Synthesis and antitumor activity of 1,2,4-triazolo[1,5-a]quinazolines

Article abstract of DOI:10.14233/ajchem.2014.16849

Cytotoxicity of 22 triazoloquinazoline compounds was evaluated in vitro against medulloblastoma (Daoy), hepatocellular carcinoma (HepG2) and melanoma (SK-MEL28) cell lines. This study showed that compounds 17, 18 and 21 exhibited remarkable in vitro cytotoxicity against all tested cell lines. Moreover, it was found that compounds 10, 17, 6, 18, 21, 7 and 19 are active against Daoy cell line with IC₅₀ values of 1.29, 2.93, 5.53, 6.14, 6.59, 9.71 and 19 μg/mL, respectively, as compared to that of the reference drug dasatinib (7.26 μg/mL). The HepG2 cell line was affected by compounds 17, 6, 21, 19 and 18 with IC₅₀ values of 4.52, 11.33, 14.69, 16.96 and 24.49 μg/mL, respectively, relative to that of dasatinib (8.21 μg/mL). In addition, compounds 17, 18 and 21 have shown significant antiproliferative activity against SK-MEL28 with IC₅₀ values of 3.88, 13.85 and 14.96, respectively, relative to an IC₅₀ value of 23.83 μg/mL of the reference drug. It is worth mentioning that compounds 6, 10, 17, 18 and 21 are more potent than the reference drug against Daoy cell. In the same manner, 17, 18 and 21 revealed higher cytotoxicity than dasatinib against SK-MEL28 cells. Notably, compound 17 was also more potent than the reference drug against HepG2 cells. In the term of selectivity, compound 10 was found to possess the highest selectivity, as it was active only against Daoy cells. These compounds could be useful as templates for further development through their structural modification to design more potent antitumor agents.

Full text of DOI:10.14233/ajchem.2014.16849

Asian Journal of Chemistry; Vol. 26, No. 7 (2014), 2173-2176
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16849
Synthesis and Antitumor Activity of 1,2,4-Triazolo[1,5-a]quinazolines
1
3
1
R. AL-SALAHI , M. MARZOUK1,2,*, A.E. ASHOUR and I. ALSWAIDAN
1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
2Chemistry of Natural Products Group, Center of Excellence for Advanced Sciences, National Research Center, Dokki, 12622, Cairo, Egypt
3Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
*Corresponding author: E-mail: msmarzouk@yahoo.co.uk
Received: 10 December 2013;
Accepted: 16 January 2014;
Published online: 22 March 2014;
AJC-14985
Cytotoxicity of 22 triazoloquinazoline compounds was evaluated in vitro against medulloblastoma (Daoy), hepatocellular carcinoma (HepG2)
and melanoma (SK-MEL28) cell lines. This study showed that compounds 17, 18 and 21 exhibited remarkable in vitro cytotoxicity against all
tested cell lines. Moreover, it was found that compounds 10, 17, 6, 18, 21, 7 and 19 are active against Daoy cell line with IC50 values of 1.29,
2.93, 5.53, 6.14, 6.59, 9.71 and 19 µg/mL, respectively, as compared to that of the reference drug dasatinib (7.26 µg/mL). The HepG2 cell line
was affected by compounds 17, 6, 21, 19 and 18 with IC50 values of 4.52, 11.33, 14.69, 16.96 and 24.49 µg/mL, respectively, relative to that
of dasatinib (8.21 µg/mL). In addition, compounds 17, 18 and 21 have shown significant antiproliferative activity against SK-MEL28 with
IC50 values of 3.88, 13.85 and 14.96, respectively, relative to an IC50 value of 23.83 µg/mL of the reference drug. It is worth mentioning that
compounds 6, 10, 17, 18 and 21 are more potent than the reference drug against Daoy cell. In the same manner, 17, 18 and 21 revealed higher
cytotoxicity than dasatinib against SK-MEL28 cells. Notably, compound 17 was also more potent than the reference drug against HepG2
cells. In the term of selectivity, compound 10 was found to possess the highest selectivity, as it was active only against Daoy cells. These
compounds could be useful as templates for further development through their structural modification to design more potent antitumor agents.
Keywords: Antitumor, 1,2,4-Triazolo[1,5-a]quinazolines, Daoy, HepG2, SK-MEL28.
1,2,4-triazoloquinazoline moiety as anticancer is relatively
INTRODUCTION
unexplored. This work has done in continuation of a progra-
Development of anticancer molecule is always a fasci-
mme a part of our interest in the search for anticancer agents.
nating challenge in the field of cancer chemotherapy. Many
Herein we report the biological activity of the synthesized
recent research programms are ongoing globally to identify
and design new lead compounds. Cancer is continuing to be a
compounds (1-22) as anticancer agents.
major health problem in developed as well as undeveloped
EXPERIMENTAL
countries1-9. Although major advances have been made in the
Uncorrected melting points were determined on a Mettler
FP 62 apparatus using an open glass capillaries. The IR (KBr,
νmax, cm-1) spectra were recorded on a Perkin Elmer FT-IR
Spectrum BX system. NMR spectra were recorded on a Bruker
AMX 500 spectrometer in DMSO-d6 and reported as δ ppm
values relative to TMS at 500 and 125 MHz for H and C
NMR, respectively. Mass spectra were measured on anAgilent
6410 TSQ system connected to Agilent 1200 HPLC interface
(samples were infused in MeOH). Follow up of the reactions
and checking the purity of compounds was made by TLC on
DC-Mikrokartenpolygram SIL G/UV254, from the Macherey-
Nagel Firm, Duren Thickness: 0.25 mm. Column chromato-
graphy was conducted on silica gel (ICN Silica 100-200, active
60 Å).
chemotherapeutic management of some patients, discovering
and designing of new lead structures still employed as one of
the most urgent research areas in contemporary medicinal
chemistry.Although a numerous number of biologically active
compounds have been investigated, however many of them
are not suitable for therapeutic use due to their toxic, carcino-
genic and mutagenic properties. Nowadays, it is possible to
make structural modifications of active compounds, in order
to synthesize new derivatives with improvement of therapeutic
activity and reduction of their toxicity10. In our previous work,
we have reported the synthesis of different 1,2,4-triazolo[1,5-
a]quinazolines types and evaluated their biological activities
as antimicrobial, antiviral, cytotoxic, antiinflammatory and
1
13
adenosine antagonist agents11-16
.
Preparation of compounds 21 and 22: At room tempe-
rature, an amount of 1.2 mmol from potassium carbonate was
In spite of various triazoloquinazolines having been
prepared and their significance studied, the investigation of

2174 Al-Salahi et al.
Asian J. Chem.
R
O
N
Ph
R
N
O
N
N
N
N
R1
N
N
N
N
N
N
N
N
S
R
Cl
R : O-Ph
R : S-CH3
(16)
(17)
R : ethoxyl
R : phenyl hydrazide (20)
(19)
R : S-CH3, R1 :4-Br-Ph, (21)
R : S-CH3, R1 : Bn,
(22)
R : SO2-CH3 (18)
R
R
Ph
O
N
N
N
N
N
N
N
N
1
N
R
N
R1
NH
N
R
O
X
S
R : O-Ph, R
1
: P-nitrobenzyl
(7)
(8)
(9)
R : O-Ph, R1 : H X: O (1)
R : S-CH3, R1 : H X: O (2)
R : O-Ph, R1 : CH3 X: O (3)
R : SO2-CH3 R1: H X: O (4)
R : O-Ph, R1: ethyl
R : ethyl
R : allyl
(13)
(14)
R : phenyl (15)
R : O-Ph, R1: allyl
R : SO2-CH3, R1: P-nitrobenzyl (10)
R: SO2-CH3, R1: ethyl
R: SO2-CH3, R1: allyl
(11)
(12)
R: O-Ph
R: S-CH3 R1 : H X: S (6)
R1: H X : S (5)
Scheme-I: Synthesized triazoloquinazolines (1-22)
added portion-wise to a solution of 17 (1 mmol) in DMF
(5 mL) over a period of 10 min. After stirring for 20 min, the
appropriate 3-aralkyl(aryl)-thioxoquinazolin-4-ones (1.3
mmol) was added in portion-wise and the reaction mixture
was stirred for 18 h at room temperature. The mixture was
poured into ice/water and then the precipitate was filtered off,
washed with water and dried. Analytically pure products 21
and 22 were obtained after recrystallization from DMF.
3-(4-Bromophenyl)-6-methyl-2-(2-methylsulfanyl-
[1,2,4]triazolo[1,5-a]quinazolin-5-ylsulfanyl)-3H-quinazolin-
4-one (21): White amorphous powder; (yield: 50 %), m.p.
290 °C IR (KBr, νmax, cm-1): 1697 (C=O). 1H NMR (DMSO-
d6): δ ppm 8.36 (1H, br d, J = 7.5 Hz, H-7'), 8.21 (2H, m, H-9/
8), 8.04 (1H, br s, H-5'), 7.99 (2H, d, J = 8 Hz, H-2"/6"), 7.60
(2H, br s, H-6/7), 7.52 (1H, d, J = 8.5 Hz, H-8'), 7.44 (2H, d,
J = 8 Hz, H-3"/5"), 2.73 (3H, s, S-CH3), 2.42 (3H, s, CH3-6');
13C NMR (DMSO-d6): δ ppm 170.5 (C-2'), 161.7 (C-2), 160.3
(C-4'), 154.2 (C-5), 151.4 (C-9a), 148.1 (C-8a), 138.3 (C-6'),
136.2 (C-3a), 136.0 (C-8), 133.4 (C-7'), 132.1 (C-1"), 128.5
(C-3"/5"), 127.1 (C-6), 126.5 (C-5'), 126.3 (C-8'), 126.2 (C-
5a), 123.4 (C-2"/6"), 120.5 (C-4'a), 117.8 (C-4"), 116.4 (C-
7), 115.3 (C-9), 20.7 (CH3-6'), 13.7 (-S-CH3); EI-MS, m/z (%):
560 (M•+, 78). Anal. calcd. for C25H17N6OS2Br (560.01).
3-Benzyl-6-methyl-2-(2-methylsulfanyl-[1,2,4]triazolo[1,5-
a]quinazolin-5-ylsulfanyl)-3H-quinazolin-4-one (22): White
t, J = 8 Hz, H-8), 8.08 (1H, br s, H-5'), 7.73 (2H, br s, H-6/7),
7.58 (1H, d, J = 8.5 Hz, H-8'), 7.14 (2H, d, J = 8.5 Hz, H-2"/
6"), 7.06 (3H, br s, H-3",4",5"), 5.50 (2H, s, -CH2-Ar), 2.65
(3H, s, -S-CH3), 2.51 (3H, s, CH3-6'); 13C NMR (DMSO-d6): δ
ppm 164.6 (C-2'), 161.5 (C-2), 160.5 (C-4'), 154.5 (C-5), 151.8
(C-9a), 148.4 (C-8a), 144.8 (C-1"), 138.6 (C-6'), 136.4 (C-
3a), 136.2 (C-8), 133.7 (C-7'), 128.1 (C-3"/5"), 127.3 (C-6),
126.8 (C-2"/6", 5'), 126.6 (C-4"), 126.2 (C-8'), 126.1 (C-5a),
120.3 (C-4'a), 116.7 (C-7), 115.1 (C-9), 49.1 (-CH2-Ar), 20.9
(CH3-6'), 13.5 (-S-CH3). EI-MS, m/z (%): 496 (M•+, 72).Anal.
calcd. for C26H20N6OS2 (413.11).
(3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium
bromide) (MTT) was purchased from SigmaAldrich (St Louis,
MO, USA). DMEM/high glucose FBS and penicillin/strepto-
mycin were obtained from Hyclone Laboratories (Logan, UT,
USA).
Cell lines: Three tumor cell lines were tested in this study,
namely human medulloblastoma (Daoy), human hepato-
cellular carcinoma (HepG2) and human melanoma (SK-Mel-
28). HepG2 cells were cultured in DMEM/high glucose
supplemented with 10 % FBS, 2 mM L-glutamine and 1 %
penicillin/streptomycin. Daoy and SK-Mel-28 were cultured
in DMEM/F12 supplemented with 10 % FBS, 2 mM L-glutamine
and 1 % penicillin/streptomycin.
Screening of antiproliferative activity of compounds
by MTT assay: The new compounds were evaluated at the
Cell Culture Laboratory, College of Pharmacy, King Saud
University, in a primary three cell line-one concentration
amorphous powder; (yield: 52 %), m.p. 270 C IR (KBr, νmax
,
cm-1): 1721 (C=O). 1H NMR (DMSO-d6): δ ppm 8.28 (1H, br
d, J = 8 Hz, H-7'), 8.19 (1H, br d, J = 8 Hz, H-9), 8.13 (1H, br

Vol. 26, No. 7 (2014)
Synthesis and Antitumor Activity of 1,2,4-Triazolo[1,5-a]quinazolines 2175
(25 µg/mL) anticancer assay against the previously mentioned
cell lines. The cytotoxic effect of the newly synthesized
compounds were evaluated by testing the capacity of the
reducing enzymes present in viable cells to convert MTT to
formazan crystals as previously described17, with some
modifications. Briefly, cells cultured in complete medium were
seeded into 96-well microtiter plates (in quintuplicates) with
2 × 104 cells per well and incubated at 37 °C under a humidified
atmosphere of 5 % CO2 for 24 h. The cell medium in test wells
were then changed to serum free medium (SFM) containing
25 µg/mL of the tested compounds, while the cell medium in
control wells were changed to serum free medium containing
an equivalent volume of solvent (dimethyl sulfoxide). After
incubation at 37 °C for 24 h, serum free medium in control
and test wells were replaced by 100 µL/well of MTT; 0.5 mg/
mL) in phosphate-buffered saline (PBS) and incubated at 37
°C for an additional 3 h. MTT solution were removed and the
purple formazan crystals formed at the bottom of the wells
were dissolved using 100 µL isopropyl alcohol/well with
shaking for 1 h at room temperature. The absorbance at 549
nm was read on a microplate reader (ELX 800; Bio-Tek Instru-
ments, Winooski, VT, USA). Cell death was estimated with
the following formula18:
S-CH3 in the structures of 21 and 22 was proved by the singlet
at 2.73 and 2.65 ppm together with their own C-signals as
13
the most upfield characteristic position at 13.7 and 13.5.Another
key 13C-signal was C-5 that interpreted at δ ≈ 154 ppm due to
the presence of 5-S-quinazolin-4-one function (21, 22). As
well, methylquinazolin-4-one moiety was deduced from its
AMX-spin coupling system for H-7', H-5' and H-8' at about
8.3 (br d, J = 8 Hz), 8 (1H, br s), 7.5 (1H, d, J = 8.5 Hz), respec-
tively. This moiety was interpreted in the 13C-spectrum in the
form of nine resonances including three characteristic signals
at 170.5 (C-2'), 160.3 (C-4') and 20.7 (CH3-6') in case of 21,
which assigned at 164.6 (C-2'), 160.5 (C-4') and 20.9 (CH3-
6') in 22. The difference between the NMR spectra of both
compounds was summarized in the form of presence the
characteristic signals for N-p-bromophenyl in case of 21 and
N-benzyl in the structure of 22. Final confirmation of their
1
structures was obtained from the comparison of all H and
13C resonances with our assigned data for structural related
triazoloquinazoline derivatives14,24
.
The in vitro antitumor activity of compounds 1-22 was
evaluated by testing their cytotoxic effects using the MTT assay
against Medulloblastoma (Daoy), Hepatocellular carcinoma
(HepG2) and Melanoma (SK-MEL28) cells17. The IC50-values
represented the drug concentration (µg/mL) required to inhibit
cell growth by 50 %, are summarized in Table-1 as a common
parameter for cytotoxicity of the investigated compounds. As
indicated in Table-1, some target molecules have higher or
comparable cytotoxicity with that of Dasatinib against the
cancer cell lines examined, with IC50 values in the range of
1.29-14.96 µg/mL. Compounds 6, 10, 17, 18 and 21 have
shown the highest cytotoxicity against Medulloblastoma with
the IC50 values of 5.53, 1.29, 2.93, 6.14 and 6.59 µg/mL in
regards to the reference drug IC50 (7.26 µg/mL). For hepato-
cellular carcinoma(HepG2) cell line, the most active compound
(17) was investigated to exhibit higher inhibition concentration
and a lower IC50 with respect to Dasatinib. The target products
17, 18 and 21 were found to possess the highest activity against
Melanoma (SK-MEL28) with their IC50 values of 3.88, 13.85
and 14.96, respectively. Compound 19 was exhibited activity
against Medulloblastoma (Daoy), Hepatocellular carcinoma
(HepG2) cells but not more potent than the respected reference
drug. Similarly, compound 6 was less potent then Dasatinib
against hepatocellular carcinoma (HepG2) cell. Throughout
our study we have noticed that structure modifications in the
parent compounds (1-4) have led to remarkable cytotoxicity
depending on the structure change and examined cell lines. In
compounds 7-12, regioselective N-alkylation of lactam has
demonstrated noticeable activity such as compound 7 and 10
that displayed a significant IC50 values (Table-1) in comparison
with their parents and Dasatinib as well. However, 10 represents
one of the most populated compound obtained during this
study. Furthermore, conversion of lactam in compounds 2 and
4 into an imidoyl chloride function (17, 18) has influenced
positively cytotoxic effect and more significant on the activity
profiles, this may be attributed to the increase of the lipophi-
licity. Whereas, further chemical transformation of chlorine
in 16 into ethoxy (19) was offered advantageous in the activity.
The S-arylation of 17 with N-(4-bromophenyl)thioxoquina-
zoline to form 21 has led to decrease the activity and in case
% Specific death = A(untreated cells)-A(treated cells)/
A(untreated cells) × 100
The dose response curves of the compounds effecting
≥ 50 % inhibition in one-dose prescreening for each cell line
were established with concentrations of 25, 12.5, 6.25, 3.125,
1.56 and 0.78 µg/mL and the concentrations causing 50 %
cell growth inhibition (IC50) were calculated. The cytotoxic
activity of the anticancer drug dasatinib, a potent multi-targeted
kinase inhibitor of BCR-ABL and SRC family kinases19,
against the three cell lines was examined at the same concen-
trations of tested compounds and utilized as a standard for
comparative purposes.
RESULTS AND DISCUSSION
In previous papers20-24, we have described the synthetic
routes for the triazoloquinazoline derivatives 1-20 (Scheme-
I). The corresponding 21 and 22 were prepared by reaction of
compound 17 with appropriate 3-aralkyl(aryl)-thioxoquina-
zolin-4-ones in dimethylformamide at room temperature. The
structures of 21 and 22 were established on the basis of IR,
MS and confirmed by 1H- and 13C NMR spectral data (splitting
pattern, δ- and J-values and comparison with literature of
structural related compounds). As it was explained in previous
article24, the 1,2,4-triazolotricyclic main structural nucleus was
proved by the assignment of its four one proton 1H-signals as
two dd (or br d) resonances with Jortho(7.5-8.5 Hz) and Jmeta(1-
2 Hz) assignable for H-9 and H-6 and two td (or br t) resonances
with Jortho and Jmeta for H-8 and H-7, respectively. Moreover,
13C NMR spectra proved the main tricyclic moiety through
characteristic nine resonances including the most downfield
key signal of C-2 assigned at ≈ 165 ppm in 2-phenoxy deriva-
tives that was observed relatively upfield at ≈ 160-161 in case
of 2-methylsulfonyl function and in 20 and 21 at about 160.5
ppm due to the stronger -R and -I (deshielding) effect of O-
phenoxy than -SO2 or S-CH3 (20 & 21)24. The presence of one

2176 Al-Salahi et al.
Asian J. Chem.
of 22 (N-benzyl) it was completely abolished. However the
same behaviour in case of compound 20 has demonstrated
with respect to 16. Thionation product 6 has showed high
significant and remarkable cytotoxic activity in regard to its
parent 2; this could be attributed to the enhancing of the
lipophilicity comparable to that of parent 2.
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TABLE-1
in vitro CYTOTOXICITY OF COMPOUNDS
AGAINST CANCER CELL LINES
Daoy1
Inhibition*
(%)
13.99
0
14.52
17.92
21.24
75.13
59.48
31.3
HepG22
Inhibition*
(%)
30
9.94
0
SK-MEL283
Inhibition*
**
Cpd.
Nr.
**
**
IC50
IC50
IC50
(%)
0
0
19.82
0
12.63
36.4
42.96
27.21
0
37.2
0
0
nt#
nt#
nt#
nt#
nt#
1
2
nt#
nt#
nt#
nt#
3
nt#
15.71
43.7
54.03
14.62
22.21
9.94
43.5
8
24.5
14.72
28.23
16.5
9.87
90.87
51.68
57.86
14.63
84.67
24.5
72.03
nt#
nt#
4
nt#
nt#
nt#
5
5.53
9.71
nt#
11.33
nt#
6
nt#
nt#
7
nt#
nt#
8
0
nt#
nt#
nt#
9
62.78
18.42
47.57
7.46
48.92
48.28
36.37
93.91
94
58.23
28.92
94.08
47.57
76.6
1.29
nt#
nt#
10
11
12
13
14
15
16
17
18
19
20
21
22
D
nt#
nt#
nt#
nt#
nt#
nt#
nt#
nt#
13.27
38.46
0
nt#
nt#
nt#
nt#
nt#
nt#
nt#
nt#
nt#
0
nt#
2.93
6.14
19.08
nt#
4.52
24.49
16.96
nt#
93.16
91.36
29.03
11.24
91.87
0
3.88
13.85
nt#
nt#
6.59
14.69
14.96
nt#
nt#
nt#
7.26
8.21
51.95
23.83
18. T. Abdollahi, N.M. Robertson, A. Abdollahi and G. Litwack, Cancer
Res., 63, 4521 (2003).
*Per cent inhibition of cell survival at 25 µg/mL, relative to control
(DMSO-treated cells); ** IC50 is expressed as µg/ml; # nt: Not tested; D
= Dasatinib; 1Medulloblastoma cell line. 2Hepatocellular carcinoma cell
line. 3Melanoma cell line
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ACKNOWLEDGEMENTS
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The authors extend their appreciation to the Deanship of
Scientific Research at King Saud University for funding this
work through research group no RGP- VPP-291.