One-pot regioselective synthesis of tetrahydroindazolones and evaluation of their antiproliferative and Src kinase inhibitory activities

Article abstract of DOI:10.1016/j.bmcl.2011.10.124

A number of 2-substituted tetrahydroindazolones were synthesized by three-component condensation reaction of 1,3-diketones, substituted hydrazines, benzaldehydes, and Yb(OTf)₃ as a catalyst in [bmim][BF₄] ionic liquid using a simple,

Full text of DOI:10.1016/j.bmcl.2011.10.124

Bioorganic & Medicinal Chemistry Letters 22 (2012) 410–414
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
One-pot regioselective synthesis of tetrahydroindazolones and evaluation
of their antiproliferative and Src kinase inhibitory activities
V. Kameshwara Rao a, Bhupender S. Chhikara b, Rakesh Tiwari b, Amir Nasrolahi Shirazi b,
a,
Keykavous Parang b, , Anil Kumar
⇑
⇑
a Department of Chemistry, Birla Institute of Technology and Science, Pilani 333031, Rajasthan, India
b Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of 2-substituted tetrahydroindazolones were synthesized by three-component condensation
Received 26 August 2011
Revised 27 October 2011
Accepted 31 October 2011
Available online 7 November 2011
reaction of 1,3-diketones, substituted hydrazines, benzaldehydes, and Yb(OTf)3 as
a catalyst in
[bmim][BF4] ionic liquid using a simple, efficient, and economical one-pot method. The synthesized tet-
rahydroindazolones were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29),
human ovarian adenocarcinoma (SK-OV-3), and c-Src kinase activity. 3,4-Dichlorophenyl tetrahydroin-
dazolone derivative (15) inhibited the cell proliferation of HT-29 and SK-OV-3 cells by 62% and 58%,
respectively. 2,3-Diphenylsubstituted tetrahydroindazolone derivatives, 19, 25, and 33, inhibited the cell
Keywords:
Antiproliferative
Cell proliferation
Inhibitor
proliferation of HT-29 cells by 65–72% at a concentration of 50
showed modest inhibition of c-Src kinase where 4-tertbutylphenyl- (32) and 3,4-dichlorophenyl- (13)
derivatives showed the inhibition of c-Src kinase with IC50 values of 35.1 and 50.7 M, respectively.
lM. In general, the tetrahydroindazolones
l
Src kinase
Ó 2011 Elsevier Ltd. All rights reserved.
Tetrahydroindazolones
Multi-component reactions (MCRs) have emerged as a powerful
synthetic strategy in organic and medicinal chemistry to generate
structurally diverse libraries of drug-like molecules.1 MCRs offer
significant advantages over conventional linear-type syntheses,
such as being rapid and one-pot reactions without the need to gen-
erate and purify intermediates.
to exhibit potent cytotoxicity and anti-tumor activity.7,8 We
hypothesized that incorporation of crucial structural features of
CA4 and THIs may generate lead compounds with anticancer prop-
erties (Fig. 2).
Furthermore, phenylpyrazolopyrimidine derivatives, such as
PP1 and PP210 have been reported as inhibitors of the Src family
of tyrosine kinases (SFKs) that play prominent roles in multiple sig-
nal transduction pathways, which involve cell growth and differen-
tiation. The nine members of non receptor SKFs (Src, Yes, Lck, Fyn,
Lyn, Fgr, Hck, Blk, and Yrk) share a great deal of structural homol-
ogy and are present in the cytoplasm.11 The expression of Src tyro-
sine kinase, the prototype of SFKs, is frequently elevated in a
number of epithelial tumors compared with the adjacent normal
tissues. Src reduces cancer cell adhesions and facilitates their
motility,12 thus it is a key modulator of cancer cell invasion and
Tetrahydroindazolones (THIs) have a broad spectrum of biolog-
ical and pharmacological activities.2 Compounds with indazoles
and indazolones scaffolds have been reported to exhibit herbi-
cidal,3 anti-inflammatory,4 anticancer,5 and antituberculosis activ-
ities.6
A tetrahydroindazolone scaffold containing SNX-2122
(Fig. 1(a)) is a heat-shock protein 90 (HSP-90) inhibitor,5a and it
exhibits potent antiproliferative activities against HER2-dependent
breast cancer cells.5b Tetrahydroindazole-based compound (b) in
Figure 1 is a potent inhibitor of Mycobacterium tuberculosis (MTB).6a
Combretastatin A-4 (CA4) (Fig. 2) is a potent antiproliferative
agent which acts through interaction with microtubules. Analogs
of CA4 and several other derivatives where cis-double bond was
replaced with a tetrazole, thiazole, imidazole, or oxazole rings have
been synthesized and studied for evaluation of anticancer activities
and establishing structure–activity relationships.7,8 THIs have also
been previously reported possessing antitumor activity.9 The
synthesized THIs have structural resemblance to the tetrazole,
triazole, imidazole, or oxazole derivatives of CA4 that were shown
N
O
N
O
CF3
N
OH
C
N
NH
O
N
H
NH2
N
N
O
tBu
b
a SNX-2122
⇑
Corresponding authors.
E-mail address: kparang@uri.edu (K. Parang).
Figure 1. Chemical structures of lead compounds containing tetrahydroindazolone
scaffolds (a) SNX-2122: HSP90 inhibitor; (b) MTB inhibitor.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.124

V. K. Rao et al. / Bioorg. Med. Chem. Lett. 22 (2012) 410–414
411
Table 1
Optimization of reaction conditions for the model reaction
H3CO
H3CO
O
N
N
S. No.
Catalyst
Moles (%)
Solvent
Time (h)
Yielda (%)
OCH3
1
2
3
4
5
6
7
8
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Zn(OTf)2
Ag(OTf)
Sc(OTf)3
Cu(OTf)2
Yb(OTf)3
Mont. K-10
pTSA
0
10
10
20
30
40
20
20
20
20
20
20
20
20
20
20
[bmim][BF4]
—
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
45
NPb
51
88
90
89
70
50
60
56
65
20
20
20
NA
NA
OCH3
OH
OCH3
Combretastatin A-4
as an antiproliferative agent
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][PF6]
Ethanol
OCH3
Combretastatin A-4 mimics
X
9
10
11
12
13
14
15
16
NH2
R2
N
O
Ethanol
Ethanol
Toluene
THF
PP1 X = Me
PP2 X = Cl
N
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
N
N
N
N
R1
Tetrahydroindazolones
a
Isolated yield.
No product formed.
Phenylpyrazolopyrimidines
as SFK inhibitors
b
Figure 2. Structural relativity of THIs to combrestatin A-4 mimics and phenylpy-
razolopyrimidines as anticancer agents and Src kinase inhibitors, respectively.
Table 2
Synthesized 2-substituted THIs (4–36)
O
X
R2
metastasis.13 Heterocyclic THIs have some structural similarity
with phenylpyrazolopyrimidine derivatives (Fig. 2), and were
investigated to determine whether they can mimic PP1 or PP2.
In continuation of our efforts towards the synthesis of small
molecules as anticancer agents and/or c-Src kinase inhibitors,14
herein we report the synthesis and evaluation of an array of 33
synthesized diversely substituted THIs.
The most common method for the synthesis of THIs is simple
condensation of arylhydrazines with 2-acylcyclohexane-1,3-
diones.15 However, this method results in regioisomeric mixtures
of tetrahydroindazolone. There are only very a few methods for
the synthesis of 2-substituted THIs. Separation of 2-substituted
THIs from a mixture of isomers is challenging and, therefore, these
compounds have not been much explored for biological activity.
We have previously reported the synthesis of other heterocyclic
compounds through MCRs catalyzed by metal triflates.16 One-pot
three component regioselective synthesis of substituted THIs cata-
lyzed by ytterbium triflate [Yb(OTf)3] in 1-butyl-3-methylimidazo-
lium tetrafluoroborate ([bmim][BF4]) ionic liquid is shown in
Scheme 1.
X
N
R3
R1
N
R1
Compd
R1
X
R2
R3
Yielda (%)
4
5
6
7
8
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
O
C
C
C
C
C
O
C
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
4-ClC6H4
4-NO2C6H4
C4H3S
4-CH3C6H4
3-OH,4-OMeC6H3
4-OHC6H4
C4H4N
4-OMeC6H4
C6H5
3-ClC6H4
4-ClC6H4
C4H3S
4-CH3C6H4
2-FC6H4
88
85
73
83
65
70
80
74
75
82
82
71
78
77
70
72
65
60
84
77
81
69
54
78
80
50
76
76
77
81
77
48
79
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
4-OMeC6H4
C6H5
4-OHC6H4
3-OH,4-OMeC6H3
4-NO2C6H4
3-OMeC6H4
4-ClC6H4
C5H4N
In a protocol standardization experiment, when 5,5-dimethyl-
cyclohexane-1,3-dione (2), 4-chloro-benzaldehyde (2), and 3,4-
dichlorophenyl hydrazine (3) were reacted in ethanol at room
temperature in presence of Yb(OTf)3 (20 mol %), the product 4
(R1 = Me, X = C, R2 = 3,4-Cl2Ph, R3 = 4-ClPh) (see A–D for general
synthesis in Scheme 1) was obtained in 20% yield. Further optimi-
zation of reaction condition was carried out by changing solvents,
H
3-Cl, 4-CH3C6H3
3-Cl, 4-CH3C6H3
3-Cl, 4-CH3C6H3
3-Cl, 4-CH3C6H3
C6H11
CH3
CH3
CH3
CH3
CH3
CH3
H
C4H4N
C4H3S
C6H11
C6H11
C6H11
C6H11
4-NO2C6H4
4-ClC6H4
3-ClC6H4
4-CH3C6H4
4-OMeC6H4
3,4-(OMe)2C6H3
4-ClC6H4
4-ClC6H4
4-CH3C6H4
H
CH3
CH3
CH3
CH3
CH3
4-(CH3)3CC6H4
4-(CH3)3CC6H4
4-(CH3)3CC6H4
4-(CH3)3CC6H4
4-(CH3)3CC6H4
O
X
R2
O
R1
X
O
R1
Yb(OTf)3
X
R3NHNH2
N
R3
A
R1
R1
a
[bmim][BF4]
100 °C
Isolated yield.
N
C
X
CHO
D
52-89%
R1 = CH3 or H
X = C or O
catalysts, and catalyst loading. As shown in Table 1, the use of
20 mol % Yb(OTf)3 in [bmim][BF4] gave the desired product 4 in
high yield (88%) (entry 4). When Yb(OTf)3 was changed with other
metal triflates such as Sc(OTf)3, Zn(OTf)2, Cu(OTf)2 or AgOTf the
yield of 4 was moderate to good (Table 1, entries 7–10). The
catalytic order Yb(OTf)3 > Zn(OTf)2 > Sc(OTf)3 > Cu(OTf)2 > AgOTf
R2
R2 = 3,4-Cl2Ph, (3-Cl, 4-CH3)Ph, C6H11, 4-(CH3)3CPh
B
R3 = 4-(X)Ph (X = Cl, NO2, Me, OH, OMe), C4H3S, 3-OH, 4-
OMe)Ph, (2-F)Ph, Ph, (3-OMe)Ph, Py, C4H4N, (3-Cl)Ph, (3,4-
OMe)Ph
Scheme 1. Synthesis of substituted tetrahydroindazolones.

412
V. K. Rao et al. / Bioorg. Med. Chem. Lett. 22 (2012) 410–414
Figure 3. ORTEP view of molecular structure of compound 27.
δ
δ
O
C
Yb(OTf)3
O
OH
H
R2
O
O
-H2O R1
H2NNHR3
R
NHNHR3
OH
R1
R1
R1
R1
NHR3
NHR3
N
N
R1
R
δ
O
Yb(OTf)3
δ
OH
CHR2
O
O
O
O
R2
R2
N
CHR2
NHR3
-H2O
N
R3
R3
R1
R1
R1
R1
R1
R1
R1
R1
N
NHR3
N
N
N
Scheme 2. Plausible mechanism for synthesis of THIs.
was established for the synthesis of 4 based on isolated yield in
[bmim][BF4]. There was not much increase in yield of 4 on chang-
ing the amount of Yb(OTf)3 from 20 mol % to 40 mol % (Table 1, en-
tries 4–6). However, reducing the amount of Yb(OTf)3 decreased
yield of 4 to 51%. It should be noted that no product formation
was observed in solvent free conditions; however 45% of 4 was
formed in the absence of Yb(OTf)3. The structure of the compound
4 was confirmed by 1H NMR, 13C NMR, and mass spectrometry. In
1H NMR three singlet peaks were observed at d 2.81, 2.42 and
1.16 ppm for C7-CH2, C5-CH2, and C6-(CH3)2, respectively, along
with other aromatic protons. It is worthy to mention that under
these conditions only 2-substituted tetrahydroindazolones were
obtained.
Under the optimized reaction conditions, various arylhydra-
zines, arylaldehydes, and 1,3-diones underwent one-pot reaction
and afforded the corresponding 2-substituted THIs (4–36) (Table 2).
Various benzaldehydes and arylhydrazines with electron with-
drawing and donating substituents, such as nitro, halo, hydroxyl,
methoxy, alkyl, and aryl, were used to establish the structure–
activity relationships.
values are in agreement with the literature report for regioselec-
tive formation of 2-substituted THIs.15d Furthermore, regioselec-
tive formation of 2-substituted THIs was confirmed by X-ray
crystallographic data for compound 6 (CCDC 848784) and 27
(CCDC 850178). The ORTEP view for compound 6 (Fig. 3A) and
27 (Fig. 3B) clearly shows that 3,4-dichlorophenyl and cyclohexyl
group are at N-2 position in 6 and 27, respectively.
The regioselective formation of N-2-substituted THI indicates
that hydrazine first attacks at carbonyl group of diketone. Based
on the product formation the reaction is believed to proceed
through the formation of hydrazone followed by attack of aldehyde
to give aldol product, which undergoes nucleophilic addition as
shown in Scheme 2. It appears that ionic liquid helps in stabiliza-
tion of charged intermediate generated by coordination of Yb(OTf)3
to aldehydes and diones. Furthermore, the acidic C-2 proton of imi-
dazolium ionic liquid also facilitates the enolization of dione.
All the synthesized compounds (4–36) were evaluated for their
effect on proliferation of ovarian adenocarcinoma cells (SK-OV-3)
and colon adenocarcinoma (HT-29), two human cancer cells lines
that overexpress c-Src.17 Doxorubicin (Dox) and DMSO were used
as positive and negative controls, respectively. The results for cell
The chemical structures of all synthesized compounds were
elucidated by 1H NMR, 13C NMR, and mass spectroscopy (Supple-
mentary data). A single peak for two protons of C7-carbon at
around 2.8 ppm confirmed formation of only a single isomer. These
proliferation at 50 lM after 72 h for compounds 4–30 are shown
in Fig. 4. All the compounds were more active against HT-29 cells
than SK-OV-3 cells. Compounds 19, 25, and 33 inhibited the cell

V. K. Rao et al. / Bioorg. Med. Chem. Lett. 22 (2012) 410–414
413
180
160
140
120
100
80
HT-29 SK-OV-3
60
40
20
0
Figure 4. Inhibition of HT-29 and SK-OV-3 cell proliferation by compounds 4–33 (50
l
M) after 72 h incubation. The results are shown as the percentage of the control DMSO
that has no compound (set at 100%). All the experiments were performed in triplicate.
Table 3
Src kinase inhibitory activity of substituted THIs (4–36)
a
a
Compd
IC50
86.0
>150
(
lM)
Compd
IC50
(lM)
4
5
6
7
8
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
>150
82.7
131.8
74.3
>150
77.3
>150
>150
58.4
57.7
35.1
>150
>150
>150
>150
0.6
>150
>150
>150
66.6
>150
94.1
62.1
50.7
81.0
9
10
11
12
13
14
15
16
17
18
19
20
21
>150
>150
>150
>150
65.8
>150
>150
Staurosporine
PP2
0.5
Figure 5. Comparison of structural complexes of Src kinase with different THIs
derivatives. 32 (yellow), PP1 (blue), and 13 (red) based on molecular modeling. The
compounds and side chains of amino acids are rendered in stick styles. Compounds
are in the lowest energy conformers predicted. The Figure is drawn using the
Accelrys visualization system.
a
The concentration at which 50% of enzyme activity is inhibited.
proliferation of HT-29 cells by 65–72% while they were not effec-
tive against SK-OV-3. Compounds 15, 16, and 27 showed 48–62%
and 49–58% inhibition in the cell proliferation of HT-29 and SK-
OV-3 cells, respectively. The presence of C4H3S– substituent as R3
or 3,4-dichlorophenyl or tolyl as R2 is critical for maximum anti-
proliferative activity as seen in compounds 15 and 16.
Synthesized substituted THIs were evaluated for c-Src kinase
inhibitory activity. The results of Src kinase inhibitory activity of
compounds (4–33) are shown in Table 3. Among all the com-
pounds, 12, 13, 19, 30, 31, and 32 showed modest inhibition of
compare with the binding mode of these compounds when com-
pared with PP1 within the ATP-binding site of the enzyme
(Fig. 5). The backbone tetrahydroindazolone in 32 and 13 and pyr-
azolopyrimidine in PP1 occupied a similar pocket in ATP-binding
site of Src. The modeling studies indicated that 3,4-dichlorophenyl
and 4-(tert)butylphenyl at R2 position in 13 and 32, respectively,
occupy and fit the hydrophobic binding pocket similar to tolyl
group of PP1 with slightly different orientations of phenyl groups
(Fig. 5). The 4-methoxyphenyl and 3-chlorophenyl at R3 position
of 32 and 13, respectively, are oriented far from the large cavity
Src kinase with IC50 values in the range of 35–69
Compounds 32 and 13 were found to show the highest Src ki-
nase inhibitory activities with IC50 values of 35.1 and 50.7 M,
lM.
that is formed from side chains of helix
aC and helix aD, where
the triphosphate group of ATP usually binds similar to that of t-bu-
tyl group of PP1, thus suggesting that substitution at R3 position of
THIs does not generate any advantageous in Src kinase inhibition
l
respectively, among all the compounds. Molecular modeling and
minimization of compounds 32 and 13 was used to explore and

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through interactions with adjacent amino acids in the ATP binding
site.
These data suggest that further structural modifications in tet-
rahydroindazolone scaffold is required to convert them to more
potent Src kinase inhibitors such as phenylpyrazolopyrimidine
derivatives PP1 and PP2. Poor correlation between inhibition of
Src kinase and the cell proliferation could be due to the differential
cellular uptake and alternative mechanisms in antiproliferative
activities of the compounds.
In conclusion, an ecofriendly and regioselective method was
developed for the synthesis of 2-substituted THIs by one-pot
three-component coupling reaction of benzaldehydes, arylhydra-
zines, and 1,3-diones using Yb(OTf)3 as a catalyst in ionic liquid.
To the best of our knowledge, this is the first report of one-pot
synthesis and evaluation of THIs as Src kinase inhibitors and
anticancer agents. The synthesized compounds were evaluated
for c-Src kinase inhibitory activity and compound 32 showed
moderate inhibition of Src kinase with an IC50 value of 35.1
Compounds 15 and 16 consistently inhibited the cell proliferation
of SK-OV-3 and HT-29 cells by 49–62% at a concentration of 50 M.
lM.
l
Further structure–activity relationship studies are required for
optimizing the Src kinase inhibition and antiproliferative activities
of THIs.
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We thank University Grant Commission, New Delhi Project #
39-733/2010 (SR) and the American Cancer Society Grant #RSG-
07-290-01-CDD for the financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.10.124.
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