Synthesis, crystal structure and evaluation of cancer inhibitory activity of 4-[indol-3-yl-methylene]-1H-pyrazol-5(4H)-one derivatives

Article abstract of DOI:10.3184/174751912X13501278349974

A series of 4-(1H-indol-3-yl-methylene)-1H-pyrazol-5(4H)-one derivatives have been synthesised. The Z structure of 4-[(1-methyl-1H-indol-3-yl)methylene]- 3-phenyl-1-p-tolyl-1H-pyrazol-5-one was determined by X-ray crystallography. The antitumour activity was evaluated against five cancer cells by MTT assay. [(1H-Indol-3-yl)methylene]-1-(2,4-dinitrophenyl)- 3-methyl-1H-pyrazole-5-one and 4-{4-[(1-benzyl-1H-indol-3-yl)methylene]-3-methyl-5-oxo-4,5-dihydro-1Hpyrazol- 1-yl}-benzoic acid have similar anticancer activity with 5-UF on the test cancer cells (exception of A375). Almost all the target compounds displayed antitumour activity against A549 and PC-9, and those with benzyl at 1- position of indole had higher activity against PC-9 (IC50 value lower than 30 μM). Those with benzyl at the indole and carboxyl at the phenyl part of of pyrazole were more active against PC-9 and A549 cells, providing a good indication for subsequent optimisation as lung cancer inhibitory agents.

Full text of DOI:10.3184/174751912X13501278349974

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 691
DECEMBER, 691–696
Synthesis, crystal structure and evaluation of cancer inhibitory activity of
4-[indol-3-yl-methylene]-1H-pyrazol-5(4H)-one derivatives
Lingling Jinga, Liang Wangb, Yinglan Zhaob, Rui Tana, Xiumei Xinga, Ting Liua, Wencai Huanga,
Youfu Luob and Zicheng Lia*
aSchool of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, P. R. China
bState Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041,
P. R. China
A series of 4-(1H-indol-3-yl-methylene)-1H-pyrazol-5(4H)-one derivatives have been synthesised. The Z structure of
4-[(1-methyl-1H-indol-3-yl)methylene]-3-phenyl-1-p-tolyl-1H-pyrazol-5-one was determined by X-ray crystallography.
The antitumour activity was evaluated against five cancer cells by MTT assay. [(1H-Indol-3-yl)methylene]-1-(2,4-dini-
trophenyl)-3-methyl-1H-pyrazole-5-one and 4-{4-[(1-benzyl-1H-indol-3-yl)methylene]-3-methyl-5-oxo-4,5-dihydro-1H-
pyrazol-1-yl}-benzoic acid have similar anticancer activity with 5-UF on the test cancer cells (exception of A375).
Almost all the target compounds displayed antitumour activity against A549 and PC-9, and those with benzyl at 1-
position of indole had higher activity against PC-9 (IC50 value lower than 30 µM). Those with benzyl at the indole and
carboxyl at the phenyl part of of pyrazole were more active against PC-9 and A549 cells, providing a good indication
for subsequent optimisation as lung cancer inhibitory agents.
Keywords: 4-(indol-3-yl-methylene)-1H-pyrazol-5(4H)-one, 1-aryl-1H-pyrazole-5(4H)-one, indole derivative, cancer inhibitory
activity
The indole unit is the key building block for a variety of com-
pounds which have crucial roles in the functions of biologi-
cally important molecules. Indole and its derivatives have
a wide range of biological activities,1 and there has been a
growing interest in their synthesis and biological studies. Intro-
duction of different groups to the modified indole structure
can produce a series of compounds with multiple activitives,2
such as antihypertensive drugs (for example, indapamide,3
indorenate),4 neuropsychiatric disorders drugs (tryptophan and
5-hydroxytryptophan),5 plant growth regulator (tryptamine),6
anticancer drugs (Sunitinib). SU5416, SU668, SU11248
(Sunitinib, Fig. 1) have been developed as anticancer agents by
Sugen,7 and SU11248 is mainly used for treatment of gastroin-
testinal stromal tumours and metastatic renal cell carcinoma.8,9
Other drugs such as indomethacin (immunosuppressive activ-
ity inhibitor),10,11 indirubin (topo II inhibitor)12 had also been
used.
Pyrazole derivatives have been widely used in drugs, such
as COX-2 inhibitor (celecoxib),13,14 free radical scavenger
(3-methyl-1-phenyl-1H-pyrazol-5(4H)-one), and acaricides
(MK-239). Diana et al.15 synthesised several Nortopsentins’
analogues (3,5-bis(3′-indolyl)pyrazole), and one compound
had low GI50 towards nine cancer cell lines, having GI50 in the
range 1.63–9.64 µM towards all the sub-panel cell lines.
Reddy et al.16 synthesised substituted (Z)-5-(N-benzylindol-
3-ylmethlene)imidazolidine-2,4-diones. Among these com-
pounds, two had IC50 values of 4.4 and 5.2 µM against MCF7
cell, respectively, compared to 5-fluorouracil (IC50=15.2 µM).
Singh et al.17 reported a series of indole–pyrazole moieties
compounds having tumour growth inhibitory activities.
Penthala et al.18 synthesised a series of structurally related
N-heterocyclic indol-3-yl-methylene derivatives, and found
that such compounds exhibited substantial activity in vitro
against human tumour cell lines. Cummings et al.19 reported a
novel small molecule natural product analogues capable of
discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C
receptor subtypes.
Based on the structural analysis of the above compounds,
and to study their SARS, N-substituted indole-3-carbaldehyde
and 1-aryl-3-methylpyrazol-5-one and 1,3-diarylpyrazol-5-
one were combined with the methylene bond. A series of com-
pounds with indole and pyrazole moieties were designed and
synthesised, and their tumour inhibitory activity was evaluated
against A549, HCT116, HepG2, PC-9, A375 by the MTT
assay.
Results and discussion
All intermediates and the target compounds were prepared
with good yield using general procedures (Scheme 1). During
the synthesis of 4d, ethyl bromoacetate was used as the starting
material, but there was some hydrolysed product under the
reaction conditions. It was therefore replaced by tert-butyl
bromoacetate for this synthesis, and tert-butyl 2-(3-formyl-
1H-indole-1-yl)acetate (4d) was prepared with high yield. The
target compounds 5–33 were obtained by Aldol condensation
from intermediate 3 or 4a–d with 2a–g catalysed by drops of
piperidine, and purified by recrystallisation from ethanol.
The geometry of the double bond in the representative com-
pound 10 was determined by X-ray crystallographic analysis.
The geometry of the other target compounds can be speculated
from the crystal structure of 10 and analogues reported by
Reddy and Singh,15,16 when hydrogen at the double bond
1
(C=CH) in H NMR displayed singlet (δ ranges from 8.08 to
8.18), the geometry was Z-form, if it displayed as a doublet or
a multiplet (because of the surrounding aryl hydrogens), the
geometry of the double bond is ambiguous.
The X-ray crystallographic analysis of compound 10
(C26H21N3O) showed the Z-structure (Fig. 2), the bond length
between C(9)–C(17) is 1.375 Å, which indicated a double
bond, and the bond angle of C(9)–C(17)–C(18) is 133.2°, this
Z-structure is consistent with that reported by Singh.17
The other parameters of crystal of compound 10 related to its
structure are listed in Table 1. The crystal of compound 10 is
monoclinic, P21 space group, whose structural parameters are
a = 13.8705(6) Å, b = 14.5185(7) Å, c = 15.2310(8) Å, α =
90.00 °, β = 93.711(4) °, γ = 90.00°, U = 3060.8(3) Å3, Z=6.
Fig. 1 Some indole derivatives as anticancer agents.
* Correspondent. E-mail: sculzc@scu.edu.cn

692 JOURNAL OF CHEMICAL RESEARCH 2012
Scheme 1 The general synthetic route for compounds 5–32.
As shown in Table 2, all the synthesised compounds are
inactive against A375 and HepG2 cancer cells (IC50 > 70 µM,
with the exception of 28 with IC50 values of 41.15 µM and
46.53 µM against these two cancer cells, and 14 with IC50 value
of 28.03 µM against HepG2, respectively). The compounds 7,
14 and 28, which contain 2,4-dinitrophenyl at 1-position of
pyrazole moiety, displayed moderate activity against HCT116
(IC50 = 36.07 µM for 7, 29.87 µM for 14 and 40.43 µM for 28,
respectively). Almost all the target compounds displayed activ-
ity against A549 and PC-9 cancer lines, and the PC-9 cell is
more sensitive to them. Compounds with benzyl at 1-position
of indole have a higher activity against PC-9 (IC50 value lower
than 30 µM for 5, 17, 26 and 28), and those containing 4-
carboxylphenyl and 2,4-dinitrophenyl at 1-position of pyrazole
showed potential inhibitory activity over A549 and PC-9.
Experimental
All starting materials and solvents were used as-received. The melting
points of products were determined on a XRC-1 micro melting point
apparatus and are uncorrected. TLC was performed on 0.20 mm silica
gel GF254 plates (Qingdao Ocean Chemical Factory, Shandong, China).
The purities of all synthetic molecules in the present work were con-
firmed as ≥97% by HPLC with a photodiode array detector (Waters,
Milford, MA) and the chromatographic column was an Atlantis C18
(150 mm×4.6 mm, i.d. 5 µm, Waters, Milford, Ireland). NMR were
recorded on 400 MHz Varian spectrometer (Varian, Palo Alto, CA)
model Gemini 400 and reported in parts per million with TMS as
internal standard. The IR spectra were recorded on VECTOR22
(Brucker, German). High resolution electron impact (EI) ionisation
mass spectra were recorded at 25 eV on a Waters Q-TOF Premier
station (magnetic sector instrument) at a resolution of greater than
10000. Crystal structure was determined on Xcalibur E X-ray single
crystal diffractometer (oxford, British).
According to the literature procedures,20 the target compounds 5–32
were obtained in 72–82% yield by the synthetic route shown in
Scheme 1, i.e. by Aldol condensation from 3 or 4 with 2 catalysed by
drops of piperidine.
Synthesis of compounds 2a–g; general procedure
A mixture of ethyl acetoacetate or ethyl benzoylacetate (0.1 mol) and
substituted phenylhydrazine (0.1 mol) in ethanol was refluxed at
90 °C for 3–5 h. The mixture was then cooled to room temperature
with stirring to afford a solid which was filtered and washed with
Table 1 Selected bond lengths (Å) and bond angles (°) for
compound 10
Atom–atom(–atom)
Bond lengths (Å) or bond angles (°)
C(8)–C(9)
1.466(4)
1.375(4)
1.409(4)
133.2(3)
126.7(3)
128.8(3)
C(9)–C(17)
C(17)–C(18)
C(9)–C(17)–C(18)
C(17)–C(9)–C(8)
C(17)–C(9)–C(10)
Fig. 2 Partially labeled ORTEP plot of C26H21N3O (10).

JOURNAL OF CHEMICAL RESEARCH 2012 693
Table 2 IC50 value of compounds 5–32 against tumour cells in vitro
Compound
IC50a,b(µM)
A549
HCT116
HepG2
PC-9
A375
5 (R1=Cl, R2=H, R3= R4=Me)
51.55
53.63
66.09
>80
>80
>80
>80
>80
>80
>80
>80
>80
>80
28.03
>80
>80
>80
>80
>80
NT
>80
>80
>80
>80
>80
>80
75.18
46.53
>80
>80
>80
>80
46.31
13.24
45.1
>80
>80
>80
>80
>80
>80
>80
>80
>80
>80
>80
>80
>80
>80
>80
NT
>80
>80
>80
>80
>80
>80
>80
>80
>80
73.69
>80
>80
46.55
11.58
6 (R1= R2=NO2, R3= Me, R4=Bn)
7 (R1= R2=NO2, R3=R4=Me)
22.42
42.78
36.85
39.33
40.06
26.61
26.41
31.51
42.47
51.06
34.63
24.01
44.22
34.95
NT
>80
>80
8 (R1=R3=Me, R2=R4=H)
43.55
62.26
47.78
61.9
27.25
74.51
34.7
48.66
35.1
65.75
44.12
37.21
NT c
55.67
>80
67.72
61.77
>80
70.82
36.81
37.24
56.82
44.88
66.23
69.48
35.05
12.35
>80
9 (R1=R3=R4=Me, R2=H,)
>80
10 (R1=R4=Me, R2=H, R3=Ph)
>80
11 (R1=Me, R2=H, R3=Ph, R4=Bn)
12 (R1=Me, R4=R2=H, R3=Ph)
>80
>80
13 (R1=Cl, R2=H, R3=Ph, R4=Bn)
14 (R1=R2=NO2, R3= Me, R4=H,)
15 (R1=CO2CH3, R2=H, R3=R4=Me)
16 (R1=CO2CH3, R2=H, R3=Me, R4=CH2CO2Bu-t)
17 (R1= CO2CH3, R2=H, R3= Me, R4=Bn,)
18 (R1=CO2H, R3= Me, R2=R4=H)
19 (R1=CO2H, R2=H, R3= R4=Me)
20 (R1=CO2H, R2=H, R3=Me, R4=Ac)
21 (R1=Cl, R2=H, R3= Ph, R4=Ac)
22 (R1=Cl, R2=H, R3=Ph, R4=CH2CO2Bu-t,)
23 (R1=Cl, R2=H, R3=Me, R4=Ac)
24 (R1=Cl, R2=H, R3=Ph, R4=Me)
25 (R1=CO2CH3, R2=R4=H, R3=Me)
26 (R1=Cl, R2=H, R3=Me, R4=Bn)
27 (R1=Cl, R2=R4=H, R3=Me)
>80
29.87
59.52
52.8
55.96
56.08
50.1
NT
>80
37.72
60.37
57.2
>80
>80
>80
52.02
43.03
30.03
38.26
21.62
41.24
39.39
49.32
59.2
55.56
78.63
63.59
40.43
54.89
56.54
>80
28 (R1=CO2H, R2=H, R3=CH3, R4=Bn)
29 (R1=CO2CH3, R2=H, R3=Me, R4=Ac)
30 (R1=CO2H, R2=H, R3= Me, R4=CH2CO2Bu-t)
31 (R1= Me, R2=H, R3=Ph, R4=Ac)
32 (R1=Me, R2=H, R3=Ph, R4=CH2CO2Bu-t)
5-FU
78.46
31.72
18.35
23.47
10.97
SU11248
a The IC50 values represent the concentration that causes 50% growth inhibition.
b The IC50 values were the mean values of three repeated experiments.
c Not tested.
cooled ethanol. The crude product was recrystallised from ethanol to
afford 2 as a white solid (characteristic data are shown in Table 3).
1-(2,4-Dinitrophenyl)-3-methyl-1H-pyrazol-5(4H)-one (2g): 1H NMR
(DMSO-d6): δ 2.12 (s, 3H, CH3), 3.54 (s, 2H, CH2), 7.84 (d, 1H,
J = 8.0 Hz, ArH), 8.41 (dd, 1H, J = 2.0 Hz, J = 8.0 Hz, ArH), 8.88 (d,
1H, J = 2.4 Hz, ArH), 10.82 (s, 1H, OH).
N-Benzyl-1H-indole-3-carbaldehyde (4c): Yield: 87%; m.p. 105–
107 °C (lit.28: m.p. 111 °C, or 102–104 °C). 1H NMR (DMSO-d6): δ
5.50 (s, 2H, CH2), 7.22–7.38 (m, 7H, ArH), 7.49 (d, 1H, J = 8.0 Hz,
ArH), 8.09 (d, 1H, J = 8.0 Hz, ArH), 8.24 (s, 1H, indole-2-H), 9.92 (s,
1H, CHO).
tert-Butyl 2-(3-formyl-1H-indol-1-yl)acetate (4d):Yield: 92%; m.p.
120–122 °C. IR (KBr, cm−1): 1695, 1742; 1H NMR (DMSO-d6): δ 1.43
(s, 9H, 3CH3), 5.18 (s, 2H, CH2), 7.24–7.33 (m, 2H, ArH), 7.51 (d, 1H,
J = 8.0 Hz, ArH), 8.10 (d, 1H, J = 7.6 Hz, ArH), 8.27 (s, 1H, indole-2-
H), 9.94 (s, 1H, CHO). ESI-HRMS: Calcd for C15H17NO3 (MH+):
260.3078, found: 260.3072.
Synthesis of indole-3-carboxaldehyde (3)
Compound 3 was synthesised by Vilsmeir reaction,24 and recrystalli-
sation from ethanol afforded a pale yellow solid with 85% yield, m.p.
194–195 °C (lit.25 193–195 °C).
Synthesis of compound 4a–d; general procedure
Synthesis of compound 5–32; general procedure
A solution of 1.2 equimolar amount of the appropriate R4X in DMF
was slowly added to a stirred mixture of compound 3 (5 g, 34 mmol)
and K2CO3 (5 g) in dry DMF (20 mL). The reaction mixture was main-
tained at room temperature until TLC indicated the end of reaction.
Then water (80 mL) was added and the mixture was extracted with
ethyl acetate (3×10 mL). The organic phase was combined, washed
twice with brine (30 mL), dried over anhydrous Na2SO4, and concen-
trated in vacuo to afford the target compound 4 as a white solid.
N-Methyl-1H-indole-3-carbaldehyde (4a): Yield: 91%; m.p. 66–
Piperidine (2–3 drops) was added to a mixture of compound 2 or 3 and
4 (1:1 equiv.) in ethanol. The mixture was refluxed for 3–5 h. The
precipitate thus obtained was collected by filtration after cooled,
washed with cold water, finally washed with methanol and dried to
afford the crude product. Crystallisation from methanol or methanol
and DMF (3:1) afforded the target compound 5–32 as an orange
crystalline product.
1-(4-Chlorophenyl)-3-methyl-4[(1-methy-1H-indol-3-yl)meth-
ylene]-1H-pyrazol-5(4H)-one (5): Yield: 78%; m.p. 196–198 °C; νmax
1
67 °C (lit.26 68–70 °C); H NMR (DMSO-d6): δ 4.15 (s, 3H, CH3),
1
(KBr, cm−1): 1674 (CO); H NMR (DMSO-d6): δ 2.42 (s, 3H, CH3),
7.20–7.30 (m, 2H, ArH), 7.46 (d, J = 7.6 Hz, ArH), 7.98 (d, 1H,
J = 8.0 Hz, ArH), 8.19 (s, 1H,indole-2-H), 9.94 (s, 1H, CHO).
N-Acetyl-1H-indole-3-carbaldehyde (4b): Yield: 82%; m.p. 158–
161 °C (lit.27 159–162 °C). 1H NMR (DMSO-d6): δ 2.56 (s, 3H, CH3),
7.24–7.35 (m, 2H, ArH), 7.49 (d, 1H, J = 8.0 Hz, ArH), 8.02 (d, 1H,
J = 8.0 Hz, ArH), 8.27 (s, 1H, indole-2-H), 9.91 (s, 1H, CHO).
4.02 (s, 3H, CH3), 7.38–7.40 (m, 2H, ArH), 7.48 (d, 2H, J = 8.4 Hz,
ArH), 7.67 (d, 1H, J = 8.4 Hz, ArH), 8.06 (d, 2H, J = 8.4 Hz, ArH),
8.11 (s, 1H, =CH), 8.20 (d, 1H, J = 7.2 Hz, ArH), 9.78 (s, 1H, ArH).
ESI-HRMS: Calcd for C20H16ClN3O (MH+): 350.1060; found:
350.1056 (100%), 352.1036 (38%).

694 JOURNAL OF CHEMICAL RESEARCH 2012
Table 3 Some characteristic data of the compounds 2a–g
Product
M.p./°C
Yield/%
2a
2b
2c
2d
2e
2f
R1=CH3, R2=H, R3=CH3
R1= Cl, R2=H, R3= CH3
R1=COOH, R2=H, R3=CH3
R1=COOCH3, R2=H, R3=CH3
R1=CH3, R2=H, R3=Ph
R1=Cl, R2=H, R3=Ph
134–135 (lit.21134–134.5)
172–174 (lit.21 172–173)
283–285 (lit.21 285)
65
60
67
66
75
70
60
127–128 (lit.21127–127.5)
141–142 (lit.21142–144)
161–163 (lit.21162.5–164)
180–181(lit.22 144–145, lit.23 201–202)
2g
R1=R2=NO2, R3=CH3
1
4-[(1-Benzyl-1H-indol-3-yl)methylene]-1-(2,4-dinitrophenyl)-3-
methyl-1H-pyrazol-5(4H)-one (6): Yield: 80%; m.p. 206–208 °C; νmax
(KBr, cm−1): 1691 (CO), 1523 (NO2), 1333 (NO2); 1H NMR (DMSO-
d6): δ 2.46 (s, 3H, CH3), 5.71 (s, 2H, CH2), 7.28–7.40 (m, 7H, ArH),
7.69–7.71 (m, 1H, ArH), 8.11 (s, 1H, =CH), 8.25 (m, 2H, ArH), 8.60
(dd, 1H, J = 2.4 Hz, J = 8.4 Hz, ArH), 8.76 (d, 1H, J = 2.4 Hz, ArH),
9.72 (s, 1H, indole-CH). ESI-HRMS: Calcd for C26H19N5O5 (MH+):
482.1464; found: 482.1467.
1-(2,4-Dinitrophenly)-3-methyl-4-[(1-methyl-1H-indol-3-yl)meth-
ylene]-1H-pyrazol-5(4H)-one (7): Yield: 82%; m.p. 258–260 °C; νmax
(KBr, cm−1): 1688 (CO), 1534 (NO2), 1329 (NO2); 1H NMR (DMSO-
d6): δ 2.45 (s, 3H, CH3), 4.02 (s, 3H, CH3), 7.41 (m, 2H, ArH), 7.70
(m, 1H, ArH), 8.11 (s, 1H, =CH), 8.23 (brs, 2H, ArH), 8.60 (dd, 1H,
J = 2.4 Hz, J = 8.4 Hz, ArH), 8.75 (d, 1H, J = 2.4 Hz, ArH), 9.57 (s,
1H, =CH). ESI-HRM: Calcd for C20H15N5O5 (MH+): 406.1151; found:
406.1147.
(KBr, cm−1): 1675 (CO); H NMR (DMSO-d6): δ 5.75 (s, 2H, CH2),
7.30–7.39 (m, 9H, ArH), 7.54 (m, 1H, ArH), 7.6–7.66 (m, 3H, ArH),
7.71 (m, 1H, ArH), 7.80 (m, 3H, ArH), 8.12 (s, 1H, =CH), 8.14 (d, 2H,
J = 8.4 Hz, ArH), 10.02 (s, 1H, indolyl-2-CH). ESI-HRMS: Calcd for
C31H22ClN3O (MH+): 488.1530; found: 488.1518 (100%), 490.1498
(35%).
4-[(1H-Indol-3-yl)methylene]-1-(2,4-dinitrophenyl)-3-methyl-1H-
pyrazole-5-one (14): Yield: 86%; m.p. 158–162 °C; νmax (KBr, cm−1):
3357 (NH), 1694 (CO), 1527 (NO2), 1330 (NO2); 1H NMR (DMSO-
d6): δ 2.47 (s, 3H, CH3), 7.35 (m, 2H, ArH), 7.62 (m, 1H, ArH), 8.09
(d, 1H, J = 8.4 Hz, =CH), 8.21 (m, 1H, ArH), 8.27 (s, 1H, ArH), 8.61
(d, 1H, J = 8.4 Hz, ArH), 8.76 (s, 1H, ArH), 9.63 (s, 1H, indolyl-2-
CH), 12.80 (s, 1H, NH). ESI-HRMS: Calcd for C19H13N5O5 (MH+):
392.0995; found: 392.0998.
Methyl 4-{3-methyl-4-[(1-methyl-1H-indol-3-yl)methylene]-5-oxo-
4,5-dihydro-1H-pyrazole-1-yl} benzoate (15): Yield: 80%; m.p. 190–
1
4-[(1H-Indol-3-yl)methylene]-3-methy-1-p-tolyl-1H-pyrazol-5-one
192 °C; νmax (KBr, cm−1): 1712 (ester CO), 1679 (CO); H NMR
(8): Yield: 78%; m.p. 204–206 °C; νmax (KBr, cm−1): 3267 (NH), 1651
(DMSO-d6): δ 2.45 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 4.05 (s, 3H,
CH3), 7.38–7.44 (m, 2H, ArH), 7.69 (d, 1H, J = 7.6 Hz, ArH), 8.04 (d,
2H, J = 8.4 Hz, ArH), 8.15 (s, 1H, =CH), 8.22 (d, 3H, J = 8.4 Hz,
ArH), 9.79 (s, 1H, indolyl-2-CH). ESI-HRMS: Calcd for C22H19N3O3
(MH+): 374.1505; found: 374.1511.
Methyl 4-{4-[[1-(2-tert-butoxy-2-oxoethyl)-1H-indol-3-yl]meth-
ylene]-3-methyl-5-oxo-4,5-dihydro-1H- pyrazol-1-yl}benzoate (16):
Yield: 76%; m.p. 220–222 °C; νmax (KBr, cm−1): 1741 (ester CO), 1708
1
(CO); H NMR (DMSO-d6): δ 2.32 (s, 3H, CH3), 2.41 (s, 3H, CH3),
7.23 (d, 2H, J = 8.4 Hz, ArH), 7.31–7.33 (m, 2H, ArH), 7.59 (m, 1H,
ArH), 7.72 (d, 1H, J = 7.2 Hz, ArH), 7.88 (d, 2H, J = 8.4 Hz, ArH),
8.11 (s, 1H, =CH), 8.16–8.19 (m, 1H, ArH), 9.82 (s, 1H, indolyl-2-
CH), 12.71 (s, 1H, NH). ESI-HRMS: Calcd for C20H17N3O (M+Na+):
338.1269; found: 338.1261.
3-Methyl-4-[(1-methyl-1H-indol-3-yl)methylene]-1-p-tolyl-1H-
pyrazol-5-one (9): Yield: 77%; m.p. 176–178 °C; νmax (KBr, cm−1):
(ester CO), 1682 (CO); H NMR (DMSO-d6): δ 1.45 (s, 9H, 3CH3),
1
1
1668 (CO); H NMR (DMSO-d6): δ 2.32 (s, 3H, CH3), 2.41 (s, 3H,
2.46 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 5.39 (s, 2H, CH3), 7.37–7.40
(m, 2H, ArH), 7.60 (m, 1H, ArH), 8.05 (d, 2H, J = 8.4 Hz, ArH), 8.17
(s, 1H, =CH), 8.24 (m, 3H, ArH), 9.78 (s, 1H, indolyl-2-CH). ESI-
HRMS: Calcd for C27H27N3O5 (MH+): 474.2029; found: 474.2036.
Methyl 4-{4-[(1-benzl-1H-indol-3-yl)methylene]-3-methyl-5-oxo-
4,5-dihydro-1H-pyrazol-1-yl}benzoate (17): Yield: 79%; m.p. 236–
CH3), 4.02 (s, 3H, CH3), 7.23 (d, 2H, J = 8.0 Hz, ArH), 7.37–7.40 (m,
2H, ArH), 7.67 (d, 1H, J = 7.2 Hz, ArH), 7.89 (d, 2H, J = 8.4 Hz,
ArH), 8.08 (s, 1H, =CH), 8.20 (d, 1H, J = 8.4 Hz, ArH), 9.80 (s, 1H,
indolyl=CH). ESI-HRMS: Calcd for C21H19N3O (MH+): 330.1606;
found: 330.1610.
(4Z)-4-[(1-Methyl-1H-indol-3-yl)methylene]-3-phenyl-1-p-tolyl-
1H-pyrazol-5-one (10): Yield: 78%; m.p. 206–208 °C; νmax (KBr,
cm−1): 1674 (CO); 1H NMR (DMSO-d6): δ 2.34 (s, 3H, CH3), 4.06 (s,
3H, CH3), 7.28 (d, 2H, J = 8.4 Hz, ArH), 7.33–7.42 (m, 2H, ArH),
7.59–7.65 (m, 3H, ArH), 7.69 (d, 1H, J= 7.6 Hz, ArH), 7.79 (m, 3H,
ArH), 7.97 (d, 2H, J = 8.4 Hz, ArH), 8.10 (s, 1H, =CH), 9.88 (s, 1H,
indolyl=CH). ESI-HRMS: Calcd for C26H21N3O (MH+): 392.1763;
found: 392.1776.
238 °C; νmax (KBr, cm−1): 1708 (ester CO), 1678 (CO); H NMR
1
(DMSO-d6): δ 2.45 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 5.73 (s, 2H,
CH2), 7.30–7.38 (m, 7H, ArH), 7.69 (m, 1H, ArH), 8.04 (d, 2H, J =
8.4 Hz, ArH), 8.17 (s, 1H, =CH), 8.25 (m, 3H, ArH), 9.93 (s, 1H,
indolyl-2-CH). ESI-HRMS: Calcd for C28H23N3O3 (MH+): 450.1818;
found: 450.1808.
4-{4-[(1H-Indol-3-yl)methylene]-3-methyl-5-oxo-4,5-dihydro-1H-
pyrazol-1-yl}benzoic acid (18): Yield: 80%; m.p. >300 °C; νmax (KBr,
cm−1): 3195 (NH, COOH), 1691 (CO),; 1H NMR (DMSO-d6): δ 2.45
(s, 3H, CH3), 7.32–7.35 (m, 2H, ArH), 7.60–7.62 (m, 1H, ArH), 8.01
(d, 2H, J = 8.4 Hz, ArH), 8.18 (m, 4H, ArH, =CH), 9.81 (s, 1H,
indolyl-2-CH), 12.75 (s, 1H, NH), 12.81 (s, 1H, COOH). ESI-HRMS:
Calcd for C20H15N3O3 (MH+): 346.1192; found: 346.1194.
4-[(1-Benzyl-1H-indol-3-yl)methylene]-3-phenyl-1-p-tolyl-1H-
pyrazol-5-one (11): Yield: 80%; m.p. 210–212 °C; νmax (KBr, cm−1):
1
1673 (CO); H NMR (DMSO-d6): δ 2.34 (s, 3H, CH3), 5.74 (s, 2H,
CH2), 7.28–7.39 (m, 9H, ArH), 7.59–7.65 (m, 3H, ArH), 7.69–7.71
(m, 1H, ArH), 7.78–7.82 (m, 3H, ArH), 7.95 (d, 2H, J = 8.4 Hz, ArH),
8.12 (s, 1H, =CH), 10.03 (s, 1H, indolyl-2-CH). ESI-HRMS: Calcd
for C32H25N3O (MH+): 468.2076; found: 468.2076.
4-[(1H-Indol-3-yl)methylene]-3-phenyl-1-p-tolyl-1H-pyrazol-5-
one (12): Yield: 80%; m.p. 174–176 °C; νmax (KBr, cm−1): 3257 (NH),
1658 (CO); 1H NMR (DMSO-d6): δ 2.34 (s, 3H, CH3), 7.28–7.34 (m,
4H, ArH), 7.57–7.65 (m, 4H, ArH), 7.74–7.81 (m, 3H, ArH), 7.96 (d,
2H, J =8.4 Hz, ArH), 8.13 (s, 1H, =CH), 9.90 (s, 1H, indolyl-2-CH),
12.78 (s, 1H, NH). ESI-HRMS: Calcd for C25H19N3O (MH+): 378.1606;
found: 378.1603.
4-{3-Methyl-4-[(1-methyl-1H-indol-3-yl)methylene]-5-oxo-4,5-
dihydro-1H-pyrazol-1-yl}benzoic acid (19): Yield: 82%; m.p. >300 °C;
νmax (KBr, cm−1): 3409 (COOH), 1685 (CO); H NMR (DMSO-d6):
1
δ 2.44 (s, 3H, CH3), 4.04 (s, 3H, CH3), 7.37–3.43 (m, 2H, ArH), 7.68
(m, 1H, ArH), 8.01–8.05 (m, 3H, ArH), 8.13 (s, 1H, =CH), 8.22 (m,
2H, ArH), 9.78 (s, 1H, indolyl-2-CH), 12.88 (s, 1H, COOH). ESI-
HRMS: Calcd for C21H17N3O3 (MH+): 360.1348; found: 360.1339.
4-{4-[(1-Acetyl-1H-indol-3-yl)methylene]-3-methyl-5-oxo-4,5-
dihydro-1H-pyrazolyl}benzoic acid (20): Yield: 79%; m.p. >300 °C;
1H NMR (DMSO-d6): δ 2.41 (s, 3H, CH3), 3.86 (s, 3H, CH3), 7.34
(dd, 2H, J = 2.4 Hz, J = 7.2 Hz, ArH), 7.60 (m, 1H, CH), 7.93 (d, 2H,
4-[(1-Benzyl-1H-indol-3-yl)methylene]-1-(4-chlorophenyl)-3-
phenyl-1H-pyrazole-5-one (13): Yield: 78%; m.p. 248–250 °C; νmax

JOURNAL OF CHEMICAL RESEARCH 2012 695
J = 8.4 Hz, ArH), 7.99 (s, 1H, CH), 8.02 (m, 2H, CH), 8.09 (s, 1H,
=CH), 9.81 (s, 1H, indolyl-2-CH), 12.80 (s, 1H, COOH). ESI-HRMS:
Calcd for C22H17N3O4 (MH+–CH2CO): 346.1192; found: 346.1190,
384.0748 (M+K+-CH2CO).
ArH), 8.28 (m, 1H, CH), 8.39 (m, 1H, CH), 10.09 (s, 1H, indolyl-
2CH). ESI-HRMS: Calcd for C23H19N3O4 (MH+): 402.1454; found,
402.1456.
4-{4-[[1-(2-tert-Butoxy-2-oxoethyl)-1H-indol-3-yl]methylene]-3-
methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl}benzoic acid (30): Yield:
79%; m.p. >300 °C; νmax (KBr, cm−1): 3458 (COOH), 1738 (COOH),
4-[(1-Acetyl-1H-indol-3-yl)methylene]-1-(4-chlorophenyl)-3-
phenyl-1H-pyrazol-5-one (21): Yield: 76%; m.p. 266–268 °C; νmax
1
1
1679 (CO); H NMR (DMSO-d6): δ 1.45 (s, 9H, CH3), 2.46 (s, 3H,
(KBr, cm−1): 1719 (acetyl CO), 1679 (CO); H NMR (DMSO-d6): δ
CH3), 5.37 (s, 2H, CH2), 7.38 (m, 2H, ArH), 7.58 (m, 1H, ArH),
8.02 (d, 2H, J = 8.4 Hz, ArH), 8.01–8.27 (m, 4H, ArH, =CH), 9.78 (s,
1H, indolyl-2-CH), 12.80 (s, 1H, COOH). ESI-HRMS: Calcd for
C26H25N3O5 (MH+): 460.1872; found: 460.1863.
2.86 (s, 3H, CH3), 7.43–7.51 (m, 2H, ArH), 7.58 (d, 2H, J = 8.4 Hz,
ArH), 7.65 (m, 3H, ArH), 7.85 (m, 3H, ArH), 8.10 (s, 1H, =CH), 8.13
(d, 2H, J = 7.2 Hz, ArH), 8.41 (d, 1H, J = 7.2 Hz, ArH), 10.16 (s, 1H,
indolyl-2-CH). ESI-HRMS:CalcdforC26H18ClN3O2 (MH+):440.1166;
found: 440.1161 (100%), 442.1147 (38%).
tert-Butyl 2-{3-[(1-(4-chlorophenyl)-5-oxo-3-phenyl-1H-pyrazol-
4(5H)-ylidene)methyl]-1H-indol-1- yl}acetate (22): Yield: 78%; m.p.
274–276 °C; νmax (KBr, cm−1): 1747 (ester CO), 1673 (CO); 1H NMR
(DMSO-d6): δ 1.45 (s, 9H, 3CH3), 5.40 (s, 2H, CH2), 7.32–7.41
(m, 2H, ArH), 7.53–7.56 (m, 2H, ArH), 7.60–7.67 (m, 4H, ArH),
7.78– 7.84 (m, 3H, ArH), 8.14 (m, 3H, ArH, =CH), 9.86 (s, 1H,
indolyl-2-CH). ESI-HRMS:CalcdforC30H26ClN3O3 (MH+):512.1741;
found: 512.1730 (100%), 514.1765 (38%).
4-[(1-Acetyl-1H-indol-3-yl)methylene]-1-(4-chlorophenyl)-3-
methyl-1H-pyrazol-5(4H)-one (23): Yield: 82%; m.p. 236–240 °C;
νmax (KBr, cm−1): 1718 (acetyl CO), 1675 (CO); 1H NMR (DMSO-d6):
δ 2.46 (s, 3H, CH3), 2.82 (s, 3H, COCH3), 7.49 (m, 2H, ArH), 7.52 (d,
2H, J = 8.4 Hz, ArH), 8.03 (d, 2H, J = 8.4 Hz, ArH), 8.15 (s, 1H,
=CH), 8.28 (m, 1H, ArH), 8.40 (m, 1H, ArH), 10.11 (s, 1H, indolyl-2-
CH). ESI-HRMS: Calcd for C21H16ClN3O2 (MH+): 378.1009; found:
378.1007 (100%), 380.1011 (38%).
4-[(1-Acetyl-1H-indol-3-yl)methylene]-3-phenyl-1-p-tolyl-1H-pyr-
azol-5-one (31):Yield: 79%; m.p. 244–246 °C; νmax (KBr, cm−1): 1721
1
(acetyl CO), 1675 (CO); H NMR (DMSO-d6): δ 2.36 (s, 3H, CH3),
2.85 (s, 3H, CH3), 7.32 (d, 2H, J = 8.0 Hz, ArH), 7.42–7.51 (m, 2H,
ArH), 7.64 (m, 3H, ArH), 7.84 (m, 3H, ArH), 7.92 (d, 2H, J = 8.0 Hz,
ArH), 8.11 (s, 1H, =CH), 8.41 (d, 1H, J = 8.0 Hz, ArH), 10.18 (s, 1H,
indolyl-2-CH). ESI-HRMS: Calcd for C27H21N3O2 (MH+): 420.1712;
found: 420.1717.
tert-Butyl 2-{3-[(5-oxo-3-phenyl-1-p-tolyl-1H-pyrazol-4(5H)-yli-
dene)methyl]-1H-indol-1-yl}-acetate (32): Yield: 76%; m.p. 264–
1
266 °C; νmax (KBr, cm−1): 1721 (ester CO), 1675 (CO); H NMR
(DMSO-d6): δ 1.45 (s, 9H, CH3), 2.34 (s, 3H, CH3), 5.39 (s, 2H, CH2),
7.28–7.39 (m, 4H, ArH), 7.60 (m, 4H, ArH), 7.80 (m, 3H, ArH), 7.96
(d, 2H, J = 8.0 Hz, ArH), 8.12 (s, 1H, =CH), 9.87 (s, 1H, indolyl-2-
CH). ESI-HRMS: Calcd for C31H29N3O3 (MH+): 492.2287; found:
492.2276, 530.1829 (M+K+).
Crystal structure of 9
A saturated solution of compound 9 in CH2Cl2-DMF (1:2) at room
temperature enabled slow solvent evaporation to improve crystal
growth. A suitable crystal was selected and placed on Xcalibur Eos
diffractometer. The crystal was kept at 293.15 K during data collec-
tion. Using Olex2,29 the structure was resolved with the ShelXS struc-
ture solution program using direct methods and refined with the
ShelXL refinement package using least squares minimisation (crystal
information is shown in Table 4).30
1-(4-Chlorophenyl)-4-[(1-methyl-1H-indol-3-yl)methylene]-3-
phenyl-1H-pyrazol-5(4H)-one (24): Yield: 79%; m.p. 216–218 °C;
1
νmax (KBr, cm−1): 1674 (CO); H NMR (DMSO-d6): δ 4.05 (s, 3H,
CH3), 7.35 (d, 1H, J = 7.2 Hz, CH), 7.40 (d, 1H, J = 7.2 Hz, CH), 7.54
(d, 2H, J = 9.2 Hz, CH), 7.60–7.70 (m, 3H, ArH), 7.69 (d, 1H, J =
7.6 Hz, ArH), 7.78 (m, 3H, ArH), 8.10 (s, 1H, =CH), 8.15 (d, 2H, J =
8.4 Hz, ArH), 9.86 (s, 1H, indolyl-2-CH). ESI-HRMS: Calcd for
C25H18ClN3O (MH+): 412.1217; found: 412.1208 (100%), 414.1221
(38%).
Bioactivity assay
All the target compounds were evaluated for their antitumour activity
against A549, HCT116, HepG2, PC-9 and A375 cancer cells by the
MTT assay with 5-FU and sunitinib as positive controls. Cells
(4–5×103/well) were seeded in 96-well plates and cultured for 24 h,
followed by various concentrations of compounds treatment for 48 h.
MTT (10 µL of 10 mg mL−1) was added per well and incubated for
Methyl 4-{4-[(1H-indol-3-yl)methylene]-3-methyl-5-oxo-4,5-dihy-
dro-1H-pyrazol-1-yl}benzoate (25): Yield: 77%; m.p. 280–282 °C;
νmax (KBr): 3257 (NH), 1713 (ester CO), 1663 (CO); 1H NMR (DMSO-
d6): δ 2.45 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 7.35 (dd, 2H, J = 2.4 Hz,
J = 7.2 Hz, CH), 7.612 (dd, 1H, J = 2.4 Hz, J = 7.2 Hz, CH), 8.04 (d,
2H, J = 8.4 Hz, CH), 8.18–8.23 (m, 4H, ArH, =CH), 9.81 (s, 1H,
indolyl-2-CH), 12.75 (s, 1H, NH). ESI-HRMS: Calcd for C21H17N3O3
(MH+): 360.1348; found: 360.1353.
4-[(1-Benzyl-1H-indol-3-yl)methylene]-1-(4-chlorophenyl)-3-
methy-1H-pyrazol-5-one (26): Yield: 76%; m.p. 240–242 °C; νmax
Table 4 Crystal structure determination information of 10
Identification code
(4Z)-4-((1-Methyl-1H-indol-
3-yl)methylene)-3-phenyl-1-
p-tolyl-1H-pyrazol-5-one
1
(KBr, cm−1): 1670 (CO); H NMR (DMSO-d6): δ 2.43 (s, 3H, CH3),
5.71 (s, 2H, CH2), 7.28–7.38 (m, 7H, ArH), 7.49 (d, 2H, J = 8.4 Hz,
ArH), 7.68 (m, 1H, ArH), 8.05 (d, 2H, J = 8.4 Hz, ArH), 8.14 (s, 1H,
=CH), 8.23 (m, 1H, ArH), 9.93 (s, 1H, indolyl-2-CH). ESI-HRMS:
Calcd for C26H20ClN3O (MH+): 426.1373; found: 426.1381 (100%),
428.1335 (38%).
Empirical formula
Mr
C26H21N3O
391.46
Crystal system
Space group
Volume/Å3
Monoclinic
P21
4-[(1H-Indol-3-yl)methylene]-1-(4-chlorophenyl)-3-methyl-1H-
pyrazol-5-one (27): Yield: 80%; m.p. 280–282 °C; νmax (KBr, cm−1):
3060.8(3)
1
Z
6
3242 (NH), 1658 (CO); H NMR (DMSO-d6): δ 2.42 (s, 3H, CH3),
µ(Mo Kα)
0.079
7.33 (dd, 2H, J = 2.4 Hz, J = 7.2 Hz, Ph), 7.49 (d, 2H, J = 7.6 Hz,
ArH), 7.60 (m, 1H, ArH), 8.06 (d, 2H, J = 8.4 Hz, ArH), 8.15 (s, 1H,
=CH), 8.18 (m, 1H, ArH), 9.81 (s, 1H, indolyl-2-CH), 12.70 (s, 1H,
NH). ESI-HRMS: Calcd for C19H14ClN3O (MH+): 336.0904; found:
336.0908 (100%), 338.0898 (38%).
4-{4-[(1-Benzyl-1H-indol-3-yl)methylene]-3-methyl-5-oxo-4,5-
dihydro-1H-pyrazol-1-yl}benzoic acid (28): Yield: 82%; m.p. 298–
302 °C; νmax (KBr, cm−1): 3434 (COOH), 1681 (CO); 1H NMR
(DMSO-d6): δ 2.45 (s, 3H, CH3), 5.73 (s, 2H, CH2), 7.3–7.38 (m, 7H,
ArH), 7.69 (d, 1H, J = 7.6 Hz, ArH), 8.01 (d, 2H, J = 8.4 Hz, ArH),
8.16 (s, 1H, =CH), 8.19 (s, 2H, ArH), 8.24 (d, 1H, J = 7.2 Hz, ArH),
9.94 (s, 1H, indolyl-2CH), 12.79 (s, 1H, COOH). ESI-HRMS: Calcd
for C27H21N3O3 (MH+): 436.1661; found: 436.1668.
ρcalcd/mg mm-3
m mm−1
1.274
0.079
F(000)
1236
Crystal size/mm3
2Θ range for data collection
Index ranges
0.38 × 0.30 × 0.25
5.94 to 50°
–14 ≤ h ≤ 16, –15 ≤ k ≤ 17,
–17 ≤ l ≤ 18
12662
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
Final R indexes [I>=2σ (I)]
Final R indexes [all data]
Largest diff. peak/hole/e Å−3
Flack parameter
8028[R(int) = 0.0205]
8028/1/817
1.031
R1 = 0.0428, wR2 = 0.0845
R1 = 0.0630, wR2 = 0.0955
0.120/–0.158
0.7(12)
Methy 4-{4-[(1-acetyl-1H-indol-3-yl)methylene]-3-methyl-5-oxo-
4,5-dihydro-1H-pyrazol-1-yl}benzoate (29): Yield: 81%; m.p. 238–
Program
Olex2, ShelXS, ShelXL
CCDC873677
1
240 °C; νmax (KBr, cm−1): 1718 (acetyl CO), 1676 (CO); H NMR
Crystal chromatography data
deposited accession number
(DMSO-d6): δ 2.50 (s, 3H, CH3), 2.84 (s, 3H, COCH3), 3.86 (s, 3H,
CH3), 7.49 (brs, 2H, ArCH), 8.07 (m, 2H, CH), 8.18 (2s, 3H, =CH,

696 JOURNAL OF CHEMICAL RESEARCH 2012
6
7
8
T.A. Smith, Phytochemistry, 1977, 16, 171.
another 2.5 h at 37 °C, then the supernatant fluid was removed and
DMSO was added 150 µL/well for 15–20 min. The light absorptions
(OD) were measured at 570 nm with SpectraMAX M5 microplate
spectrophotometer (Molecular Devices). The effect of compounds on
tumour cells viability was expressed by the IC50 of each cell lines, the
IC50 values are shown in Table 2.
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Conclusion
A series of 4-(indol-3-yl-methylene)-1H-pyrazol-5(4H)-one
compounds have been synthesised and evaluated for their
anti-proliferative activity against five cancer cells in culture.
All compounds exhibited anti-proliferative activity against the
PC-9 cell line, and most compounds also were active against
the A549 cell line. We consider analogues containing carboxyl
or 2,4-dinitro at 1-phenyl of pyrazole moieties and benzyl at
1-position of indole worthy of consideration for further struc-
tural optimisation and development as potential anticancer
agents for the treatment of lung cancer.
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Received 24 April 2012; accepted 30 July 2012
Paper 1201278 doi: 10.3184/174751912X13501278349974
Published online: 5 December 2012
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