Synthesis and Cytotoxicity of Quinazolin-4(3H)-one Based Peptides

Article abstract of DOI:10.1134/S1070363220040246

Abstract: A novel series of quinazolin-4(3H)-one derivatives has been synthesized in high yields using the multicomponent Ugi reaction and characterized by IR, NMR and mass spectral data. The products have been tested for their cytotoxic activity against HeLa cells. Two tested compounds have shown potent activity compared to standard drug Doxorubicin. The in silico docking studies of the compounds against quinone reductase-2 (4ZVM) enzyme have also supported their activity.

Full text of DOI:10.1134/S1070363220040246

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 4, pp. 720–724. © Pleiades Publishing, Ltd., 2020.
Synthesis and Cytotoxicity of Quinazolin-4(3H)-one
Based Peptides
a,b
a,
b
a
P. Shankaraiah , A. K. D. Bhavani *, A. Kishore Kumar , and K. Ramakrishna
a
Department of Chemistry, University College of Science, Osmania University, Hyderabad, 500007 India
b
Department of Humanities and Sciences, Vardhaman College of Engineering, Shamshabad,
Hyderabad, Telangana, 501218 India
*
e-mail: shankarpou@gmail.com
Received February 12, 2020; revised March 18, 2020; accepted March 21, 2020
Abstract—A novel series of quinazolin-4(3H)-one derivatives has been synthesized in high yields using the mul-
ticomponent Ugi reaction and characterized by IR, NMR and mass spectral data. The products have been tested
for their cytotoxic activity against HeLa cells. Two tested compounds have shown potent activity compared to
standard drug Doxorubicin. The in silico docking studies of the compounds against quinone reductase-2 (4ZVM)
enzyme have also supported their activity.
Keywords: quinazolin-4(3H)-one, Ugi multicomponent reaction, cytotoxic, isocyanide
DOI: 10.1134/S1070363220040246
INTRODUCTION
quinazolin-4(3H)-one derivatives (9b–9l) (Scheme 1).
The structure of products was confirmed by IR, NMR
and mass spectral data. IR spectra of the products 9a–9l
demonstrated the characteristic bands for three different
Quinazolin-4(3H)-one is a building block of naturally
occurring alkaloids and utilized as a drug like scaffolds in
some natural products such as trypanthrin, rutaecarpine
and luotoninA. Quinazolin-4(3H)-one and its derivatives
demonstrate a wide range of biological activities
including anti-tumor [1], anti-inflammatory [2], analgesic
–
1
C=O groups in the range of 1740–1605 cm . Formation
of the amido groups was also confirmed by three
characteristic signals in the range of 157.2–171.1 ppm of
13
1
their C NMR spectra. In H NMR spectrum the benzylic
proton signals were recorded between 6.15 and 6.65.
[
3], and antimicrobial [4]. In the current study we have
designed and synthesized quinazolin-4(3H)-one based
peptides utilizing the Ugi multi-component reaction, and
tested cytotoxicity of the products against cancer cell line
HeLa cells).
RESULTS AND DISCUSSION
-Amino quinazolinone (5) was chosen as a precursor
Cytotoxicity of the synthesized compounds. The
in vitro cytotoxic activity of the newly synthesized
quinazolin-4(3H)-one derivatives 9a–9l was tested
against human cervical carcinoma (HeLa) cells by using
the MTT assay [10] and compared with the standard drug
doxorubicin. The IC values of quinazolin-4(3H)-one-
(
6
5
0
in development of a multifunctional aliphatic chain
at the position-6 of quinazolin-4(3H)-one via the Ugi
reaction [5]. The compound 5 was synthesized from
isatin as presented in Scheme 1 [6–9]. A reaction of
peptide derivatives 9a–9l exhibited cytotoxic effect close
to that of doxorubicin, which was particularly pronounced
for compounds 9b and 9g (Table 1).
EXPERIMENTAL
6
-amino quinazolin-4(3H)-one (5) with benzaldehyde
(
(
6a), benzoic acid (7a) and tert-butyl isocyanide
8a) in methanol gave the corresponding N-[2-(tert-
Melting points were measured in open capillary tubes
and are uncorrected. IR spectra (KBr discs) were recorded
1
13
butylamino)-2-oxo-1-phenylethyl]-N-(3-methyl-4-oxo-
,4-dihydroquinazolin-6-yl)benzamide (9a) in 76% yield.
on a Perkin-Elmer 337 spectrophotometer. H and
C
3
NMR spectra were measured on a Varian Gemini 400 or
This multicomponent reaction was extended to different
Bruker 100 spectrometers using CDCl as a solvent and
3
substituted aromatic aldehydes 6b–6e, aromatic acids
TMS as an internal standard. HRMS were measured on
a Q-TOF mass spectrometer.
7
b, 7c and isocyanide 8b that gave the corresponding
7
20

SYNTHESIS AND CYTOTOXICITY OF QUINAZOLIN-4(3H)-ONE
721
Synthesis of quinazolin-4(3H)-one-peptide
derivatives 9a–9l. An isocyanide 8a, 8b (1.61 mmol) was
added to a stirred mixture of 6-amino-3-methylquinazolin-
Table 1. In vitro сytotoxicity (IC ) of compounds 9a–9l and
5
0
doxorubicin
Compound
Concentration, μM
IC50 values,
4
(3H)-one 5 (0.857 mmol) with appropriate substituted
benzoic acid 7a–7c (1.02 mmol) and aromatic aldehyde
a–6e (0.99 mmol) in methanol. The reaction mixture was
2
0
40
78
65
72
80
70
80
65
71
85
70
80
67
60
57
45
56
73
64
68
52
54
65
64
68
55
80
50
42
54
56
44
44
41
44
44
44
44
44
μM
9
a
90
78
87
97
86
98
90
86
92
86
98
82
3.82
3.00
4.00
4.51
3.75
3.72
3.25
3.46
3.80
3.75
3.72
3.43
6
9
b
heated at 60°C for 12 h. After completion of the process,
as indicated by TLC, methanol was evaporated and the
crude product was purified by column chromatography
9
c
9
d
(eluent 20% ethyl acetate in petroleum ether) to afford
9e
9f
the corresponding target product 9a–9l.
N-[2-(tert-Butylamino)-2-oxo-1-phenylethyl]-N-(3-
methyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzamide
9g
9h
(
9a). Yield 76%, white solid, mp 163–164°C. IR
9
i
–1
spectrum, ν, cm : 3329 (N–H), 3065 (C–H, aromatic),
9
j
2
923 (C–H, CH ), 1734, 1672 br (C=O, amide), 1486 (Ar-
2
9
k
1
H). H NMR spectrum, δ, ppm: 1.39 s (9H), 3.48 s (3H),
9
l
5
.75 s (1H), 6.21 s (1H), 7.09–7.17 m (3H), 7.20–7.21
Controla
100
66
m (3H), 7.26–7.27 m (1H), 7.31–7.38 m (3H), 7.45–7.53
1
3
Doxorubicin
87
72
56
4.5
m (1H), 7.58–7.62 m (1H), 7.71 s (1H), 7.94 s (1H). C
a
NMR spectrum, δ, ppm: 28.6, 33.9, 51.7, 66.5, 121.3,
HaLa cells not treated with the compounds.
1
1
1
27.5, 127.8, 128.5, 128.6, 129.6, 130.0, 132.5, 133.1,
34.4, 135.6, 136.5, 140.1, 146.4, 147.0, 160.6, 168.4,
71.2. HRMS: 469.2116.
1
1
31.8, 135.4, 137.9, 138.4, 146.9, 147.1, 160.5, 165.9,
71.7. HRMS: 503.18375.
N-(tert-Butyl)-2-(2-chlorophenyl)-3-(3-methyl-
N-[2-(tert-Butylamino)-1-(4-methoxyphenyl)-2-
4
-oxo-3,4-dihydroquinazolin-6-yl)-4-oxo-4-
oxoethyl]-N-(3-methyl-4-oxo-3,4-dihydroquinazolin-
6-yl)benzamide (9d). Yield 83%, white solid, mp
130–131°C. IR spectrum, ν, cm : 3331 (N–H), 3066
phenylbutanamide (9b). Yield 78%, white solid, mp
1
–
1
–1
25–126°C. IR spectrum, ν, cm : 3314 (N–H), 3062
(
(
C–H, aromatic), 2975 (C–H, CH ), 1728, 1673, 1640
C=O, amide), 1533 (Ar-H). H NMR spectrum, δ,
2
(C–H, aromatic), 2970 (C–H, CH ), 1738, 1669, 1645
2
1
1
(C=O, amide), 1488 (Ar-H). H NMR spectrum, δ, ppm:
ppm: 1.41 s (9H), 3.47 s (3H), 5.72 s (1H), 6.56 s (1H),
7
1
1
.38 s (9H), 3.48 s (3H), 3.72 s (3H), 5.71 s (1H), 6.15 s
.01–7.16 m (5H), 7.29–7.33 m (5H), 7.66 d (J = 8.03,
(1H), 6.70–6.91 m (3H), 7.09–7.18 m (5H), 7.18–7.37 m
1
3
H), 7.83 s (1H), 7.89 d (J = 7.47 Hz, 1H). C NMR
(
2H), 7.58 m (1H), 7.74 s (1H),7.92 d (J = 7.47 Hz, 1H).
C NMR spectrum, δ, ppm: 28.0, 33.4, 50.8, 54.5, 64.7,
13.2, 122.2, 123.6, 123.7, 126.7, 127.1, 127.8, 128.7,
spectrum, δ, ppm: 28.6, 33.9, 52.0, 62.8, 126.9, 127.3,
13
1
1
1
27.8, 127.9, 128.5, 128.9, 129.6, 129.7, 130.1, 137.5,
32.4, 135.4, 135.6, 136.4, 142.9, 146.6, 147.0, 160.6,
68.8, 171.1. HRMS: 503.18375.
1
1
1
30.8, 133.4, 133.9, 135.9, 146.7, 155.8, 160.8, 166.1,
68.4. HRMS: 499.23436.
N-[2-(tert-Butylamino)-1-(4-chlorophenyl)-2-
N-[2-(tert-Butylamino)-2-oxo-1-phenylethyl]-4-
oxoethyl]-N-(3-methyl-4-oxo-3,4-dihydroquinazolin-
6
8
aromatic), 2985 (C–H, CH ), 1728, 1673, 1640 (C=O,
amide), 1433 (Ar-H). H NMR spectrum, δ, ppm: 1.39 s
(
(
chloro-N-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-
benzamide (9e). Yield 73%, white solid, mp 110–111°C.
-yl)benzamide (9c). Yield 77%, white solid, mp
–1
0–81°C. IR spectrum, ν, cm : 3310 (N–H), 3063 (C–H,
–1
IR spectrum, ν, cm : 3329 (N–H), 3065 (C–H, aromatic),
2
1
2963 (C–H, CH ), 1734, 1672 br (C=O, amide), 1486 (Ar-
2
1
H). H NMR spectrum, δ, ppm: 1.38 s (9H), 3.49 s (3H),
9H), 3.49 s (3H), 5.85 s (1H), 6.17 s (1H), 7.09–7.23 m
7H), 7.28 d (J = 7.0 Hz, 2H), 7.36 d (J = 8.78 Hz, 1H),
5
.68 s (1H), 6.19 s (1H), 7.08–7.10 m (2H), 7.19–7.27 m
7
.56–7.60 m (1H), 7.77 s (1H), 7.94 d (J = 7.47 Hz ,1H).
C NMR spectrum, δ, ppm: 28.5, 33.8, 51.7, 60.9, 121.0,
27.3, 127.9, 128.1, 128.8, 129.1, 129.2, 130.6, 131.0,
(7H), 7.38 d (J = 8.69 Hz, 1H), 7.60–7.69 m (2H), 7.94
d (J = 7.47 Hz, 1H). C NMR spectrum, δ, ppm: 28.6,
33.9, 51.8, 66.5, 121.5, 124.7, 127.6, 128.1, 128.6, 130.0,
1
3
13
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 4 2020

722
SHANKARAIAH et al.
Scheme 1. Synthetic approach to quinazolin-4(3H)-one based peptides 9a–9l.
1
1
30.1, 134.1, 134.2, 134.3, 135.6, 136.3, 139.8, 146.7,
47.1, 160.6, 168.3, 170.1. HRMS: 503.2101.
7.21–7.25 m (3H), 7.27–7.37 m (5H), 7.58–7.60 m (1H),
7.69 s (1H), 7.91 d (J = 7.47 Hz, 1H). C NMR spectrum,
δ, ppm: 24.1, 25.1, 32.2, 33.4, 48.0, 64.0, 120.4, 126.3,
13
N-[2-(Cyclohexylamino)-2-oxo-1-phenylethyl]-
1
1
27.7, 127.8, 127.9, 129.1, 130.0, 131.7, 133.3, 135.1,
36.4, 136.8, 138.8, 146.1, 148.5, 159.9, 168.4, 169.8.
N-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-
benzamide (9f). Yield 73%, white solid, mp 123–124°C.
IR spectrum, ν, cm : 3268 (N–H), 3025 (C–H, aromatic),
–1
HRMS: 495.3814.
2
1
925 (C–H, CH ), 1736, 1679, 1651, (C=O, amide),
495 (Ar-H). H NMR spectrum, δ, ppm: 1.13–1.42 m
N-[1-(4-Bromophenyl)-2-(cyclohexylamino)-2-
oxoethyl]-N-(3-methyl-4-oxo-3,4-dihydroquinazolin-
6-yl)benzamide (9g). Yield 74%, white solid, mp
2
1
(7H), 1.86–2.01 m (3H), 3.48 s (3H), 3.84–3.94 m (1H),
–
1
5
.72 d (J = 7.85 Hz, 1H), 6.27 s (1H), 7.08–7.15 m (3H),
167–168°C. IR spectrum, ν, cm : 3270 (N–H), 3027
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 4 2020

SYNTHESIS AND CYTOTOXICITY OF QUINAZOLIN-4(3H)-ONE
723
–
1
(
(
C–H, aromatic), 2925 (C–H, CH ), 1739, 1678, 1647
C=O, amide), 1486 (Ar-H). H NMR spectrum, δ,
white solid, mp 239-240°C. IR spectrum, ν, cm :
2
1
3201(N–H), 3065 (C–H, aromatic), 2932 (C–H, CH ),
2
1
ppm: 1.05–1.44 m (7H), 1.90–2.01 m (3H), 3.50 s (1H),
1738, 1665 br (C=O, amide), 1488 (Ar-H). H NMR
3
7
7
.86–3.90 m (1H), 5.82 d (J = 7.78 Hz, 1H), 6.19 s (1H),
spectrum, δ, ppm: 1.08–1.42 m (7H), 1.89–2.04 m
(3H), 3.48 s (3H), 3.69 s (6H), 3.76 s (3H), 3.86–3.94 m
(1H), 5.79 d (J = 8.06 Hz,1H), 6.21 s (1H), 7.08–7.17 m
(4H), 7.31–7.38 m (3H), 7.47–7.54 m (1H), 7.61 d (J =
7.70 Hz, 1H), 7.75 s (1H), 7.92 d (J = 7.47 Hz, 1H). C
NMR spectrum, δ, ppm: 24.8, 25.4, 32.7, 33.9, 49.0, 65.4,
121.5, 124.2, 127.1, 127.7, 128.0, 128.5, 128.6, 128.7,
.09–7.19 m (5H), 7.29–7.45 m (5H), 7.55–7.57 m (1H),
1
3
.76 m (1H), 7.77 s (1H), 7.93 d (J = 8.37 Hz, 1H). C
NMR spectrum, δ, ppm: 24.6, 25.3, 32.7, 34.0, 48.9, 65.4,
13
1
1
1
21.6, 122.8, 127.5, 127.8, 128.4, 129.7, 131.6, 131.7,
33.3, 135.2, 136.1, 139.9, 146.6, 147.2, 160.5, 167.9,
71.3. HRMS: 573.14996.
1
1
29.5, 130.3, 132.6, 133.7, 135.8, 138.1, 145.2, 147.2,
47.4, 160.3, 167.5, 167.9. HRMS: 585.2805.
N-[1-(2-Chlorophenyl)-2-(cyclohexylamino)-2-
oxoethyl]-N-(3-methyl-4-oxo-3,4-dihydroquinazolin-
6
1
-yl)benzamide (9h). Yield 74%, white solid, mp 158-
59°C. IR spectrum, ν, cm : 3303 (N–H), 3067 (C–H,
N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-
–
1
N-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-2-
nitrobenzamide (9l). Yield 72%, light yellow solid,
aromatic), 2930 (C–H, CH ), 1740, 1657 br (C=O, amide),
1
2
1
–1
484 (Ar-H). H NMR spectrum, δ, ppm: 1.08–1.45 m
mp 143–144°C. IR spectrum, ν, cm : 3299 (N–H),
(
7H), 1.92–2.10 m (3H), 3.46 s (3H), 3.89–3.98 m (1H),
3098 (C–H, aromatic), 2931 (C–H, CH ), 1738, 1664 br
(C=O, amide), 1490 (Ar-H). H NMR spectrum, δ,
ppm: 1.11–1.43 m (7H), 1.94–2.05 m (3H), 3.46 s (3H),
3.89–3.96 m (1H), 5.83 d (J = 7.62 Hz, 1H), 6.36 s (1H),
2
1
5
7
7
.75 d (J = 7.69 Hz, 1H), 6.65 s (1H), 6.93–7.15 m (5H),
.27–7.34 m (4H), 7.40–7.55 m (1H), 7.65–7.67 m (1H),
.79 s (1H), 7.88 d (J = 8.17 Hz, 1H). HRMS: 529.19916.
7
7
.20–7.23 m (4H), 7.26–7.32 m (4H), 7.41–7.46 m (3H),
.88 s (1H), 7.90 d (J = 8.24, 1H). C NMR spectrum,
N-[1-(4-Chlorophenyl)-2-(cyclohexylamino)-2-
oxoethyl]-N-(3-methyl-4-oxo-3,4-dihydroquinazolin-
1
3
δ, ppm: 24.7, 24.8, 25.4, 33.2, 33.96, 49.0, 65.4, 121.5,
124.2, 127.1, 127.7, 128.0, 128.5, 128.6, 128.7, 129.5,
130.3, 132.6, 133.7, 135.8, 138.1, 145.2, 147.4, 160.3,
167.5, 167.9. HRMS: 540.2367.
6
1
-yl)benzamide (9i). Yield 74%, white solid, mp
84–185°C. IR spectrum, ν, cm : 3303 (N–H), 3089
–
1
(
(
C–H, aromatic), 2927 (C–H, CH ), 1738, 1661 br
C=O, amide), 1488 (Ar-H). H NMR spectrum, δ,
2
1
ppm: 1.07–1.43 m (7H), 1.88–2.08 m (3H), 3.48 s (3H),
.86–3.95 m (1H), 5.81 d (J = 7.58 Hz, 1H), 6.58 s
Biological activity. The synthesized quinazolin-
(3H)-one derivatives 9a–9l cytotoxicity was tested in
3
4
(
1H), 6.99–7.02 m (1H), 7.09–7.16 m (3H), 7.29–7.35 m
vitro using the method of viability staining by trypan blue
dye exclusion on HeLa cancer cells. The cells were seeded
in 96-well plates. Each concentration of the compounds
was seeded, and triplicate plates were used. Then, the
cells were incubated at 37°C in the atmosphere of CO2.
After 24 h, the medium was replaced by fresh medium
containing different concentrations of the synthesized
compounds. The percent viability and cytotoxicity were
calculated.
(5H), 7.40–7.52 m (1H), 7.59–7.65 m (1H), 7.91 d (J =
1
3
7
2
1
1
.57 Hz, 1H), 7.87 s (1H). C NMR spectrum, δ, ppm:
4.5, 28.9, 32.0, 33.3, 49.6, 57.8, 105.5, 122.3, 123.3,
28.1, 129.2, 130.2, 131.0, 134.9, 140.8, 143.4, 143.8,
43.9, 151.6, 157.2, 160.6, 171.4. HRMS: 529.19916.
N-[2-(Cyclohexylamino)-1-(4-methoxyphenyl)-2-
oxoethyl]-N-(3-methyl-4-oxo-3,4-dihydroquinazolin-
6
1
aromatic), 2933 (C–H, CH ), 1710, 1688, 1656 (C=O,
amide), 1507 (Ar-H). H NMR spectrum, δ, ppm: 1.06–
1
3
6
-yl)benzamide (9j). Yield 82%, white solid, mp 172–
–
1
73°C. IR spectrum, ν, cm : 3394 (N–H), 3063 (C–H,
Cytotoxicity of the samples was measured by micro-
culture tetrazolium (MTT) assay [10]. Stock solutions
of compounds 9a–9l were applied to make a series of
dilutions (20, 40, 60, and 80 μM) with a final DMSO
concentration of 0.1% and tested in quadruplicate in a
2
1
.40 m (7H), 1.90–2.00 m (3H), 3.48 s (3H), 3.73 s (3H),
.87–3.89 m (1H), 5.70 d (J = 7.47 Hz, 1H), 6.22 s (1H),
.72–6.73 d.d (J = 1.58 Hz, 8.54 Hz, 2H), 7.08–7.37 m
CO incubator. After 48 h of incubation, cell viability
2
(8H), 7.58–7.60 m (1H), 7.73 s (1H), 7.91 d (J = 7.47 Hz,
was determined by adding tetrazolium salt (Sigma) as a
1
H). HRMS: 525.2812.
3
cytotoxicity indicator. After 24 h of incubation, 10 mm
3
N-[2-(Cyclohexylamino)-2-oxo-1-(3,4,5-
of MTT (5 mg/cm ) in phosphate buffered saline (PBS)
trimethoxyphenyl)ethyl]-N-(3-methyl-4-oxo-3,4-
dihydroquinazolin-6-yl)benzamide (9k). Yield 85%,
were added to each well and incubated at 37°C for 4 h.
The medium with MTT was then flicked off, and the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 4 2020

724
SHANKARAIAH et al.
3
formed formazan crystals were solubilized in 100 mm of
DMSO. The absorbance at 570 nm was measured using
a micro-plate reader.
Said, E.G., and Kamel, G.M., Eur. J. Med. Chem.,
012, vol. 53, p. 141.
2
https://doi.org/10.1016/j.ejmech.2012.03.050
4
. Al-Omary, F.A., Abou-Zeid, L.A., Nagi, M.N.,
Habib, E.-S.E., Alaa, A.-M., El-Azab, A.S., Abdel-
Hamide, S.G., Al-Omar, M.A., Al-Obaid, A.M., and El-
Subbagh, H.I., Bioorg. Med. Chem., 2010, vol. 18,
p. 2849. https://doi.org/10.1016/j.bmc.2010.03.019
CONCLUSIONS
Novel quinazolin-4(3H)-one based dipeptide
derivatives have been synthesized, and their structures
have been characterized by IR, NMR and mass spectral
data. Concentration dependent cytotoxicity studies in
HeLa cells have revealed toxicity of all compounds
particularly 9b and 9g.
5
. Domling, A., Wang, W., and Wang, K., Chem.
Rev., 2012, vol. 112, p. 3083.
https://doi.org/10.1021/cr100233r
6
. Kilic-Kurt, Z., Bakar, F., and Olgen, S., Arch. Pharm.,
ACKNOWLEDGMENTS
2
015, vol. 348, p. 715.
https://doi.org/10.1002/ardp.201500109
P. Shankaraiah thanks to UGC, New Delhi, India for
providing research fellowship and Department of chemistry,
Osmania University for providing research facilities.
7. Montoya-Pelaez, P.J., Uh, Y.-S., Lata, C., Thomp-
son, M.P., Lemieux, R.P., and Crudden, C.M.,
J. Org. Chem., 2006, vol. 71, p. 5921.
CONFLICT OF INTEREST
https://doi.org/10.1021/jo060553d
No conflict of interest was declared by the authors.
8. Kulkarni, S.S., Singh, S., Shah, J.R., Low, W.-K., and
Talele, T.T., Eur. J. Med. Chem. 2012, vol. 50, p. 264.
https://doi.org/10.1016/j.ejmech.2012.02.001
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