Synthesis and antitumor evaluation of novel 5-bromo indole-aryl keto hydrazide-hydrazone analogues

Article abstract of DOI:10.14233/ajchem.2018.21114

A wide variety of indole, substituted benzaldehyde linked keto hydrazide-hydrazone analogues were designed, synthesized and evaluated for their cytotoxicity against eight human cancer cell lines HeLa, A549, MCF-7, K562, HEK293, HT29, SF295 and HL60. All these synthesized compounds showed potent antitumor activities on the above eight human cancer cell lines. Among them, 6a and 6h compounds exhibited potent antitumor activity on HL 60 and A549 cancer cell lines with IC₅₀ value of 3.913 and 4.838 μM than the standard drug cisplatin with IC₅₀ values of 27 and 36 μM, respectively.

Full text of DOI:10.14233/ajchem.2018.21114

Asian Journal of Chemistry; Vol. 30, No. 6 (2018), 1201-1204
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2018.21114
Synthesis and Antitumor Evaluation of Novel
5-Bromo Indole-Aryl Keto Hydrazide-Hydrazone Analogues
1
2
1
1,*
DURGESH RUDAVATH , REDDYMASU SREENIVASULU , SRINIVASA RAO PINAPATI and RUDRARAJU RAMESH RAJU
1Department of Chemistry, Acharya Nagarjuna University, Nagarjuna Nagar-522 510, India
2Department of Chemistry, University College of Engineering (Autonomous), Jawaharlal Nehru Technological University, Kakinada-533 003,
India
*Corresponding author: E-mail: rrraju1@gmail.com
Received: 31 October 2017;
Accepted: 9 February 2018;
Published online: 30 April 2018;
AJC-18864
A wide variety of indole, substituted benzaldehyde linked keto hydrazide-hydrazone analogues were designed, synthesized and evaluated
for their cytotoxicity against eight human cancer cell lines HeLa, A549, MCF-7, K562, HEK293, HT29, SF295 and HL60. All these
synthesized compounds showed potent antitumor activities on the above eight human cancer cell lines.Among them, 6a and 6h compounds
exhibited potent antitumor activity on HL 60 and A549 cancer cell lines with IC50 value of 3.913 and 4.838 µM than the standard drug
cisplatin with IC50 values of 27 and 36 µM, respectively.
Keywords: 5-Bromo indole, Keto hydrazide-hydrazones, Lung cancer, Bone marrow cancer, MTT assay.
INTRODUCTION
EXPERIMENTAL
Heterocycles by far are the largest classical division of
organic chemistry and are of immense importance. Synthesis
of such heterocyclic compounds are pharmaceutical impor-
tant and a foremost task of chemists due to its vast pharma-
cological and industrial applications. A large number of
heterocyclic systems with different hetero moieties act as good
anticancer agents in cancer chemotherapy and showed potent
anticancer activities against a panel of human cancer cell lines
[1-10].
From these heterocyclic compounds, indole fused aryl
aldehyde compounds constitute an important class of compounds
for new drug development, in order to discover an effective
indole hydrazide-hydrazone derivatives against human cancer
cell lines. Previously indole-hydrazide-hydrazone derivatives
shows antimicrobial [11-17], antifungal [18], anticonvulsant
[19], anti-inflammatory, antiplatelet [20-24] and antituber-
culosis activities [25-28]. But these series of indole fused aryl
aldehydes analogues shows potent antitumor [29-33] activity
on anticancer [34-36] human cell lines.
All the chemicals, reagents and solvents were purchased
from AVRA Pvt. Ltd and Sigma Aldrich. Purity of the comp-
ounds was checked by TLC on silica gel plates and spots were
visualized by exposure to Ultra Violet light. Micro analysis
was done on Perkin-Elmer model 240 analyzer and the values
were found within 0.4 % of the theoretical values. 1H NMR
spectra were recorded on BRUKER-400 Ultra Shield TM spectro-
meter. Chemical shifts (δ) are expressed in ppm using DMSO-
d6 solvent and tetra methyl saline (TMS) as internal standard.
The physical constants and spectral data of the synthesized
compounds are presented.
General procedure: The synthesis of novel indole-aryl
fused keto hydrazide-hydrazone analogues were shown in
Scheme-I. 5-Bromo indole (1) on methylation with DMC,
K2CO3 at 130 °C in DMF as solvent over a period of 4 h gave
5-bromo-N-methyl indole (2). The compound 2 treated with
oxalyl chloride at 0 °C in diethyl ether as solvent for 6 h then
afforded 5-bromo-N-methyl indolyl mono oxolyl chloride (3).
This mono oxolyl chloride (3) was refluxed with hydrazine
hydrate with ethanol over 6 h gave 5-bromo N-methyl indolyl
keto-3-carbohydrazide (4). Finally, this keto carbohydrazide
(4) refluxed with different aryl aldehydes (5a-i) in ethanol
and glacial acetic acid over 6 h afforded new indole-aryl fused
keto hydrazide-hydrazone derivatives (6a-i) with good yields.
Similarly, hydrazide-hydrazone (-CO-NH-N=CH-)
moiety was also evaluated for different biological activities
including antitubercular, antimicrobial, antimalarial, anti-
convulsant, anti-inflammatory, antileishmanial and antitumour
activities.

1202 Rudavath et al.
Asian J. Chem.
O
O
Cl
Br
Br
O
Cl-C-C-Cl
O
Br
DMF/DMC
Di ethyl ether
00C (4hrs)
NH2NH2
C2H5OH
+
N
K2CO3
Reflux 130 0C (4 hrs)
N
N
H
CH3
CH3
(1)
(3)
(2)
O
O
O
H
CHO
N
NHNH2
Br
Br
R
N
Ethanol
+
CH3COOH
R
O
N
N
CH3
CH3
(4)
(5) (a-j)
(6) (a-j)
5a: R =
5b: R =
5c: R =
5d: R =
o
-NO2
5f: R =
5g: R =
5h: R = H
5i: R =
5j: R =
o
m
-OH
-OH
6a: R =
6b: R =
6c: R =
6d: R =
o
o
p
p
-NO2
-Cl
-F
-OH
-CH3
6f: R =
6g: R =
6h: R = H
o
-OH
o
-Cl
-F
-OH
-CH3
m-OH
p
p
p
p-N(CH3)2
6i: R =
6j: R =
p
-N(CH3)2
5e: R =
6e: R = p
m
-Br
m-Br
Scheme-I: Schematic representation for the synthesis of novel keto hydrazide-hydrazones
Synthesis of (E)-N’-(2-nitrobenzylidene)-2-(5-bromo-
1-methyl-1H-indol-3-yl)-2 oxoaceto hydrazide (6a): 500 mg
(1.7 mmol, 1.0 eq) of 2-(5-bromo-1-methyl-1H-indol-3-yl)-
2-oxoacetohydrazide (4) was dissolved in 3 mL of acetic acid,
to this 179 mg (1.7 mmol, 1 eq) of o-nitro benzaldehyde was
added and stir for 6 h at 90 °C. Later the reaction mass was
neutralized with a cold NaHCO3 solution, filtered and recrysta-
llize from ethanol then afforded 6a. m.p. = 328-330 °C; m.w.
= 429; IR (KBr, νmax, cm-1) = 3195, 1666, 1527, 1344, 1197,
The compound 6d was prepared by following the method des-
cribed for the preparation of the compound 6a, employing 500
mg, 1.0 eq. 4 with 1.7 mmol, 1.0 eq p-hydroxy benzaldehyde
5d then gave 6d. m.p. = 332-334 °C; m.p. = 400; IR (KBr,
ν
max, cm-1) = 3246, 1665, 1513, 1373, 1241, 979, 791; 1H NMR
(DMSO-d6,400 MHz, δ ppm) = 8.28 (s, 1H CH) 8.05 (brs, 1H
NH); 7.77-7.86 (m, 4H Ar-H); 7.27-7.46 (m, 4H Ar-H) 4.09
(s, 3H CH3); ESI-MS:400 (M+H)+.
Synthesis of (E)-N’-(4-methylbenzylidene)-2-(5-bromo-
1-methyl-1H-indol-3-yl)-2-oxoacetohydrazide (6e): The
compound 6e was prepared by following the method described
for the preparation of the compound 6a, employing 500 mg,
1.0 eq. 4 with 1.7 mmol, 1.0 eq p-methyl benzaldehyde 5e
then afforded 6e. m.p. = 320-321 °C; m.w. = 398; IR (KBr,
1
980, 790; H NMR (DMSO-d6, 400 MHz, δ ppm) = 8.17 (s,
1H CH) 8.15 (brs, 1H NH); 7.64-7.83 (m, 4H Ar-H); 7.23-
7.42 (m, 4H Ar-H); 4.04 (s, 3H CH3); ESI-MS: 429 (M+H)+.
Synthesis of (E)-N’-(2-chlorobenzylidene)-2-(5-bromo-
1-methyl-1H-indol-3-yl)-2-oxoacetohydrazide (6b): The
compound 6b was prepared by following the method described
for the preparation of the compound 6a, employing 500 mg,
1.0 eq. 4 with 1.7 mmol, 1.0 eq. o-chloro benzaldehyde 5b then
gave 6b. m.p. = 325-327 °C; m.w. = 418; IR (KBr, νmax, cm-1)
= 3193, 1662, 1550, 1371, 1236, 959, 792; 1H NMR (DMSO-
d6, 400 MHz, δ ppm) = 8.62 (s, 1H CH) 8.40 (brs, 1H NH);
7.66-8.06 (m, 4H Ar-H); 7.25-7.51 (m, 4H Ar-H); 3.75 (s, 3H
CH3); ESI-MS: 418 (M+H)+.
Synthesis of (E)-N’-(4-fluorobenzylidene)-2-(5-bromo-
1-methyl-1H-indol-3-yl)-2-oxoaceto hydrazide (6c): The
compound 6c was prepared by following the method described
for the preparation of the compound 6a, employing 500 mg,
1.0 eq. 4 with 1.7 mmol, 1.0 eq p-fluoro benzaldehyde 5c
ν
max, cm-1) = 3202, 1664, 1546, 1370, 1235, 975, 788; 1H NMR
(DMSO-d6,400 MHz, δ ppm) = 8.23 (s, 1H CH) 8.02 (brs, 1H
NH); 7.61-7.85 (m, 4H Ar-H); 7.38-7.46 (m, 4H Ar-H) 3.81
(s, 3H CH3); ESI-MS: 398 (M+H)+.
Synthesis of (E)-N’-(2-hydroxybenzylidene)-2-(5-bromo-
1-methyl-1H-indol-3-yl)-2-oxoacetohydrazide (6f): The
compound 6f was prepared by following the method described
for the preparation of the compound 6a, employing 500 mg,
1.0 eq. 4 with 1.7 mmol, 1.0 eq o-hydroxy benzaldehyde 5f
then afforded 6f. m.p. = 326-328 °C; m.w. = 402; IR (KBr,
1
ν
max, cm-1) = 3038, 1660, 1559, 1372, 1225, 758; H NMR
(DMSO-d6,400 MHzδ ppm) = 8.16 (s, 1H, CH) 7.95 (brs, 1H
NH); 7.41-7.84 (m, 4H Ar-H); 6.84-7.33 (m, 4H Ar-H) 3.81
(s, 3H CH3); ESI-MS: 400 (M+H)+.
then given 6c. m.p. = 320-322 °C; m.w. = 402; IR (KBr, νmax
,
1
cm-1) = 3248, 1667, 1510, 1372, 1238, 977, 792; H NMR
(DMSO-d6, 400 MHz, δ ppm) = 8.28 (s, 1H CH), 8.05 (brs,
1H NH); 7.77-7.86 (m, 4H Ar-H); 7.27-7.46 (m, 4H Ar-H);
4.09 (s, 3H CH3); ESI-MS: 402 (M+H)+.
Synthesis of (E)-N’-(3-hydroxybenzylidene)-2-(5-bromo-
1-methyl-1H-indol-3-yl)-2-oxoacetohydrazide (6g): The
compound 6g was prepared by following the method described
for the preparation of the compound 6a, employing 500 mg,
1.0 eq. 4 with 1.7 mmol, 1.0 eq m-hydroxy benzaldehyde 5g
Synthesis of (E)-N’-(4-hydroxybenzylidene)-2-(5-
bromo-1-methyl-1H-indol-3-yl)-2-oxoacetohydrazide (6d):
then gave 6g. m.p. = 333-335 °C; m.w. = 402; IR (KBr, νmax
,

Vol. 30, No. 6 (2018)
Synthesis and Antitumor Evaluation of Novel 5-Bromo Indole-Aryl Keto Hydrazide-Hydrazone Analogues 1203
cm-1) = 3238, 1648, 1540, 1372, 1234, 792; 1H NMR (DMSO-
d6, 400 MHz δ ppm) = 8.18 (s, 1H CH) 7.97 (brs, 1H NH);
7.43-7.85 (m, 4H Ar-H); 7.09-7.40 (m, 4H Ar-H) 3.82 (s, 3H
CH3); ESI-MS: 400 (M+H)+.
Synthesis of (E)-N’-benzylidene-2-(5-bromo-1-methyl-
1H-indol-3-yl)-2-oxoacetohydrazide (6h): The compound
6h was prepared by following the method described for the
preparation of the compound 6a, employing 500 mg, 1.0 eq.
4 with 1.7 mmol, 1.0 eq benzaldehyde 5h then afforded 6h.
m.p. = 327-329 °C; m.w. = 384; IR (KBr, νmax, cm-1) = 3212,
1663, 1554, 1328, 1240, 794; 1H NMR (DMSO-d6, 400 MHz
δ ppm) = 8.23 (s, 1H CH) 8.01 (brs, 1H NH); 7.71-7.80 (m,
4H Ar-H); 7.23-7.67 (m, 4H Ar-H) 3.82 (s, 3H CH3); ESI-
MS: 384 ESI-MS: 400 (M+H)+.
Synthesis of (E)-N’-(4-(dimethylamino)benzylidene)-
2-(5-bromo-1-methyl-1H-indol-3-yl)-2-oxoacetohydrazide
(6i): The compound 6i was prepared by following the method
described for the preparation of the compound 6a, employing
500 mg, 1.0 eq. 4 with 1.7 mmol, 1.0 eq N,N-dimethyl benzal-
dehyde 5i then gave 6i. m.p. = 335-337 °C; m.w. = 427; IR
(KBr, νmax, cm-1) = 3205, 1605, 1524, 1368, 1249, 791; 1H NMR
(DMSO-d6,400 MHzδ ppm) = 8.12 (s, 1H CH) 7.92 (brs, 1H
NH); 7.52-7.85 (m, 4H Ar-H); 6.79-7.45 (m, 4H Ar-H) 4.04
(s, 3H CH3), 3.62-3.81 (s, 3H CH3), 3.01-3.37 (s, 3H CH3);
ESI-MS: ESI-MS:400 (M+H)+.
tested (0.1 to 100 µM) with an incubation period of not more
than 48 h. In order to account for the toxicity of DMSO,
the values obtained for the DMSO control were subtracted
from those of the test compounds. Dose-response curves were
plotted for the test compounds and controls after correction
by subtracting the background absorbance from that of the
blanks. The anticancer potency of these hydrazide hydrazones
compounds (6a-j) indicated by IC50 values (50 % inhibitory
concentration) were calculated by compared to the standard
drug cisplatin. From plotted absorbance data for the dose-
response curves. Statistical analysis was performed using SPSS
software version 16.0. IC50 values (µM) are expressed as the
mean SD of five independent experiments. Human cancer
cell lines were used, HeLa (cervical cancer cell line), A549
(alveolar adenocarcinoma cell line), SF295 (glioblastoma-
multiforme cell line), HT-29 (colorectal adenocarcinoma),
MCF-7 (breast cancer), K562 (chronic myelogenous leukemia
cell line) HEK 293 (normal embryonic kidney cell line) and
HL60 (acute myelogenous leukemia) obtained from the Cell
Bank of the Nexcelom Sciences (NCI 60). All cell lines were
maintained in Eagle’s minimal essential medium (MEM) with
5 % of Fetal bovine serum (FBS), gentamicin 50 µg/mL.
Cultures were maintained in 75 cm2 culture flasks at 37°C,
5 % CO2 and 100 % relative humidity and media was changed
at least twice a week.
Synthesis of (E)-N’-(3-bromobenzylidene)-2-(5-bromo-
1-methyl-1H-indol-3-yl)-2-oxoacetohydrazide (6j): The
compound 6e was prepared by following the method described
for the preparation of the compound 6a, employing 500 mg,
1.0 eq. 4 with 1.7 mmol, 1.0 eq m-bromo benzaldehyde (5j)
RESULTS AND DISCUSSION
in vitro Cytotoxicity: The synthesized 10 analogues were
screened for their anticancer activity against the selected human
cancer cell lines such as cervical (HeLa), alveolar (A549), breast
(MCF-7), chronic myelogenous leukemia (K562), colorectal
(HT29), glioblastomamultiforme (SF295) and acute myelogenous
leukemia (HL60) as per reported protocol.The anticancer activities
of tested compounds ranged between 3.913-57.06 µM (Table-1).
Compound 6a show potent cytotoxicity against four cell lines
with IC50 values 7.433 µM (HeLa), 4.291 µM (MCF-7), 5.43
µM (HT29) and 3.913 µM (HL60) whereas compound 6b shows
potent anticancer activity against six cell lines with IC50 values
9.053 µM (HeLa), 12.419 µM (A549), 9.71 µM (MCF-7) 11.94
µM (K562), 8.11 µM (SF295), 7.791 µM (HL60). The com-
pounds 6c, 6f and 6g showed good anticancer activities against
then afforded 6j. m.p. = 312-314 °C; m.w. = 463; IR (KBr,
1
ν
max, cm-1) = 3197, 1654, 1576, 1331, 1236, 785; H NMR
(DMSO-d6 400 MHz,δ ppm) = 8.24 (s, 1H CH) 8.03 (brs, 1H
NH); 7.82-7.96 (m, 4H Ar-H); 7.52-7.79 (m, 4H Ar-H) 3.82
(s, 3H CH3); ESI-MS: 461 (M+H)+.
Detection method
in vitro cytotoxicity assay: Cytotoxicity activities against
human cancer cell lines of these synthesized compounds were
tested by method of MTT assay. These compounds were dissolved
in dimethyl sulphoxide and diluted in culture media prior to
the application. Different dilutions of each compound were
TABLE-1
BIOLOGICAL ACTIVITY OF 5-BROMO INDOLE ARYL KETO HYDRAZIDE
HYDRAZONE DERIVATIVES WITH STANDARD ANTICANCER DRUG CISPLATIN
Compd.
HeLa
A549
MCF-7
K562
HEK293
HT29
5.43 0.591 17.610 0.331
9.31 0.484 8.110 0.702
SF295
HL60
3.913 0.758
7.791 0.159
6a
6b
6c
6d
6e
7.433 0.233 10.8010 0.922
9.053 0.312 12.4190 0.119
14.711 0.481 45.3300 0.293
4.291 0.502 16.930 0.280 23.714 0.973
9.710 0.910 11.940 0.741 26.560 0.418
5.420 0.240 15.410 0.854 29.440 0.261 14.51 0.751 14.490 0.229 26.040 0.449
7.59 0.638 11.054 0.471 32.590 0.592
49.041 0.492 38.2990 0.450 21.110 0.284 12.380 0.318 15.040 0.611 19.38 0.119 11.621 0.641 25.530 0.628
23.827 0.829 57.0600 0.720 14.600 0.590 27.900 0.300 18.140 0.917
6f
6g
19.115 0.731 15.7390 0.710
9.822 0.491 18.4233 0.381
7.990 0.222 16.590 0.769 12.990 0.594 19.66 0.420 17.940 0.300 15.038 0.749
9.800 0.601 22.500 0.999 25.610 0.731 21.29 0.711 15.820 0.550 19.580 0.495
6h
6i
11.193 0.559
11.361 0.391
4.8380 0.521 15.730 0.109 26.480 0.428 27.550 0.817 17.44 0.351 12.740 0.181 24.920 0.285
8.3000 0.441 19.390 0.841 25.190 0.316 32.680 0.666 14.99 0.109 19.280 0.460 14.060 0.388
6j
11.094 0.694 13.7000 0.803 24.700 0.733 17.370 0.449 44.100 0.269 21.77 0.177 23.050 0.704 19.390 0.571
13.000 0.650 36.0000 0.154 15.000 0.639 28.072 0.881 19.520 0.397 9.05 0.731 14.455 0.770 27.281 0.418
Cisplatin
where, HeLa - Human Cervical cancer cell line; A549 - Human alveolar adenocarcinoma cell line; MCF-7 - Human breast adenocarcinoma cell
line; K562 - Human chronic myelogenous leukemia cell line; HEK 293 - Human normal embryonic kidney cell line; HT29 - Human colorectal
adenocarcinoma; SF295 - Human glioblastoma-multiforme; HL60 - Human acute myelogenous leukemia.

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Among them, 6a and 6h compounds exhibited potent antitumor
activity on HL60 andA549 cancer cell lines with IC50 value of
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IC50 values of 27 µM and 36 µM, respectively. These two comp-
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