and dried to afford 9 (2.14 g, 98%
1
was conducted using
spectrometer.
a
Micromass Q-ToF mass
yield) as a brown solid. H NMR (400 MHz, DMSO-d6)
δ = 11.62 (s, 1H), 8.84, (s, 1H), 7.63–7.58 (m, 1H), 7.51 (t,
J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.07–7.06 (m, 1H), 4.04 (s,
3H), 3.99 (s, 3H) ppm; HRMS (ESI) calcd. for C16H15N6O2
[M + H]+ 323.1256, found 323.1250. Anal. calcd. for
C16H14N6O2: C, 59.62; H, 4.38; N, 26.07. Found: C, 59.56;
H, 4.34; N, 25.98.
Experimental procedures for chemical synthesis
6,7-Dimethoxyquinazolin-4(3H)-one (6)
A mixture of methyl 2‐amino‐4,5‐dimethoxybenzoate 5
(5.00 g, 23.67 mmol) in formamide (50 mL) was stirred at
170 °C overnight under a nitrogen atmosphere. The
reaction mixture was cooled to room temperature and the
precipitate was collected by filtration and washed with
H2O, Et2O, and dried. Recrystallization from EtOH pro-
vided 6 (4.29 g, 88% yield) as a beige solid. Analytical
data for compound 6 are in agreement with the literature
(Li et al. 2016).
General procedure for the preparation of triazolyl 4-
anilinoquinazolines 12a–12i (click reaction)
To a stirred mixture of compound 11a (0.62 mmol) in
EtOH:H2O (2:1, 9 mL) was added alkyne (1.86 mmol) and
sodium ascorbate (0.50 mmol).
A fresh solution of
CuSO4·5H2O (0.25 mmol) in H2O (1 mL) was added
dropwise and the reaction mixture was vigorously stirred at
80 °C for 16 h. The reaction mixture was cooled to room
temperature and poured into H2O (50 mL). The resulting
precipitate was sonicated, filtered, and the filter cake was
washed with cold H2O, cold Et2O, and dried. Recrystalli-
zation from EtOH afforded the triazole products.
4‐Chloro‐6,7‐dimethoxyquinazoline (7)
A mixture of compound 6 (4.00 g, 19.40 mmol) and phos-
phoryl chloride (40 mL) was stirred at 120 °C for 6 h. The
solvent was removed in vacuo and the residue was dis-
solved in ice-H2O and washed with saturated aqueous
NaHCO3 solution (three times) followed by brine. The
organic layer was dried over MgSO4, filtered, and the sol-
vent was evaporated in vacuo. Recrystallizaton from EtOH
afforded the chlorinated product 7 (3.58 g, 82%) as a yellow
solid. Analytical data for compound 7 are in agreement with
the literature (VanBrocklin et al. 2005).
6,7‐Dimethoxy‐N‐[3‐(4‐phenyl‐1H‐1,2,3‐triazol‐1‐yl)phenyl]
quinazolin‐4‐amine (12a)
1
Brown solid, 96% yield; IR (KBr): 1616, 1563 cm−1; H
NMR (400 MHz, DMSO-d6) δ = 10.22 (s, 1H), 9.33 (s,
1H), 8.48 (s, 1H), 8.13 (s, 1H), 7.99–7.96 (m, 3H),
7.74–7.66 (m, 2H), 7.53–7.49 (m, 2H), 7.39 (t, J = 7.3 Hz,
1H), 4.00 (s, 3H), 3.99 (s, 3H) ppm; HRMS (ESI) calcd. for
C24H21N6O2 [M + H]+ 425.1726, found 425.1729; Anal.
calcd. for C24H20N6O2: C, 67.91; H, 4.75; N, 19.80. Found:
C, 67.88; H, 4.70; N, 19.73.
N1-(6,7-dimethoxyquinazolin-4-yl)benzene-1,3-diamine (8)
A mixture of compound 7 (2.00 g, 8.90 mmol) and 1,3-
phenylenediamine (1.06 g, 9.79 mmol) in EtOH (35 mL)
was stirred at 80 °C for 2 h. The reaction mixture was
allowed to cool to room temperature and the precipitate was
then collected by filtration, washed with cold EtOH, cold
Et2O, and dried to afford 8 (2.51 g, 95%) as a green solid.
Analytical data for compound 8 are in agreement with the
literature (Garske et al. 2011).
N‐{3‐[4‐(4‐tert‐butylphenyl)‐1H‐1,2,3‐triazol‐1‐yl]phenyl}‐
6,7‐dimethoxyquinazolin‐4‐amine (12b)
1
Brown solid, 89% yield; IR (KBr): 1620, 1562 cm−1; H
NMR (400 MHz, DMSO-d6) δ = 9.84 (s, 1H), 9.26 (s, 1H),
8.50 (s, 1H), 8.03 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H),

Medicinal Chemistry Research
7.68–7.61 (m, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.39 (s, 1H),
4.00 (s, 6H), 1.32 (s, 9H) ppm; HRMS (ESI) calcd. for
C28H29N6O2 [M + H]+ 481.2352, found 481.2348; Anal.
calcd. for C28H28N6O2: C, 69.98; H, 5.87; N, 17.49. Found:
C, 69.90; H, 5.82; N, 17.41.
N‐[3‐(4‐butyl‐1H‐1,2,3‐triazol‐1‐yl)phenyl]‐6,7‐
dimethoxyquinazolin‐4‐amine (12g)
Brown solid, 94% yield; IR (KBr): 1626, 1566 cm−1; H
NMR (400 MHz, DMSO-d6) δ = 9.80 (s, 1H), 8.58 (s, 1H),
8.42 (s, 1H), 7.98 (s, 1H), 7.58 (m, 3H), 5.28 (s, 1H), 3.99
(s, 6H), 2.73–2.70 (m, 2H), 1.66 (quin, J = 7.2 Hz, 2H),
1.38 (sext, J = 7.2 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H) ppm;
HRMS (ESI) calcd. for C22H25N6O2 [M + H]+ 405.2039,
found 405.2037; Anal. calcd. for C22H24N6O2: C, 65.33; H,
5.98; N, 20.78. Found: C, 65.31; H, 5.97; N, 20.75.
1
6,7‐Dimethoxy‐N‐{3‐[4‐(3‐methylphenyl)‐1H‐1,2,3‐triazol‐1‐
yl]phenyl}quinazolin‐4‐amine (12c)
1
Brown solid, 79% yield; IR (KBr): 1626, 1560 cm−1; H
NMR (400 MHz, DMSO-d6) δ = 9.82 (s, 1H), 9.29 (s, 1H),
8.52 (s, 1H), 8.04 (s, 1H), 7.80–7.75 (m, 3H), 7.67–7.62 (m,
2H), 7.38 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 4.01
(s, 6H), 2.39 (s, 3H) ppm; HRMS (ESI) calcd. for
C25H23N6O2 [M + H]+ 439.1882, found 439.1875; Anal.
calcd. for C25H22N6O2: C, 68.48; H, 5.06; N, 19.17. Found:
C, 68.53; H, 4.99; N, 19.11.
1‐(1‐{3‐[(6,7‐Dimethoxyquinazolin‐4‐yl)amino]phenyl}‐1H‐
1,2,3‐triazol‐4‐yl)cyclohexan‐1‐ol (12h)
Brown solid, 76% yield; IR (KBr): 3236, 1625, 1558 cm−1
;
1H NMR (400 MHz, DMSO-d6) δ = 9.78 (s, 1H), 8.61 (s,
1H), 8.50 (s, 1H), 8.46 (s, 1H), 8.01 (s, 1H), 7.64–7.58 (m,
2H), 5.01 (s, 1H), 3.99 (s, 6H), 1.99–1.31 (m, 10H) ppm;
HRMS (ESI) calcd. for C24H27N6O3 [M + H]+ 447.2144,
found 447.2149; Anal. calcd. for C24H26N6O3: C, 64.45; H,
5.87; N, 18.82. Found: C, 64.50; H, 5.90; N, 18.74.
N‐(3‐{4‐[4‐(dimethylamino)phenyl]‐1H‐1,2,3‐triazol‐1‐yl}
phenyl)‐6,7‐dimethoxyquinaz-olin‐4‐amine (12d)
1
Brown solid, 79% yield; IR (KBr): 1618, 1564 cm−1; H
NMR (400 MHz, DMSO-d6) δ = 9.81 (s, 1H), 9.62 (s, 1H),
9.07 (s, 1H), 8.48 (s, 1H), 8.02 (s, 1H), 7.77 (d, J = 7.8 Hz,
2H), 7.70–7.61 (m, 3H), 7.40 (m, 1H), 6.82 (d, J = 7.8 Hz,
2H), 4.00 (s, 6H), 2.95 (s, 6H) ppm; HRMS (ESI) calcd. for
C26H26N7O2 [M + H]+ 468.2148, found 468.2141; Anal.
calcd. for C26H25N7O2: C, 66.79; H, 5.39; N, 20.97. Found:
C, 66.83; H, 5.35; N, 20.92.
2‐(1‐{3‐[(6,7‐Dimethoxyquinazolin‐4‐yl)amino]phenyl}‐1H‐
1,2,3‐triazol‐4‐yl)propan‐2‐ol (12i)
Brown solid, 72% yield; IR (KBr): 3285, 1627, 1564 cm−1
;
1H NMR (400 MHz, DMSO-d6) δ = 9.90 (s, 1H), 8.60 (s,
1H), 8.41 (s, 1H), 7.97 (s, 1H), 7.65–7.57 (m, 2H), 5.28 (s,
1H), 4.00 (s, 6H), 1.55 (s, 6H) ppm; HRMS (ESI) calcd. for
C21H23N6O3 [M + H]+ 407.1831, found 407.1828; Anal.
calcd. for C21H22N6O3: C, 62.06; H, 5.46; N, 20.68. Found:
C, 62.01; H, 5.43; N, 20.63.
6,7‐Dimethoxy‐N‐{3‐[4‐(4‐methoxyphenyl)‐1H‐1,2,3‐triazol‐
1‐yl]phenyl}quinazolin‐4‐amine (12e)
1
Brown solid, 85% yield; IR (KBr): 1623, 1556 cm−1; H
NMR (400 MHz, DMSO-d6) δ = 9.79 (s, 1H), 9.18 (s, 1H),
8.84 (s, 1H), 8.50 (s, 1H), 8.03 (m, 1H), 7.88 (d, J = 8.2 Hz,
2H), 7.65–7.60 (m, 2H), 7.06 (d, J = 8.2 Hz, 2H), 4.00 (s,
6H), 3.80 (s, 3H) ppm; HRMS (ESI) calcd. for C25H23N6O3
[M + H]+ 455.1832, found 455.1826; Anal. calcd. for
C25H22N6O3: C, 66.07; H, 4.88; N, 18.49. Found: C, 65.99;
H, 4.91; N, 18.45.
General biology
The human breast adenocarcinoma (MCF-7) and ovarian
adenocarcinoma (SKOV-3) cell lines were purchased from
the American Type Culture Collection (ATCC, Manassas,
VA, USA). Both cell lines were independently cultured in
Dulbecco’s minimal essential medium containing low glu-
cose (DMEM-LG) supplemented with 10% fetal bovine
serum (FBS), 2 mM Glutamax, antibiotic solution of peni-
cillin (50 IU), and streptomycin (50 µg/mL). Additionally,
0.01 mg/mL bovine insulin was added to the media used for
MCF-7. Both cancer cell lines were cultured at 37 °C in a
humidified 5% CO2 atmosphere.
6,7‐Dimethoxy‐N‐{3‐[4‐(phenoxymethyl)‐1H‐1,2,3‐triazol‐1‐
yl]phenyl}quinazolin‐4‐amine (12f)
1
Brown solid, 77% yield; IR (KBr): 1622, 1554 cm−1; H
NMR (400 MHz, DMSO-d6) δ = 9.81 (s, 1H), 8.95 (s, 1H,),
8.48 (s, 1H), 8.02 (s, 1H), 7.61 (m, 2H), 7.34–7.28 (m, 3H),
7.08 (d, J = 8.0 Hz, 2H), 6.98–6.96 (m, 2H), 5.24 (s, 2H),
4.00 (s, 6H) ppm; HRMS (ESI) calcd. for C25H23N6O3 [M
+ H]+ 455.1832, found 455.1826. Anal. calcd. for
C25H22N6O3: C, 66.07; H, 4.88; N, 18.49. Found: C, 66.12;
H, 4.85; N, 18.42.
Experimental procedure for anticancer biological
evaluation
The inhibition of proliferation on human cancer cell lines
(MCF-7 and SKOV-3) of triazolyl 4-anilinoquinazolines

Medicinal Chemistry Research
12a–12i was analyzed using the MTT reagent [3-(4,5-
dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide].
calculated as control–test/control × 100 and IC50 for each
compound was estimated.
Briefly, the human cancer cell lines MCF-7 (2 × 104 cells/
well) and SKOV-3 (2 × 104 cells/well) were seeded in 24-
well tissue culture plates and allowed to attach overnight.
The cells were then treated with different concentrations of
each compound (0.1, 1, 3, 10, 30, 100 µM) and incubated at
37 °C in a humidified atmosphere of 5% CO2 for 24, 48,
and 72 h. Following the treatment period, the MTT reagent
(5 mg/ml) in 100 µL of fresh culture medium was added to
each well and incubated for 3 h. The formazan crystals
formed after MTT treatment were solubilized with DMSO
and the optical density was measured at 570 nm with a
reference wavelength of 630 nm using a microplate ELISA
reader (SpectraMax i3 Multimode Reader; Molecular
Devices, Sunnyvale, USA). Percentage of inhibition was
Results and discussion
The synthetic approach to prepare the designed triazolyl 4-
anilinoquinazolines 12a‒i is outlined in Scheme 1, com-
mencing the synthesis from the commercially available
methyl 2-amino-4,5-dimethoxybenzoate 5. The quinazoli-
none ring system of 6 was constructed using a modified
Niementowski quinazolinone reaction through cyclo-
condensation reaction of 5 with formamide at 170 °C, which
afforded 6,7-dimethoxyquinazolin-4(3H)-one 6 in 88%
yield. Chlorination of 6 was accomplished with phosphoryl
chloride to provide 4-chloro-6,7-dimethoxyquinazoline 7 in
O
O
Cl
Scheme 1 A click chemistry
synthetic approach towards the
synthesis of triazolyl 4-
anilinoquinazolines 12a–i
O
O
O
O
O
O
NH chlorination
N
Niementowski
O
NH2
N
N
5
6
7
nucleophilic
substitution
N
HN
N
N
HN
N3
HN
NH2
N
O
O
O
O
O
azidation
N
CuAAC
N
N
R
'click'
N
O
N
12a-i
9
8
Table 1 Optimization of the click reaction using azido quinazoline 9 and phenylacetylene 11a as substrates for the synthesis of triazolyl 4-
anilinoquinazoline 12a
Entry
Phenylacetylene 11a
T (°C)
Yield (%)a
(equiv.)
1
2
3
4
1.5
1.5
1.5
3
rt
No reaction
60
80
80
61
79
96
aAll reactions were carried out using 9 (0.62 mmol), 11a (equiv.), CuSO4·5H2O (20 mol%), NaAsc (40 mol%), and temperature for 16 h

Medicinal Chemistry Research
Table 2 Small library synthesis of triazolyl 4-anilinoquinazolines 12a–i employing alkynes 11a–i
Entry
1
Alkyne
Product
Yield (%)
96
2
3
4
89
79
79
11b
12b
11c
12c
12d
11d
5
6
85
77
11e
12e
7
8
9
94
76
72
82% yield. Treatment of compound 7 with 1,3-phenylene-
diamine under refluxing EtOH displaced the chlorine sub-
stituent and delivered amino quinazoline 8 in 95% yield.
Conversion of the amino group to an azido group was
achieved through diazotisation under the influence of
sodium nitrite and HCl followed by nucleophilic substitu-
tion reaction with sodium azide to provide the key click
chemistry precursor 9 in quantitative yield (98%).

Medicinal Chemistry Research
Table 3 Anticancer activity of triazolyl 4-anilinoquinazolines 12a–i
against MCF-7 and SKOV-3 cell lines
SKOV-3 cell line while compound 12f was slightly more
potent against MCF-7 cell line with an IC50 of 6.7 µM.
Compounds 12d and 12e were selective towards MCF-7
cell line (7.8 and 9.4 µM, respectively) than SKOV-3 cell
line (14.2 and 15.2 µM, respectively). In contrast, com-
pounds 12h and 12i were slightly more active towards
SKOV-3 cell line (9.4 µM and 9.2 µM, respectively) than
MCF-7 cell line (10.5 µM and 11.7 µM, respectively). A
phenyl group directly attached at C4 of the triazole het-
erocycle does not seem to be important for the anticancer
activity as replacement of the phenyl group with a non-
phenyl moiety also gave molecules with similar potencies
(compare e.g. compound 12b vs. 12g in both cell lines). On
the basis of the above biological results, compound 12f
could be used as a starting point for further structural
optimization for the discovery of more potent derivatives.
Compounds
IC50 values (µM)a
MCF-7b
SKOV-3c
12a
12b
12c
12d
12e
12f
9.7
8.9
10.2
9.8
9.0
7.9
7.8
14.2
15.2
7.8
9.4
6.7
12g
12h
12i
7.7
9.1
10.5
11.7
42.7
9.4
9.2
5-FU
26.3
aIC50 = concentration that induces 50% inhibition (IC50 values above
are the average of three independent experiments)
bHuman breast adenocarcinoma
cOvarian carcinoma
Conclusions
A novel triazolyl 4-anilinoquinazolines 12a–i were syn-
For the click chemistry reaction, we opted to utilize
azido quinazoline 9 and phenylacetylene 11a to explore
suitable click reaction conditions. We began by performing
a CuAAC reaction between compounds 9 and 11a at room
temperature for 16 h, which proved unfruitful as no triazole
product formation was observed to provide 12a (Table 1,
entry 1). When we increased the temperature to 60 °C,
compound 12a was generated in 61% yield while
increasing the temperature further to 80 °C afforded 12a in
79% yield (Table 1, entries 2 and 3). In a bid to improve the
yield further, we conducted the reaction using three
equivalents of 11a at 80 °C, which resulted in the formation
of 12a in a high yield of 96% (Table 1, entry 4; Table 2,
entry 1).
thesized through a copper-catalyzed click chemistry
approach for anticancer biological evaluation against MCF-
7 and SKOV-3 cell lines. The biological tests revealed the
identification of highly active anticancer compounds with
triazolyl 4-anilinoquinazoline 12f emerged as the most
potent anticancer molecule. Compound 12f, therefore, could
be used as a template for optimization studies. Further
studies are required to elucidate the exact mechanism of
action of these molecules.
Acknowledgements This work was funded by the Deanship of Scien-
tific Research (DSR), King Abdulaziz University, under grant number G-
203-141-1436. We, therefore, thank DSR for financial support.
Compliance with ethical standards
Azido quinazoline 9 was then subjected to click reactions
with alkyne substrates 11b–i using our optimized reaction
conditions to afford triazole products 12b–i (Table 2, entries
2–9).
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
All the synthesized triazolyl 4-anilinoquinazoline pro-
ducts 12a–i were evaluated for their anticancer activity
using an MTT-based assay against human breast adeno-
carcinoma (MCF-7) and ovarian carcinoma (SKOV-3) cell
lines. The biological results revealed compounds 12a–i
showed promising anticancer activity against both cell lines
with half-maximal inhibitory concentration (IC50) values
from 6.7–15.2 µM, most of which were in the single digit
micromolar range (Table 3). Compound 12f was the most
potent compound identified and was highly active against
both cell lines (6.7 µM for MCF-7; 7.8 µM for SKOV-3).
Compound 12f was sixfold (MCF-7) and threefold (SKOV-
3) more potent than the drug 5-fluorouracil (5-FU). Com-
pounds 12c and 12f were equipotent (~7.9 µM) against
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