Mercuric chloride catalyzed synthesis of some anticancer 2-aryl-2,3-dihydroquinizolin-4(1H)-ones

Article abstract of DOI:10.1007/s00044-016-1630-y

A series of ten 2,3-dihydroquinizolin-4(1H)-one derivatives were synthesized by ethanol-mediated condensation of anthranilamide with various aryl aldehydes in presence of catalytic amount of mercuric chloride (HgCl₂). The temperature of the reactions was maintained at 60 °C for good yield of the products. The highlights of the method include use of lab grade of chemicals as reagents and ease of work up in obtaining the product with high purity. Out of ten derivatives synthesized, three compounds 3f, 3i, and 3j are new and all the compounds were evaluated for their cytotoxic activity against six cancer cell lines. The compounds 3b (IC50: 26.1 μg mL^?1), 3c (42.7 μg mL^?1) ,and 3e (31.1 μg mL^?1) have shown activity against the cell line MDA-MB-231. Compounds 3b, 3c, 3d, 3e, and 3g showed significant total growth inhibition (TGI) values against the cell line MDA-MB-231 and compound 3j showed good TGI value against the cell line PANC 1. Compounds were also screened for their antibacterial activity and antioxidant activity by DPPH method.

Full text of DOI:10.1007/s00044-016-1630-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1630-y
ORIGINAL RESEARCH
Mercuric chloride catalyzed synthesis of some anticancer
2-aryl-2,3-dihydroquinizolin-4(1H)-ones
Navudu Ramesh1 Mannem Gangadhara Rao1 Ravi Varala2
●
●
●
V. Umamaheswra Rao3 B. Hari Babu1
●
Received: 11 March 2015 / Accepted: 27 June 2016
© Springer Science+Business Media New York 2016
Abstract A series of ten 2,3-dihydroquinizolin-4(1H)-one
derivatives were synthesized by ethanol-mediated condensa-
tion of anthranilamide with various aryl aldehydes in presence
of catalytic amount of mercuric chloride (HgCl2). The tem-
perature of the reactions was maintained at 60 °C for good
yield of the products. The highlights of the method include
use of lab grade of chemicals as reagents and ease of work up
in obtaining the product with high purity. Out of ten deriva-
tives synthesized, three compounds 3f, 3i, and 3j are new and
all the compounds were evaluated for their cytotoxic activity
against six cancer cell lines. The compounds 3b (IC50:
26.1 µg mL−1), 3c (42.7 µg mL−1) ,and 3e (31.1 µg mL−1) have
shown activity against the cell line MDA-MB-231. Com-
pounds 3b, 3c, 3d, 3e, and 3g showed significant total growth
inhibition (TGI) values against the cell line MDA-MB-231
and compound 3j showed good TGI value against the cell line
PANC 1. Compounds were also screened for their anti-
bacterial activity and antioxidant activity by DPPH method.
Introduction
2,3-dihydroquinizolin-4(1H)-ones have been reported to
possess wide range of biological activities (Bonola et al.,
1968; Alaimo and Russel, 1972; Cohen et al., 1959;
Okumura et al., 1968; Levin et al., 1994; Chinigo et al.,
2008) such as anticancer, antitumor, antibiotic, anti-
defibrillator, antipyretic, analgesic, antihypertonic, anti-
malarial, and diuretic activities. Synthesis of these
compounds comprises of condensation of anthranilamide
with substituted carbonyl compounds in the presence of
various catalysts such as H3BO3 (Karimi-Jaberi and Zarei,
2012), BU4N(+)Br(-)-CuCl2 (Davoodnia et al., 2010),
NaHSO4 (Wang, et al., 2012), CHCl3-SiO2 (Rueping et al.,
2009), ruthenium (Watson et al., 2012), gallium (Chen et al.,
2008), 2,2,2-trifloro ethanol (Qiao et al., 2007), citric acid
(Ding et al., 2012), Ticl4-Zn (Shi et al., 2005) and ZrCl4
(Abdollahi-Aalibeik and Shabani, 2011). This is the first
report in view of HgCl2 as catalyst for cyclocondensation of
anthralinamide and substituted aryl aldehydes (Scheme 1).
Moreover this approach was found to be an effective reagent
for the synthesis of 2,3-dihydroquinizolin-4(1H)-ones.
●
Keywords 2-aryl-2,3-dihydroquinizolin-4(1H)-ones Anthra-
●
●
●
linamide Anticancer activity Antioxidant activity HgCl2
Electronic supplementary material The online version of this article
(doi:10.1007/s00044-016-1630-y) contains supplementary material,
which is available to authorized users.
Results and discussion
The initial attempts for the cyclocondensation of anthrali-
namide with vanillin (2d) were not successful when reac-
tions were carried under room temperature in presence of
mercuric chloride and ethanol. We have found that the
reaction progresses smoothly in catalytic amount of mer-
curic chloride in ethanol at 60 °C. The reactions were
monitored by TLC and after completion of the reaction an
aqueous workup afforded 2,3-dihydroquinizolin-4(1H)-
ones (3d) in 93 % yield. The generality of this methodology
* B. Hari Babu
dr.b.haribabu@gmail.com
1
Department of Chemistry, Acharya Nagarjuna University, NNagar
522 510 AP, India
2
Department of Chemistry, RGUKT- Basara (TS-IIIT), Adilabad
504 107 Telangana, India
3
Department of Microbiology, Acharya Nagarjuna University,
NNagar 522 510 AP, India

Med Chem Res
Scheme 1 Synthesis of 2,3-
dihydroquinizolin-4(1H)-ones
DPPH Free radical scavenging activity of 2-
aryldihydroquinizoline-4(1H)-ones
100
80
60
40
20
0
100
200
300
400
500
Concentration in µg/ml
3f
3i
3j
Ascorbic acid
was established by extending to other various aromatic
aldehydes. A variety of aryl aldehydes (2a–2j) (Table 1)
were treated with anthranilamide in the presence of catalytic
amount of mercuric chloride in ethanol at about 60 °C for
60–120 min (Scheme 1) and their corresponding products,
i.e., 2,3-dihydroquinizolin-4(1H)-ones (3a–j) were obtained
in good yield (Table 1). The compounds 3f, 3i, and 3j are
novel and the structures were confirmed by 1H NMR,
13C NMR, and HRMS spectral data, and the remaining
compounds were confirmed by their corroboration of the
literature data (Ghashang, 2012; VNS Murthy et al., 2012;
Zong et al., 2010; Ali Saffar and Shiva, 2010; Kamal et al.,
2011).
From Table 1 it was observed that in the condensation of
anthranilamide with aromatic aldehydes having either
electron donating groups, like -OH (2a, 91 %; 2b, 89 %) or
electron withdrawing like o-NO2 (2h, 90 %), p-NO2 (2g,
88 %) gave the products in good yield. Moreover, the pro-
ducts obtained were tested for the absence of mercury by
atomic absorption spectroscopy (Agilent Techtron AA-
1275) and the products have <0.1 ppm of mercury.
moderate TGI values on the same cell line. Considerable
activity is not observed with the other cell lines studied.
Antibacterial activity
The results summarized in Table 3 clearly show that anti-
bacterial activity of some samples were good when com-
pared with the positive control Streptomycin and some of
the samples exhibited zone of inhibition nearly to the
positive control. Sample 3i showed good antibacterial
activity against Bacillus megaterium and Staphylococcus
aureus. Sample 3h and 3g inhibited the growth of both
Bacillus subtilisand and Staphylococcus aureus, likewise
sample 3g also exhibited the antibacterial activity against
Bacillus megaterium.
Antioxidant activity
The three novel compounds 3f, 3i, and 3j were tested for
their antioxidant activity by using DPPH method and
compared with ascorbic acid as standard at different con-
centrations (Table 4). Among the tested compounds, com-
pound 3j showed good antioxidant activity at all tested
concentrations compared with the standard.
Anticancer activity
All the synthesized compounds (3a–j) were tested on six cell
lines, namely, PANC 1, HepG2, SKNSH, MDA-MB 231,
and IMR 32 (cervical, pancreatic, hepatic, neuroblastoma,
breast, and neuroblastoma, respectively) for their anticancer
activity study the results are summarized in the Table 2.
Compounds 3b (IC50: 26.1 µg mL−1), 3c (42.7 µg mL−1),
and 3e (31.1 µg mL−1) have shown significant IC50 values
against the cell line MDA-MB-231; moreover, the com-
pounds 3b, 3c, 3d, 3e, and 3g showed better total growth
inhibition (TGI) values against the same cell line (MDA-
MB-231). Compound 3j showed good TGI value against the
cell line PANC 1 and 3a, 3c, 3e, 3g compounds showed
Materials and methods
All the chemicals used were of Merck. Reagent grade sol-
vents (E. Merck) were used as such. All melting points were
obtained by Remi melting point apparatus. All reactions
were monitored by TLC and all yields refer to isolated
products. Proton NMR spectra were recorded in DMSO-d6
on Bruker 400 MHz and 13C NMR spectra was on Bruker
100 MHz.

Med Chem Res
Table 1 Mercuric chloride catalyzed synthesis of 4-(1H)-quinazolines in ethanol
Entry
R1
R2
R3
R4
Product
Time (min)
60
Yield (%)
91
2a
OH
H
H
H
O
NH
OH
N
H
(3a)
2b
2c
H
H
OH
OH
H
H
H
70
80
89
90
O
NH
OH
N
H
(3b)
OCH3
O
NH
OH
N
H
OMe
(3c)
2d
H
OCH3
OH
H
85
93
O
NH
OMe
OH
N
H
(3d)
(3e)
(3f)
2e
H
OCH3
OCH3
H
80
94
O
NH
OMe
OMe
N
H
2f
H
Br
OH
H
100
92
O
NH
Br
N
H
OH
2g
H
H
NO2
H
90
88
O
NH
N
H
NO2
(3g)

Med Chem Res
Table 1 continued
Entry
R1
R2
R3
R4
Product
Time (min)
85
Yield (%)
90
2h
NO2
H
H
H
O
NH NO2
N
H
(3h)
2i
H
OCH3
OH
Br
100
92
O
NH
OMe
N
H
OH
Br
(3i)
2j
NO2
OCH3
OCH3
H
120
89
O
NH
OMe
OMe
N
H
O2N
(3j)
General procedure for the preparation of
2,3-dihydroquinizolin-4(1H)-ones
this study were procured from American Type Culture
Collection, United States. The synthesized test compounds
were evaluated for their in vitro antiproliferative activity in
these six different human cancer cell lines. A protocol of 48
h continuous drug exposure was used, and a SRB cell
proliferation assay was used to estimate cell viability or
growth. All the cell lines were grown in Dulbecco’s mod-
ified Eagle’s medium (containing 10 % FBS in a humidified
atmosphere of 5 % CO2 at 37 °C). Cells were trypsinized
when subconfluent from T25 flasks/60 mm dishes and
seeded in 96 well plates in 100 μL aliquots at plating den-
sities depending on the doubling time of individual cell
lines. The micro titer plates were incubated at 37 °C, 5 %
CO2, 95 % air, and 100 % relative humidity for 24 h prior to
addition of experimental compounds and were incubated for
48 h with different doses (0.01, 0.1, 1, 10, 100 µM) of
prepared derivatives. After 48 h incubation at 37 °C, cell
monolayer’s were fixed by the addition of 10 % (wt/vol)
cold trichloroacetic acid and incubated at 4 °C for 1 h and
were then stained with 0.057 % SRB dissolved in 1 % acetic
acid for 30 min at room temperature. Unbound SRB was
washed with 1 % acetic acid. The protein bound dye was
dissolved in 10 mM Tris base solution for OD determination
at 510 nm using a micro plate reader (Enspire, Perkin
Elmer, USA). Using the seven absorbance measurements
[time zero, (Tz), control growth, (C), and test growth in the
presence of compound at the five concentration levels (Ti)],
To a mixture of anthralinamide (1 mmol) and aromatic
aldehyde (1 mmol) in ethanol (5 mL), catalytic amount of
mercuric chloride was added and the reaction mixture was
stirred at 60 °C in water bath for about 60–120 min and the
reaction was monitored by TLC. After completion of the
reaction the ethanol was distilled off from the reaction
mixture and the solid mass poured into cold water (25 mL),
filtered off and the product was washed with conc. KI
solution 5–6 times to remove remaining mercuric salts, if
any, then further purified using recrystallization from
ethanol. Finally, the dried compounds were confirmed by
their physical constants or spectral data.
Biological activity experimental section
Anticancer activity experimental
Materials and methods, cell cultures, maintenance, and
antiproliferative evaluation
The cell lines HeLa, PANC 1, HepG2, SKNSH, MDA MB
231, and IMR 32(cervical, pancreatic, hepatic, neuro-
blastoma, breast, and neuroblastoma), which were used in

Med Chem Res
the percentage growth was calculated at each of the drug
concentrations levels. Percentage growth inhibition was
calculated as:
ꢀ
ꢀ
ꢁ
ðTi ꢀ TzÞ
ðC ꢀ TzÞ
´ 100 for concentrations for which Ti >=¼Tz
ꢁ
ðTiꢀTzÞ
´ 100 for concentrations for which Ti < Tz:
Tz
Three dose response parameters were calculated for each
experimental agent. Growth inhibition of 50 % (GI50) was
calculated from [(Ti−Tz)/(C−Tz)] × 100 = 50, which is the
compound concentration resulting in a 50 % reduction in
the net protein increase (as measured by SRB staining) in
control cells during the drug incubation. The compound
concentration resulting in TGI was calculated from Ti = Tz.
The LC50 (concentration of compound resulting in a 50 %
reduction in the measured protein at the end of the drug
treatment as compared to that at the beginning) indicating a
net loss of cells following treatment was calculated from
[(Ti−Tz)/Tz] × 100 = −50. Values were calculated for each
of these three parameters if the level of activity is reached;
however, if the effect is not reached or is exceeded, the
value for that parameter was expressed as greater or less
than the maximum or minimum concentration tested.
Antibacterial activity experimental
The antibacterial activity was examined by using agar well
diffusion method (Sharief Md and Uma Maheswara Rao,
2011). Bacterial cultures of one day old were used for
antibacterial analysis. About 0.3 mL of the each bacterial
suspension was added to sterile petri plates and to these
plates by using pour plate method molten state nutrient agar
medium was poured. After complete solidification, wells
were bored with sterile cork borer of 6 mm diameter. The
samples were prepared by dissolving 500 µg in 1 mL
DMSO. Wells were filled with 100 µL of the sample. The
plates were incubated at 37 °C for 24 h. After incubation,
the diameter of the zone of inhibition was measured. For
each sample and bacterial species, triplicates were main-
tained. Streptomycin standard antibiotic with the con-
centration of 10 µg/mL DMSO was used as positive
control.
Antioxidant activity experimental procedure
2, 2-diphenyl-1-picryl hydrazyl (DPPH) free radical
scavenging method
The DPPH free radical scavenging activity of the six novel
analogs (3f, 3i, and 3j) was measured according to the
following method (Ai Lan et al., 2012). The different

Med Chem Res
Table 3 Antibacterial activities
Sample
Test organisms
of synthesized compounds
Bacillus
subtilis
Pseudomonas
aeroginosa MTCC aureus MTCC 737
Staphylococcus
Proteus
vulgaris
Bacillus
megaterium
MTCC 441 1688
MTCC 426 MTCC 428
3a
3b
3c
3d
3e
3f
–
–
–
–
–
–
4 mm
–
–
–
–
–
–
4 mm
–
–
–
–
–
4 mm
–
5 mm
–
–
4 mm
–
–
4 mm
4 mm
–
–
–
3g
3h
3i
6 mm
4 mm
–
–
–
6 mm
–
5 mm
5 mm
–
–
–
–
5 mm
–
3j
–
–
4 mm
7 mm
Streptomycin 7 mm
7 mm
6 mm
7 mm
Table 4 Antioxidant activity of three new compounds 3f, 3i, and 3j
and their comparison graph
1H, J = 8.0 Hz), 7.60 (s, 1H), 7.26 (d, 1H, J = 8.0 ), 8.03
(s,1H), 10.13 (s,1H); 13C NMR (100 MHz, DMSO-d6):
δ (ppm) 65.79, 108.84, 114.20, 114.80, 115.70, 116.79,
126.93, 127.19, 131.28, 132.73, 133.35, 147.62, 154.13,
163.32; MS m/z (M, M+2) 319,321 for M.F.
C14H11N2O2Br.
Concentration (µg mL−1
)
Percentage of inhibition
3f
3i
3j
Ascorbic acid
100
200
300
400
500
15.4
18.2
19.7
17.46 35.37 50.67
18.5
19.1
45.97 53.25
58.2 79.08
21.49 19.85 59.57 83.51
24.77 20.89 62.38 91.26
2-(3-Br, 4-OH, 5-OMe phenyl)-2,3 dihydroquinizolin-4
(1H)-one (3i)
This compound was obtained as a white solid (mp.
246–248 °C); 1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.9
(s, 3H), 5.8 (s, 1H), 6.7–6.8 (m, 2H), 7.15 (s,1H), 7.25 (d,
1H, J = 8.0 Hz), 7.3 (s, 1H), 7.65 (s, 1H), 7.7 (d, 1H, J =
8.0 Hz), 7.8 (s, 1H), 9.08 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) δ (ppm) 56.19, 66.04, 108.78, 109.81, 114.56,
114.96, 117.29, 122.71, 127.47, 133.25, 133.30, 144.05,
147.82, 148.29, 163.81; MS m/z (M, M+2) 349,351 for
M.F. C15H13N2O3Br.
concentrations of the titled compounds, i.e., 100 µg/mL,
200 µg/mL, 300 µg/mL, 400 µg/mL, and 500 µg/mL were
prepared in DMSO. 1 mL of each concentration was mixed
with 4 mL of the 0.004 % (w/v) solution of DPPH prepared
in methanol. The reaction mixture was kept for incubation
in dark for 30 min. Methanol was used as control and
ascorbic acid was used as positive control. The absorbance
was measured at 517 nm. The DPPH scavenging activity
(%) was calculated by using the following formula
DPPH scavenging activity ð%Þ ¼ ½ðA0ꢀAsÞ = A0ꢁ ´ 100;
2-(3,4-di methoxy,6-nitro phenyl)-2,3 dihydroquinizolin-4
where, A0 = absorbance of the control, As = absorbance
(1H)-one (3j)
of the sample.
This compound was obtained as a light yellow solid (mp.
Spectral data of the new compounds 3f, 3i, and 3j
176–178 °C); 1H NMR (400 MHz, DMSO-d6) δ 3.84 (s,
,
3H), 3.89 (s, 3H), 6.41(s, 1H), 6.71(t, 1H, J = 7.2 Hz), 6.79
(d, 2H, J = 8.4 Hz), 7.24 (t, 1H, J = 7.6 Hz), 7.34 (s,1H),
7.62 (s,1H), 7.66 (d, 1H, J = 8.0 Hz), 8.02 (s,1H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ (ppm) 55.69, 55.83, 62.30,
107.68, 110.24, 114.58, 117.29, 127.11, 130.20, 132.95,
132.95, 139.85, 147.38, 148.22, 152.68, 163.45; MS m/z
(M+H)+ 330 for M.F. C16H15N3O5.
2-(4-OH,3-Br phenyl)-2,3 dihydroquinizolin-4(1H)-one (3f)
This compound was obtained as a white solid (mp.
228–230 °C); 1H NMR (400 MHz, DMSO-d6): δ (ppm)
5.63 (s,1H), 6.66 (t, 1H, J = 7.6 Hz), 6.71 (d, 1H, J = 8.0 Hz),
6.92 (d, 2H, J = 8.0 Hz), 7.19 (t, 1H, J = 8.4 Hz), 7.60 (d,

Med Chem Res
Cohen E, Klarberg B, Vaughan JR (1959) Quinazolinone sulfona-
mides as diuretic agents. J Am Chem Soc 81:5508–5509
Conclusion
Davoodnia A, Allameh S, Fakhari AR, Tavakoli-Hoseini N (2010)
Highly efficient solvent-free synthesis of quinazolin-4(3H)-ones
A simple and reliable protocol was developed for the
synthesis of 2-aryl substituted 2,3-dihydroquinazolin-4
(1H)-ones by using HgCl2. The greatest advantage of this
methodology was that the products obtained were of good
yields and with reasonably pure state. Three novel com-
pounds 3f, 3i, and 3j were also reported. The compounds
3b, 3c, and 3e were showed good IC50 values against the
cell line MDA-MB-231, compounds 3b, 3c, 3d, 3e, and 3g
showed better TGI values against the cell line MDA-MB-
231. Compound 3j showed good TGI value against the cell
line PANC 1 and 3a, 3c, 3e, 3g compounds showed mod-
erate TGI values on the same cell line.
and
2,3-dihydroquinazolin-4(1H)-ones
using
tetra-
butylammonium bromide as novel ionic liquid catalyst. Chin
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Ding QS, Zhang JL, Chen JX, Liu MC, Ding JC, Wu HY (2012)
Tandem synthesis of 2,3-dihydroquinazolin-4(1H)-ones on
grinding under solvent-free conditions. J Heterocyclic Chem
49:375–380
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as an efficient catalyst for the eco-friendly synthesis of 2,3-
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Acknowledgments The authors are highly thankful to Acharya
Nagarjuna University for constant encouragement and UGC, New
Delhi for providing financial support through BSR Fellowship (F.4-1/
2006(BSR)/11-67/2008 (BSR) dt. 22 October 2013).
Karimi-Jaberi Z, Zarei L (2012) Rapid synthesis of 2-substituted2,3-
dihydro-4(1H)-quinazolinones using boric acid or sodium dihy-
drogen phosphate under solvent-free conditions. S Afr J Chem
65:36–38
Compliance with ethical standards
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Okumura K, Oine T, Yamada Y, Hayashi G, Nakama M (1968)
4-Oxo-1,2,3,4-tetrahydroquinazolines I. Synthesis and pharma-
Conflict of interest The authors declare that they have no conflict of
interest.
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properties
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2-methyl-3-aryl-4-oxo-1,2,3,4-
tetrahydroquinazolines and their 1-acyl derivatives. J Med Chem
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