InCl3-catalysed synthesis of 2-aryl quinazolin-4(3H)-ones and 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones and their evaluation as potential anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2012.06.003

A convenient and practical methodology for the synthesis of 2-aryl quinazolin-4(3H)-ones by the condensation of o-aminobenzamides with aromatic aldehydes under mild conditions using catalytic InCl₃ with good yields and high selectivities. This method has been extended for the synthesis of 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones which have potential applications in medicinal chemistry. Many of these compounds were evaluated for their anti-proliferative properties in vitro against four cancer cell lines and several compounds were found to be active. Further in vitro studies indicated that inhibition of sirtuins could be the possible mechanism of action of these molecules.

Full text of DOI:10.1016/j.bmcl.2012.06.003

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5063–5066
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
InCl3-catalysed synthesis of 2-aryl quinazolin-4(3H)-ones and 5-aryl
pyrazolo[4,3-d]pyrimidin-7(6H)-ones and their evaluation as potential
anticancer agents
Naveen Mulakayala a, , Bhaskar Kandagatla a, Ismail a, Rajesh Kumar Rapolu a, Pallavi Rao a,
⇑
Chaitanya Mulakayala b, Chitta Suresh Kumar b, Javed Iqbal a, Srinivas Oruganti a,
⇑
a Cosmic Discoveries, Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India
b Department of Biochemistry, Sri Krishnadevaraya University, Anatapur 515003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and practical methodology for the synthesis of 2-aryl quinazolin-4(3H)-ones by the conden-
sation of o-aminobenzamides with aromatic aldehydes under mild conditions using catalytic InCl3 with
good yields and high selectivities. This method has been extended for the synthesis of 5-aryl pyrazol-
o[4,3-d]pyrimidin-7(6H)-ones which have potential applications in medicinal chemistry. Many of these
compounds were evaluated for their anti-proliferative properties in vitro against four cancer cell lines
and several compounds were found to be active. Further in vitro studies indicated that inhibition of sir-
tuins could be the possible mechanism of action of these molecules.
Received 26 April 2012
Revised 22 May 2012
Accepted 1 June 2012
Available online 13 June 2012
Keywords:
2-Aryl quinazoline-4(3H)-one
2-Aminobenzamides
InCl3
Ó 2012 Elsevier Ltd. All rights reserved.
5-Aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones
antitumor activity
Quinazolinones occur widely in nature and exhibit a wide range
of biological activities viz. epidermal growth factor (EGF) receptors
of tyrosine kinase,1 anticancer,2 antiviral,3 anti-tubercular agents,4
treatment of diabetes and obesity,5 anti-inflammatory,6 insecti-
cidal and anti-microbial activity.7 Quinazolin-4(3H)-ones are used
as ligands for benzodiazepine and AMPA receptors in the CNS sys-
tem8 or as DNA binders.9 Naturally occurring alkaloids such as
luotonin A 1 from Peganum nigellastrum,10a 2-methyl-4(3H)-qui-
nazolinone 2 from Bacillus cereus,10b 2-(4-hydroxybutyl) quinazo-
Our interest in the use of Lewis acids for the construction of var-
ious heterocyclic motifs, prompted us to study the quinazolinone
cyclization using various Lewis acids. In particular, InCl3 has
emerged as a mild Lewis acid catalyst for a variety of organic trans-
formations.15–23 Compared to conventional Lewis acids, InCl3 has
advantages of higher stability in water, operational simplicity,
strong tolerance to oxygen and nitrogen containing substances
and functional groups and it can often be employed in catalytic
amounts.
Our initial effort was the cyclic condensation of o-aminobenz-
amide 7 with various aromatic aldehydes 8 as model substrates
for the preparation of 2-aryl quinazolin-4(3H)-ones 9 (Scheme 1).
We were delighted to find that o-aminobenzamide reacted with
aromatic aldehydes in the presence of 10 mol % of InCl3 to furnish
2-arylquinazolin-4(3H)-ones 9a–g24 in good to excellent isolated
yields (Table 1).
In the absence of InCl3, the condensation of o-aminobenzamide
and aromatic aldehyde did not proceed neither at room tempera-
ture nor at reflux temperature. We presume that the presence of
InCl3 promotes the cyclisation via an imine intermediate.
In our efforts to optimize the reaction conditions, we studied
the formation of 9a and have observed that yields were higher in
acetonitrile as compared to other solvents (Table 2). Reduction in
the amount of InCl3 from 10 to 1 mol % produced cyclized product
9a in diminished yields. This suggests that the use of 5–10 mol %
InCl3 in acetonitrile is critical to obtain the products in good yields.
lin-4-one
3
from Dichroa febrifuga,10c bouchardatine
4
from
Bouchardatia neurococca10d and EGFR Tyrosine Kinase inhibitors
(cellular trans-membrane tyrosine kinases that is over-expressed
in a significant number of human tumors) that is PD 153035 5
and Gefitinib 610e have Quinazolinone skeleton (Fig. 1).
In the last decade, several methods have been reported for the
syntheses of quinazoline11 and quinazolinone derivatives.12–14
However, most of the methods requires higher temperatures for
the condensation, which may preclude the presence of sensitive
functionalities. We were interested in identifying mild reaction
conditions for the construction of substituted quinazolinone deriv-
ative structurally present in complex alkaloids with multiple
functionalities.
⇑
Corresponding authors. Tel.: +91 40 665 71626; fax: +91 40 665 71158 (N.M.).
E-mail addresses: naveen071280@gmail.com, naveenm@ilsresearch.org (N.
Mulakayala).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.06.003

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N. Mulakayala et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5063–5066
Table 1
O
N
InCl3-catalyzed synthesis of 2-aryl quinazolin-4(3H)-one derivatives
O
N
Compound Aldehyde Product
Time
(min)
Yielda
(%)
NH
N
CHO
CHO
O
1
2
NH
NH
Luotonin A
2-Methyl-4(3H)-quinazolinone
9a
9b
30
45
88
94
N
O
O
OH
O
NH
CHO
NH
N
N
HN
N
O
3
4
F
2-(4-Hydroxybutyl)-4(3H)-
quinazolinone
F
Bouchardatine
CHO
F
NH
9c
9d
9e
60
40
45
87
92
92
HN
Cl
O
O
N
O
N
N
N
OCH3
CHO
N
OCH3
Cl
N
O
6
5
NH
NH
PD 153035
Gefitinib (Iressa)
N
O
O
Cl
O
N
N
NH
NH
O
O
O
O
CHO
N
N
S
N
N
N
N
N
N
O
N
O
Cl
8
7
Cl
Acetildenafil
Sildenafil
CHO
Figure 1. Bioactive compounds containing quinazolin-4(3H)-one and pyrazolo[4,3-
d]pyrimidin-7(6H)-one skeleton.
NH
NH
9f
45
60
92
88
N
O
Br
Br
O
CHO
CHO
O
InCl3
NH
NH2
9g
MeCN,RT
N
N
NH2
R
NO2
NO2
R
7
8
9
a
Isolated yield.
Scheme 1. InCl3-catalyzed reaction between o-amino-benzamide and aromatic
aldehyde.
Table 2
Optimisation of InCl3-catalyzed reaction of 2-phenyl quinazolin-4(3H)-one 9a
The catalytic activity of InCl3 in the synthesis of 2-aryl quinaz-
olin-4(3H)-ones prompted us to investigate its application for the
synthesis of other therapeutically relevant scaffolds. In this regard,
we employed the InCl3 methodology for the construction of 5-aryl
pyrazolo[4,3-d]pyrimidin-7(6H)-one systems which are the key
structural motifs of important drugs like Sildenafil 5 and acetilde-
nafil 6 (Fig. 1).
The catalytic activity of other Lewis acids like AlCl3, TiCl4, BF3-
OEt2, FeCl3, CuCl2 in the synthesis of 2-aryl quinazolin-4(3H)-ones
give moderate yields of the desired product (Table 3).
Entry
Mol % of InCl3
Solvent
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
8
7
10
5
10
5
10
10
10
10
CH3CN
CH3CN
MeOH
MeOH
CH2Cl2
CHCl3
iPrOH
EtOAc
rt
rt
rt
rt
rt
rt
rt
rt
0.5
1
2
4
6
9
12
18
92
88
86
84
67
65
62
60
a
Isolated yield.
We observed that 4-amino-1-methyl-3-propylpyrazole-5-car-
boxamide25 reacted with aromatic aldehydes in the presence of
10 mol % of InCl3 at room temperature to furnish 5-aryl pyrazol-
o[4,3-d]pyrimidin-7(6H)-ones 11a–h24 (Scheme 2) in good to
excellent isolated yields (Table 4).
Having the optimized reaction condition for the preparation of
5-aryl pyrazolo [4,3-d]pyrimidin-7(6H)-ones and pyrazolo[4,3-
d]pyrimidin-7(6H)-ones in hand we then examined the generality
and scope of this methodology. Thus a variety of aromatic alde-
hydes 8 were reacted with amino benzamide 7 and substituted
pyrazole-5-carboxamide 10 in MeCN at room temperature using
InCl3 and results are presented in Tables 1–3. The reaction pro-
ceeded well in all these cases and the substituents like F, Cl, Br,
OMe, Me, NO2 and –OCHF2 present in the aromatic aldehydes 8
were well tolerated. The reaction appeared to be clean as no forma-
tion of side product was observed and the desired product 9 & 11
were isolated in good to excellent yield in each case. All the com-
pounds synthesized were well characterized by spectral (NMR, MS
and IR) data.

N. Mulakayala et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5063–5066
5065
Table 3
Optimisation of the catalyst for the preparation of 2-phenyl quinazolin-4(3H)-one 9a
Table 4
InCl3-catalyzed synthesis of pyrazolo[4,3-d] pyrimidin-7(6H)-ones
Entry
Mol %
Lewis acid
Temp (°C)
Time (h)
Yielda (%)
Compound Aldehyde
Product
Time
(min) (%)
Yielda
1
2
3
4
5
6
8
7
10
5
InCl3
InCl3
rt
rt
rt
60
rt
rt
rt
rt
0.5
1
4
4
6
6
6
6
92
88
66
70
53
50
54
45
CHO
O
10
10
10
10
10
10
AlCl3
AlCl3
TiCl4
FeCl3
BF3.OEt2
CuCl2
N
N
N
N
N
N
N
N
NH
N
N
N
N
N
N
N
N
11a
40
45
45
50
40
45
65
90
92
90
92
91
94
91
N
O
N
O
N
O
N
O
N
O
N
O
N
O
N
Cl
Cl
a
CHO
Isolated yield.
NH
11b
O
O
N
H2N
CHO
InCl3
Br
NH
N
N
Br
Cl
N
+
H2N
MeCN,RT
N
CHO
R
R
NH
11c
10
8
11
Cl
Scheme 2. InCl3-catalyzed synthesis of 5-aryl pyrazolo [4,3-d]pyrimidin -7(6H)-
ones.
CHO
NH
11d
Based on the precedence of known anticancer activity of known
quinazolin-4(3H)-one10e derivatives we were interested to test
anticancer properties in vitro. We evaluated our compounds for
their anti-proliferative properties in vitro against a number of can-
cer cell lines for example, human chronic myeloid leukemia cells
(K562), human colon carcinoma cells (Colo-205), and human
breast cancer cell line (MDA-Mb 231MR32). The test compounds
were examined at various concentrations in a MTT (3-(4,5-di-
methyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay
and the IC50 values obtained for each compounds are summarized
in Table 5. Harmine, a member of b-carboline family of compounds
showed cytotoxicity against HL60 and K562 cell lines26 was used
as a reference compound. While most of these compounds showed
inhibition of leukemia cell growth as reflected by their IC50 values
the good results however were obtained using compounds 9b,
OCH3
OCH3
CHO
NH
11e
CH3
CH3
Br
CHO
NH
11f
Br
CHO
OH
NO2
NH OH
9d,11a, 11b, 11c, 11h (IC50 <19
lM, Table 5). Interestingly, except
NO2
11g
11h
compounds 9e and 11b all other compounds (IC50 <20
l
M, Table 5)
were found to be active against colon carcinoma cells and except
compounds 9a, 9d, 9f, 11a, 11b, 11e and 11g rest of the compounds
(IC50 <45 lM, Table 5) showed good activities against breast cancer
cells. Overall, compound 11h possessing a 4-hydroxy-3-difluoro-
CHO
OH
NH
methoxy phenyl group at C-5 position was found to be promising
CHF2
O
75
88
(IC50 ꢀ7–25
lM, Table 5).
OH
CHF2
In order to understand the mechanism of action some of the
compounds were tested for their inhibitory potential against sirtu-
ins. Being considered as important targets for cancer therapeutics
sirtuins (class III NAD-dependent deacetylases) are shown to up-
regulated in various types of cancer.27 Inhibition of sirtuins allows
re-expression of silenced tumor suppressor genes, leading to re-
duced growth of cancer cells. The activity of test compounds was
determined using Sirt1 fluorescence activity assay using suramin,
a known inhibitor of Sirt1 as a reference compound. At the concen-
O
a
Isolated yield.
amino acid residues, for example, Gly261, Ala262, Ile270, Pro271,
Phe273, Arg274, Gln345, Ile347, and His363 were found to play
key roles in this interaction with the overall binding energy of
À9.6 Kcal/mol indicating that molecule 11h interacts well with
this protein.
tration of 10 lM compounds 9b, 11f, 11g and 11h showed 48%,
In summary, we have developed a convenient methodology for
the synthesis of 2-aryl quinazolinone derivatives in high yields via
the cyclisation of o-aminobenzamide with aromatic aldehydes
using InCl3 catalyst. This novel approach for the synthesis of 2-aryl
quinazolin-4(3H)-ones and 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-
ones is convenient, mild, cost-effective and practically free of chro-
matographic separation.
59%, 61%, and 63% inhibition, respectively, in compared to sura-
min’s 79% inhibition indicating that the anticancer properties of
these molecules are possibly due to their sirtuin inhibiting proper-
ties. To understand the nature of interactions between these com-
pounds and the Sir1 protein a molecular docking simulation study
was carried out using a representative compound 11h (Fig. 2). The
three dimensional model of hSirt1 (NCBI gi no: 7555471, 200–500
amino acid residues) was developed by homology modeling using
the templates PDB: 2HJH and PDB: 1J8F in the Modeller9v6. Nine
General experimental procedure:To a solution of aromatic alde-
hyde (1.0 mmol) in acetonitrile, o-aminobenzamide (1.0 mmol)

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N. Mulakayala et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5063–5066
Table 5
References and notes
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Figure 2. Docking of compound 5b into the active site of hSirt1.
and InCl3 (10 mol %) were added at room temperature and the
reaction mixture was stirred till the completion of the starting
materials (indicated by TLC). After filtration through celite, the sol-
vent was evaporated under reduced pressure and the crude prod-
uct was triturated with 10% diethyl ether in hexane to obtain the
pure product. All the compounds isolated were characterized by
24. Analytical data of selected compounds: Compound 9a: mp 237–238 °C; 1H NMR
(DMSO-d6, 400 MHz): d 12.6 (br, 1H), 8.18–8.00 (m, 3H), 7.85–7.39 (series of m,
6H); 13C NMR (100 MHz, DMSO-d6): d 162.7, 152.8, 149.0, 135.0, 133.0, 131.8,
129.0, 128.2, 127.7, 127.0, 126.3, 121.3; Mass (ESI): m/z = 222 [M+H]+;
Compound 11h: mp 276–278 °C; 1H NMR (400 MHz, CDCl3+DMSO d6):
d
11.56 (br s, 1H), 9.48 (s, 1H), 7.74 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.18 (d,
J = 8.4 Hz, 1H), 6.70 (t, J = 75.6 Hz, 1H), 4.25 (s, 3H), 2.88 (t, J = 7.2 Hz, 2H), 1.84
(q, J = 7.2, 14.0 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3+DMSO d6,
100 Hz): d 155.1, 149.3, 148.7, 146.0, 140.7, 138.2, 131.1, 124.5, 121.8, 118.9,
116.3, 113.3, 38.0, 27.5, 22.1, 13.9; Mass (ESI): m/z = 349.1 [MÀH]+.
25. Haning, H.; Niewohner, U.; Schenke, T.; Lampe, T.; Hillisch, A.; Bischoff, E.
Bioorg. Med. Chem. Lett. 2005, 15, 3900.
13
1H NMR, C NMR and Mass.
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N.M. and C.M. thanks CSIR, New Delhi, for the award of
fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.bmcl.2012.06.003.