Design, synthesis, and spectroscopic study of 7-azaindolyl hydrazones with anti-breast cancer activity

Article abstract of DOI:10.5562/cca3418

A series of 7-azaindolyl hydrazones were prepared by reacting of hydrazides of 7-azaindole-3-acetic acids with aromatic aldehydes and N-substituted indolyl-3-carboxyaldehydes. Structure of all the synthesized compounds were satisfactorily correlated by IR, ¹H NMR, ¹³C NMR and mass spectroscopic evidences. The synthesized compounds were evaluated for their possible anticancer potential against MCF-7 induced breast carcinoma. It is worth mentioning that most of the compounds were considerably active against MCF-7 cell line with GI50 values ranging from 22.3–81.0 μM. The hydrazones of N-1-substituted indole-3-carboxyaldehydes 9f, 9g, 9h, 9c, and 9j were active against MCF-7 cell line with GI50 values less than 40 μM (GI50 = 22.3 and 24.9, 29.6, 30.2 and 37.8 μM respectively) with moderate TGI values (TGI = 56.6, 59.5, 65.5, 70.7 and 94.6 μM respectively). The active compounds were also screened against the normal Vero monkey cell line, which showed moderate selectivity against inhibition of cancer cells.

Full text of DOI:10.5562/cca3418

O R I G I NA L S C I E N T I F I C P A P E R
Croat. Chem. Acta 2019, 92(1), 1–9
Published online: February 28, 2019
DOI: 10.5562/cca3418
Design, Synthesis, and Spectroscopic Study of
7-Azaindolyl Hydrazones with Anti-Breast
Cancer Activity
Sakharam B. Dongare,1 Babasaheb. P. Bandgar,1 Pravin S. Bhale,1 Sadanand N. Shringare,1 Hemant V. Chavan1,2,
*
1
2
Medicinal Chemistry Research Laboratory, School of Chemical Sciences, Solapur University Solapur, Maharashtra, India-413255
Department of Chemistry, A. S. P. College, Devrukh, Dist: Ratnagiri (Affiliated to University of Mumbai), Maharashtra, India-415804
Corresponding author’s e-mail address: hemantchavan.sus@rediffmail.com
*
RECEIVED: September 18, 2018
REVISED: December 10, 2018
ACCEPTED: December 11, 2018
Abstract: A series of 7-azaindolyl hydrazones were prepared by reacting of hydrazides of 7-azaindole-3-acetic acids with aromatic aldehydes
1
and N-substituted indolyl-3-carboxyaldehydes. Structure of all the synthesized compounds were satisfactorily correlated by IR, H NMR, 13C
NMR and mass spectroscopic evidences. The synthesized compounds were evaluated for their possible anticancer potential against MCF-7
induced breast carcinoma. It is worth mentioning that most of the compounds were considerably active against MCF-7 cell line with GI50 values
ranging from 22.3–81.0 μM. The hydrazones of N-1-substituted indole-3-carboxyaldehydes 9f, 9g, 9h, 9c, and 9j were active against MCF-7 cell
line with GI50 values less than 40 μM (GI50 = 22.3 and 24.9, 29.6, 30.2 and 37.8 μM respectively) with moderate TGI values (TGI = 56.6, 59.5,
65.5, 70.7 and 94.6 μM respectively). The active compounds were also screened against the normal Vero monkey cell line, which showed
moderate selectivity against inhibition of cancer cells.
Keywords: 7-azaindole, hydrazone, breast carcinoma.
framework of hydrazide / hydrazone (-CO-NH-N=CH-) has
INTRODUCTION
NDOLE is the most active pharmacophoric nucleus and
applications in building heterocyles[7] with potential anti-in-
flammatory, antimalarial, anticonvulsant, anti-tuberculo-
sis, antitumor, and antimicrobial activities.[8] Apart from
biological importance of hydrazine core, these derivatives
I
major constituent of number of bio-molecules viz in-
dole-3-acetic acid (IAA), oncracin-1, indole 3-carbinol (I3C),
tryptophan, serotonin and melatonin.[1] It is also found in
various natural compounds such as alkaloids.[2] The substi-
tuted bis-indole derivatives like nortopsentin, coscinamide
A-C, indibulin, rhopaladin, labradorin, tenidap and ap-
lysinopsins exhibited various pharmacological properties
such as anti-inflammatory, analgesic and antitumor.[3] One
of the preferred approaches during drug development is to
synthesize analogues of the lead compound. In this regard
indole can be replaced with azaindole where the main core
would be replaced with bioisosteric conceptual atom and
to evaluate the effect on activity. This approach may en-
hance the biological activity with reducing side effects.
Among the various bioisosters of azaindole,[4] 7-azaindole
has received a great deal of attention due to wide variety
of biological activities (Figure 1).[5,6] Similarly, the functional
Figure 1. Bioactive compounds having hydrazide, hydrazone
core with indole or other N-heterocycles.
This work is licensed under a Creative Commons Attribution 4.0 International License.

2
S. B. DONGARE et al.: Design, Synthesis, and Spectroscopic Study …
have been studied and applied in supramolecular chemis-
try, metal and covalent organic framework, dynamic com-
binatorial chemistry, dyes and pigments chemistry.[9]
In continuation of our studies in synthesizing various
biologically active compounds[10] and all the above men-
tioned facts guided us to design and synthesize novel
7-azaindolyl hydrazones in order to evaluate their
anticancer potential.
PROCEDURE FOR PREPARATION OF (2-METHYL-1H-
PYRROLO[2,3-B]PYRIDIN-3-YL)ACETIC ACID
HYDRAZIDE (5)
A solution of hydrazine hydrate (15 mL, 99 %) was added to
a solution of methyl ester of 2-methyl-7-azaindole-3-acetic
acid 4 (10 mmol) in methanol (25 mL). The reaction mixture
was refluxed for 5 h. At the end of reaction monitored by
TLC, the reaction mixture was evaporated under reduced
pressure to ¼ volume and by cooling the white crystalline
pure product was obtained.
Yield: 85 %; m.p. 192–194 °C; IR (KBr, cm–1): 3155,
2952 (CH), 1626 (C=O), 1600 (C=C), 1196, 1167, 993, 796,
769, 664, 652; 1H NMR (400 MHz, DMSO-d6) δ / ppm: 2.35
(s, 3H, CH3), 3.38 (s, 2H, CH2), 4.17 (s, 2H, NH2), 6.95 (dd, J =
6.8 and 4.0 Hz, 1H, ArH), 7.85 (d, J = 8.0 Hz, 1H, ArH), 8.06
(d, J = 5.2 Hz, 1H, ArH), 9.13 (s, 1H, NH), 11.29 (s, 1H, Indole-
NH); ESI-MS: m/z 205.1 (M+1).
EXPERIMENTAL
Materials and Methods
All the chemicals used were of synthetic grade and pro-
cured from Sd-fine, Spectrochem and Aldrich chemicals.
Completion of the reactions was monitored by thin layer
chromatography (TLC) using E-Merck 0.25 mm silica gel
plates using methanol: chloroform (1 : 9) as eluting me-
dium. Visualization was accomplished with UV light and or
iodine vapors. All the solvents were dried using appropriate
drying agents before use. Melting points were determined
by open end capillary method and are uncorrected. All the
1H NMR spectra were recorded in DMSO-d6 / CDCl3 and
chemical shifts in ppm were reported on instrument Bruker
AV-400 MHz, for 1H NMR and 75 MHz for 13C NMR relative
to TMS as an internal standard. The IR spectra were
recorded on Shimadzu FT-IR spectrophotometer by using
1 % potassium bromide discs. The electron ionization mass
spectra were recorded on Agilent 1100 series.
GENERAL PROCEDURE FOR PREPARATION OF
HYDRAZONE DERIVATIVES (8a–l)
A mixture of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-ace-
tic acid hydrazide 5 (1.0 mmol) and substituted aromatic
benzaldehyde 6a–l (1.0 mmol) in 10 mL of ethanol and few
drops of glacial acetic acid was stirred for 3–4 h at room
temperature. A solid was separated out within 15–
20 minutes and the stirring was continued for 3–4 h to com-
plete the reaction. The reaction progress was monitored by
TLC (chloroform / methanol). After completion of the reac-
tion, the product was collected with vacuum filtration and
washed with cold ethanol to give off white crystals of the
desired pure product.
Synthesis
PROCEDURE FOR PREPARATION OF (2-METHYL-1H-
PYRROLO[2,3-B]PYRIDIN-3-YL)ACETIC ACID METHYL
ESTER (4)
N'-(2,4-Dichlorobenzylidene)-2-(2-methyl-1H-pyrrolo[2,3-
b]pyridin-3-yl)acetohydrazide (8a)
The 2-methyl-7-azaindole-3-acetic acid (3)[11] (10 mmol)
were esterified in a classical manner with methanol and cat-
alytic amount of con H2SO4 under reflux for 7 h. After com-
pletion, the reaction mixture was cooled and solvent
methanol was removed under reduced pressure. The residue
was then poured onto crushed ice and extracted repeatedly
with ethyl acetate. The ethyl acetate layer was washed with
saturated sodium bicarbonate solution followed by water.
The ethyl acetate layer was dried over sodium sulphate and
distilled off under reduced pressure. The solid product ob-
tained was filtered, washed with cold ethyl acetate and dried.
Yield: 82 %; m.p. 182–184 °C; IR (KBr, cm–1): 3154
Yield: 91 %; m.p. 272–274 °C; IR (KBr, cm–1): 3155, 3064,
2944, 2763, 1667, 1542, 1473, 1408, 1348, 1295, 1165,
1143, 1100, 1313, 907, 822, 737; 1H NMR (400 MHz, DMSO-
d6) δ / ppm: 2.36 (s, 3H, CH3), 4.03 (s, 2H, CH2), 6.95 (dd, J =
4.8 and 2.8 Hz, 1H, ArH), 7.51 (d, J = 8.8 Hz, 1H, ArH), 7.70–
7.71 (m, 1H, ArH), 7.80 (d, J = 7.6 Hz, 1H, ArH), 8.07-8.08 (m,
2H, ArH), 8.34 (s, 1H, N=CH), 11.32 (s, 1H, NH), 11.54 (s, 1H,
CONH); 13C NMR (75 MHz, DMSO-d6): 11.87, 28.27, 103.20,
115.27, 121.14, 126.05, 128.39, 129.77, 131.08, 134.17,
134.52, 135.22, 138.43, 141.63, 148.24, 167.81, 173.15;
ESI-MS: m / z 361.1 (M+).
1
(NH), 2952 (CH), 1730 (C=O), 1626, 1586, 1558; H NMR
N'-(3,4-Difluorobenzylidene)-2-(2-methyl-1H-pyrrolo[2,3-
b]pyridin-3-yl)acetohydrazide (8b)
(400 MHz, CDCl3) δ / ppm: 2.55 (s, 3H, CH3), 3.70 (s, 3H,
CH3), 3.73 (s, 2H), 7.07–7.10 (m, 1H, ArH), 7.88 (d, J = 4.0 Hz,
Yield 86 %; m.p. 239–241 oC; IR (KBr, cm–1): 3146, 3075 (N-
H), 2944, 2913, 1670, 1613, 1552, 1526, 1497, 1469, 1341,
1H, ArH), 8.25 (d, J = 4.0 Hz, 1H, ArH), 12.03 (s, 1H, NH), 13
C
1
NMR (75 MHz, CDCl3): 21.83, 30.11, 51.97, 102.41, 115.39,
121.56, 126.35, 134.29, 140.64, 148.32, 172.29; ESI-MS:
m / z 205.0 (M+1).
1188, 828; H NMR (400 MHz, DMSO-d6) δ / ppm: 2.36 (s,
3H, CH3), 4.03 (s, 2H, CH2), 6.95 (dd, J = 4.8 and 2.8 Hz, 1H,
ArH), 7.51 (d, J = 8.8 Hz, 1H, ArH), 7.70–7.72 (m, 1H, ArH),
Croat. Chem. Acta 2019, 92(1), 1–9
DOI: 10.5562/cca3418

S. B. DONGARE et al.: Design, Synthesis, and Spectroscopic Study …
3
7.93 (d, J = 8.4 Hz, 1H, ArH), 8.07-8.08 (m, 2H, ArH), 8.34 (s,
1H, N=CH), 11.32 (s, 1H, NH), 11.54 (s, 1H, CONH); ESI-MS:
m / z 328.11 (M+1).
6.30 (s, 2H, ArH), 6.89–6.92 (m, 1H, ArH), 7.89–7.90 (m, 1H,
ArH), 8.03–8.04 (m, 1H, ArH), 8.15 (s, 1H, N=CH), 10.91 (s,
1H, NH), 11.27 (s, 1H, CONH); ESI-MS: m / z 383.2 (M+1)
2-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N'-(3,4,5-
trimethoxybenzylidene)acetohydrazide (8c)
N'-(3-Bromobenzylidene)-2-(2-methyl-1H-pyrrolo[2,3-
b]pyridin-3-yl)acetohydrazide (8h)
Yield 93 %; m.p. 259–261 °C; IR (KBr, cm–1): 3197, 3066,
2987, 2940, 1669, 1579, 1499, 1465, 1368, 1156, 954, 806,
769, 664; 1H NMR (400 MHz, DMSO-d6) δ / ppm: 2.39 (s, 3H,
CH3), 3.58 (s, 2H, CH2), 3.70 (s, 3H OCH3), 3.82 (s, 6H, 2-
OCH3), 6.91–6.93 (m, 1H, ArH), 6.95 (s, 1H, ArH), 7.02 (s, 1H,
ArH), 7.87–7.91 (m, 1H, ArH), 8.05–8.08 (m, 1H, ArH), 8.17
(s, 1H, N=CH), 11.32 (s, 1H, NH), 11.46 (s, 1H, CONH); ESI-
MS: m / z 383.2 (M+1)
Yield 89 %; m.p. 290–292 C; IR (KBr, cm–1): 3156, 3062,
o
2952, 1672, 1588, 1558, 1468, 1443, 1343, 1270, 1068, 887,
703, 682; 1H NMR (400 MHz, DMSO-d6) δ / ppm: 2.39 (s, 3H,
CH3), 4.01 (s, 2H, CH2), 6.92–6.95 (m, 1H, ArH), 7.37–7.42
(m, 1H, ArH), 7.59–7.61 (m, 1H, ArH), 7.65–7.70 (m, 1H,
ArH), 7.82–7.87 (m, 1H, ArH), 7.96 (s, 1H, ArH), 8.05–8.08
(m, 1H, ArH), 8.20 (s, 1H, N=CH), 11.41 (s, 1H, NH), 11.63 (s,
1H, CONH); ESI-MS: m / z 371.1 (M+) (79Br).
N'-(Benzo[d][1,3]dioxol-5-yl-methylene)-2-(2-methyl-1H-
N'-(4-Hydroxybenzylidene)-2-(2-methyl-1H-pyrrolo[2,3-
pyrrolo[2,3-b]pyridin-3-yl)acetohydrazide (8d)
b]pyridin-3-yl)acetohydrazide (8i)
o
o
Yield 90 %; m.p. 235–237 C; IR (KBr, cm–1): 3206, 3063,
Yield 92 %; m.p. 270–272 C; IR (KBr, cm–1): 3649, 3195,
2941, 2901, 1665, 1624, 1588, 1547, 1489, 1450, 1389,
1199, 1185, 1007, 867, 716, 666; 1H NMR (400 MHz, DMSO-
d6) δ / ppm: 2.39 (s, 3H, CH3), 3.98 (s, 2H, CH2), 6.08 (s, 2H,
OCH2), 6.95–6.98 (m, 2H, ArH), 7.11 (d, J = 8.0 Hz, 1H, ArH),
7.21-7.33 (m, 1H, ArH), 7.82–7.90 (m, 1H, ArH), 8.04–8.07
(m, 1H, ArH), 8.15 (s, 1H, N=CH), 11.19 (s, 1H, NH), 11.38 (s,
1H, CONH); ESI-MS: m / z 337.2 (M+1).
3047, 2938, 2902, 1671, 1572, 1441, 1417, 1286, 1183, 902,
736; H NMR (400 MHz, DMSO-d6) δ / ppm: 2.41 (s, 3H,
1
CH3), 3.96 (s, 2H, CH2), 6.70–6.75 (m, 1H, ArH), 6.95–6.98
(m, 1H, ArH), 7.31 (s, 1H, ArH), 7.76–7.82 (m, 1H, ArH),
8.03–8.07 (m, 3H, ArH), 8.13 (s, 1H, N=CH), 9.43 (s, 1H, -
OH), 11.23 (s, 1H, -NH), 11.47 (s, 1H, CONH); ESI-MS: m / z
309.2 (M+1).
N'-(2,4-Difluorobenzylidene)-2-(2-methyl-1H-pyrrolo[2,3-
b]pyridin-3-yl)acetohydrazide (8e)
N'-(3-Fluoro-4-methoxybenzylidene)-2-(2-methyl-1H-
pyrrolo[2,3-b]pyridin-3-yl)acetohydrazide (8j)
o
Yield 86 %; m.p. 239–241 oC; IR (KBr, cm–1): 3146, 3075 (N-
H), 2944, 2913, 1670, 1613, 1552, 1526, 1497, 1469, 1341,
Yield 86 %; m.p. 210–212 C; IR (KBr, cm–1): 3649, 3246,
3156, 3059, 2994, 2943, 1667, 1577, 1549, 1470, 1440,
1
1
1188, 828; H NMR (400 MHz, DMSO-d6) δ / ppm: 2.36 (s,
1189, 1020, 871; H NMR (400 MHz, DMSO-d6) δ / ppm:
3H, CH3), 4.03 (s, 2H, CH2), 6.95 (dd, J = 4.8 and 2.8 Hz, 1H,
ArH), 7.51 (d, J = 8.8 Hz, 1H, ArH), 7.70–7.72 (m, 1H, ArH),
7.93 (d, J = 8.4 Hz, 1H, ArH), 8.07–8.08 (m, 2H, ArH), 8.34 (s,
1H, N=CH), 11.32 (s, 1H, NH), 11.54 (s, 1H, CONH); ESI-MS:
m / z 328.11 (M+1).
2.39 (s, 3H, CH3), 3.88 (s, 3H, OCH3), 3.99 (s, 2H, CH2), 6.91–
6.94 (m, 1H, ArH), 7.20–7.24 (m, 1H, ArH), 7.46 (d, J = 8.0 Hz,
1H, ArH), 7.60 (d, J = 12.0 Hz, 1H, ArH), 7.83 (d, J = 7.6 Hz, 1H,
ArH), 7.92 (s, 1H, N=CH), 8.04-8.07 (m, 1H, ArH), 11.26 (s, 1H,
NH), 11.45 (s, 1H, CONH); ESI-MS: m / z 341.2 (M+1).
2-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N'-(3-
nitrobenzylidene)acetohydrazide (8f)
N'-(4-Hydroxy-3-methoxybenzylidene)-2-(2-methyl-1H-
pyrrolo[2,3-b]pyridin-3-yl)acetohydrazide (8k)
Yield 85 %; m.p.238–240 oC; IR (KBr, cm–1): 3154, 3079,
2953, 1673, 1560, 1531, 1471, 1439, 1588, 1347, 1293,
1144, 954, 736; 1H NMR (400 MHz, DMSO-d6) δ / ppm: 2.40
(s, 3H, CH3), 4.04 (s, 2H, CH2), 6.92–6.93 (m, 1H, ArH), 7.72–
7.74 (m, 1H, ArH), 7.83–7.85 (m, 1H, ArH), 8.06–8.16 (m,
3H, ArH), 8.37 (s, 1H, N=CH), 8.50-8.54 (m, 1H, ArH), 11.37
(s, 1H, NH), 11.55 (s, 1H, CONH); ESI-MS: m / z 338.2 (M+1).
Yield 90 %; m.p. 230–232 C; IR (KBr, cm–1): 3649, 3222,
o
3201, 3047, 2836, 1664, 1543, 1514, 1455, 1430, 1388,
1144, 1075, 955, 803; 1H NMR (400 MHz, DMSO-d6) δ / ppm:
2.39 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 3.98 (s, 2H, CH2), 6.79–
6.83 (m, 1H, ArH), 6.91–6.94 (m, 1H, ArH), 6.96–6.99 (m, 1H,
ArH), 7.31 (s, 1H, ArH), 7.82–7.88 (m, 1H, ArH), 8.04–8.07 (m,
1H, ArH), 8.12 (s, 1H, N=CH), 9.49 (s, 1H, OH), 11.26 (s, 1H,
NH), 11.45 (s, 1H, CONH); ESI-MS: m/z 339.2 (M+1).
2-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N'-(2,4,6-
trimethoxybenzylidene)acetohydrazide (8g)
N'-(4-Cyanobenzylidene)-2-(2-methyl-1H-pyrrolo[2,3-
o
Yield 85 %; m.p. 280–282 C; IR (KBr, cm–1): 3199, 3060,
b]pyridin-3-yl) acetohydrazide (8l)
o
2997, 2940, 1667, 1578, 1497, 1462, 1368, 1156, 952, 806,
767, 664; 1H NMR (400 MHz, DMSO-d6) δ / ppm: 2.33 (s, 3H,
CH3), 3.76 (s, 3H, OCH3), 3.82 (s, 6H, OCH3), 3.92 (s, 2H, CH2),
Yield 88 %; m.p. 195–197 C; IR (KBr, cm–1): 3650, 3242,
3208, 3156, 3050, 2843, 2764, 2227, 1670, 1505, 1460,
1392, 1361, 1253, 1167, 1110, 1015, 974, 932, 739; 1H NMR
DOI: 10.5562/cca3418
Croat. Chem. Acta 2019, 92(1), 1–9

4
S. B. DONGARE et al.: Design, Synthesis, and Spectroscopic Study …
(400 MHz, DMSO-d6) δ / ppm: 2.43 (s, 3H, CH3), 3.98 (s, 2H,
CH2), 6.72–6.77 (m, 1H, ArH), 6.96–6.98 (m, 1H, ArH), 7.76
(d, J = 8 Hz, 2H), 8.03–8.09 (m, 3H), 8.13 (s, 1H, N=CH), 11.26
(s, 1H, NH), 11.49 (s, 1H, CONH); ESI-MS: m / z 318.2 (M+1).
N'-((1-(2,4-difluorobenzyl)-1H-indol-3-yl)-methylene)-2-
(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetohydrazide
(9d)
o
Yield 85 %; m.p. 225–227 C; IR (KBr, cm–1): 3246, 3158,
2993, 2765, 1670, 1615, 1506, 1409, 1373, 1293, 1253,
1
GENERAL PROCEDURE FOR PREPARATION OF
HYDRAZONE DERIVATIVES (9a–j)
mixture of 2-(2-methyl-1H-pyrrolo[2,3-b]pyridine-3-
1167, 1140, 1090, 974, 851, 812, 739, 652; H NMR (400
MHz, DMSO-d6) δ / ppm: 2.37 (s, 3H, CH3), 4.06 (s, 2H, CH2),
5.49 (s, 2H, N-CH2), 6.87–6.90 (m, 1H, ArH), 7.06–7.13 (m,
1H, ArH), 7.16–7.29 (m, 3H, ArH), 7.51–7.56 (m, 1H, ArH),
7.81 (d, J = 7.6 Hz, 1H, ArH), 7.87–7.91 (m, 2H, ArH), 8.02
(d, J = 4.0 Hz, 1H, ArH), 8.17–8.20 (m, 1H, ArH), 8.21 (s, 1H,
N=CH), 11.06 (s, 1H, NH), 11.35 (s, 1H, CONH); ESI-MS: m / z
458.29 (M+1).
A
yl)acetohydrazide 5 (1.0 mmol) and N-1 substituted-indole-
3-carbaldehyde 7a–j (1.0 mmol) in 10 ml ethanol and few
drops of glacial acetic acid was refluxed for 3–4 h to com-
plete the reaction. The reaction progress was monitored by
TLC (chloroform/methanol). After completion of the reac-
tion, the mixture was cooled to room temperature and col-
lected the product with filtration and washed with cold
ethanol to give white crystals of the desired pure product.
N'-((1-(2,4-Dichlorobenzyl)-5-methoxy-1H-indol-3-yl)-
methylene)-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-
yl)acetohydrazide (9e)
o
N'-((1-(4-Chlorobenzyl)-1H-indol-3-yl)-methylene)-2-(2-
Yield 81 %; m.p. 220–222 C; IR (KBr, cm–1): 3155, 3068,
methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetohydrazide (9a)
2942, 1667, 1541, 1505, 1471, 1255, 1230, 1165, 1046, 905,
851; H NMR (400 MHz, DMSO-d6) δ / ppm: 2.37 (s, 3H,
o
1
Yield 81 %; m.p. 192–194 C; IR (KBr, cm–1): 3154, 3067,
2941, 2842, 1668, 1583, 1545, 1491, 1460, 1235, 1141, 762;
1H NMR (400 MHz, DMSO-d6) δ / ppm: 2.33 (s, 3H, CH3),
4.07 (s, 2H, CH2), 5.46 (s, 2H), 6.87–6.90 (m, 1H ), 7.10–7.29
(m, 4H), 7.37–7.40 (m, 1H), 7.47–7.52 (m, 1H), 7.81 (d, J =
7.2 Hz, 1H), 7.95-7.98 (m, 1H), 7.98 (s, 1H), 8.05 (d, J =
4.0 Hz, 1H), 8.17-8.20 (m, 1H), 8.22 (s, 1H), 11.06 (s, 1H,
NH), 11.32(s, 1H, CONH); ESI-MS: m / z 456.29 (M+).
CH3), 3.66 (s, 3H, OCH3), 4.08 (s, 2H, CH2), 5.45 (s, 2H, N-
CH2), 6.84–6.89 (m, 2H, ArH), 7.04–7.06 (m, 1H, ArH), 7.21–
7.30 (m, 2H, ArH), 7.45 (d, J = 8.8 Hz, 1H, ArH), 7.73 (s, 1H,
ArH), 7.79–7.85 (m, 2H, ArH), 8.04 (d, J = 4.0 Hz, 1H, ArH),
8.20 (s, 1H, N=CH), 11.05 (s, 1H, NH), 11.32 (s, 1H, CONH);
ESI-MS: m / z 520.26 (M+).
N'-((1-(2,4-Difluorobenzyl)-5-methoxy-1H-indol-3-yl)-
methylene)-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-
yl)acetohydrazide (9f)
N'-((1-(4-Fluorobenzyl)-1H-indol-3-yl)-methylene)-2-(2-
methyl-1H-pyrrolo[2,3-b]pyridin-3-yl) acetohydrazide (9b)
o
o
Yield 83 %; m.p. 210–212 C; IR (KBr, cm–1): 3158, 3054,
Yield 86 %; m.p. 195–197 C; IR (KBr, cm–1): 3152, 3095,
2939, 2843, 1640, 1574, 1562, 1445, 1418, 1292, 1156, 747;
1H NMR (400 MHz, DMSO-d6) δ / ppm: 2.37 (s, 3H, CH3),
4.06 (s, 2H, CH2), 5.44 (s, 2H, N-CH2), 6.87–6.90 (m, 1H,
ArH), 7.14–7.21 (m, 3H, ArH), 7.31–7.33 (m, 2H, ArH), 7.55
(d, J = 8.0 Hz, 1H, ArH), 7.81 (d, J = 7.2 Hz, 1H, ArH), 7.95–
7.98 (m, 1H, ArH), 7.98 (s, 1H, ArH), 8.05 (d, J = 4.0 Hz, 1H,
ArH), 8.17–8.19 (m, 1H, ArH), 8.22 (s, 1H,N=CH), 11.10 (s,
1H, NH), 11.32 (s, 1H, CONH); ESI-MS: m / z 440.28 (M+1).
3064, 2939, 1669, 1586, 1507, 1485, 1472, 1318, 1293, 938,
853; H NMR (400 MHz, DMSO-d6) δ / ppm: 2.38 (s, 3H,
1
CH3), 3.67 (s, 3H, OCH3), 4.12 (s, 2H, CH2), 5.49 (s, 2H, N-
CH2), 6.85–6.92 (m, 2H, ArH), 7.04–7.06 (m, 1H, ArH), 7.21–
7.30 (m, 2H, ArH), 7.45 (d, J = 8.8 Hz, 1H, ArH), 7.73 (s, 1H,
ArH), 7.79–7.85 (m, 2H, ArH), 8.04 (d, J = 4.0 Hz, 1H, ArH),
8.20 (s, 1H, N=CH), 11.05 (s, 1H, NH), 11.32 (s, 1H, CONH);
ESI-MS: m / z 488.33 (M+1).
N'-((1-(2,4-Dichlorobenzyl)-1H-indol-3-yl)-methylene)-2-
(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetohydrazide
(9c)
N'-((1-(4-Bromobenzyl)-5-methoxy-1H-indol-3-yl)-
methylene)-2-(2-methyl-1H-pyrrolo[2,3-b] pyridin-3-
yl)acetohydrazide (9g)
o
o
Yield 84 %; m.p. 201–203 C; IR (KBr, cm–1): 3155, 3064,
Yield 87 %; m.p. 215–217 C; IR (KBr, cm–1): 3154, 3059,
2944, 1667, 1587, 1558, 1473, 1441, 1371, 1261, 1054, 868,
809; H NMR (400 MHz, DMSO-d6): δ / ppm = 2.38 (s, 3H,
2935, 1664, 1587, 1539, 1456, 1436, 1165, 1138, 1071, 765;
1H NMR (400 MHz, DMSO-d6) δ / ppm: 2.37 (s, 3H, CH3),
3.56 (s, 3H, OCH3), 4.09 (s, 2H, CH2), 5.40 (s, 2H, N-CH2),
6.82–6.89 (m, 2H, ArH), 7.16–7.20 (m, 2H, ArH), 7.40 (d, J =
8.8 Hz, 1H, ArH), 7.50–7.53 (m, 2H, ArH), 7.79 (s, 1H, ArH),
7.89–7.93 (m, 2H, ArH) 8.04 (d, J = 4.0 Hz, 1H, ArH), 8.22 (s,
1H, N=CH) 11.05 (s, 1H, NH), 11.32 (s, 1H, CONH); ESI-MS:
m / z 530.25 (M+) (79Br).
1
CH3), 4.07 (s, 2H, CH2), 5.54 (s, 2H, N-CH2), 6.76–6.80 (m,
1H, ArH), 6.88–6.91 (m, 1H, ArH), 7.13–7.24 (m, 2H, ArH),
7.34–7.37 (m, 1H, ArH), 7.41–7.47 (m, 1H, ArH), 7.71 (s, 1H,
ArH), 7.82–7.92 (m, 2H, ArH), 8.05 (d, J = 4.0Hz, 1H, ArH),
8.22 (s, 1H, N=CH), 8.23–8.25 (m, 1H, ArH), 11.08 (s, 1H,
NH), 11.36 (s, 1H, CONH); ESI-MS: m / z 490.26 (M+).
Croat. Chem. Acta 2019, 92(1), 1–9
DOI: 10.5562/cca3418

S. B. DONGARE et al.: Design, Synthesis, and Spectroscopic Study …
5
N'-((5-Bromo)-1-(2,4-dichlorobenzyl)-1H-indol-3-yl)-
methylene)-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-
yl)acetohydrazide (9h)
plate. The cells were allowed to grow for one day at 37 oC
in a CO2 incubator as mentioned above. The test materials
at different concentrations were then added to the wells
and cells were further allowed to grow for another 48 h.
Suitable blanks and positive controls were also included.
Each test was performed in triplicate. The cell growth was
stopped by gently layering of 50 μL of 50 % trichloroacetic
acid. The plates were incubated at 4 oC for an hour to fix the
cells attached to the bottom of the wells. Liquids of all the
wells were gently pipette out and discarded. The plates
were washed five times with doubly distilled water to re-
move TCA, growth medium, etc. and were air-dried. 100 μL
of SRB solution (0.4 % in 1 % acetic acid) was added to each
well and the plates were incubated at ambient tempera-
ture for half an hour. The unbound SRB was quickly re-
moved by washing the wells five times with 1 % acetic acid.
Plates were air dried, tris-buffer (100 μL of 0.01 M, pH 10.4)
was added to all the wells and plates were gently stirred for
5 min on a mechanical stirrer. The optical density was
measured on ELISA reader at 540 nm. The cell growth at
absence of any test material was considered 100 % and in
turn growth inhibition was calculated. Percent growth cal-
culated on a plate-by-plate basis for test wells relative to
control wells. Percent growth expressed as the ratio of av-
erage absorbance of the test well to the average absorb-
ance of the control wells 100. Using the six absorbance
measurements (time zero, control growth [C] and test
growth in the presence of drug at the four concentration
levels [Ti]), the percentage growth calculated at each of the
extracts and standard drug concentration levels. Percent-
age growth inhibition calculated as [Ti/C] × 100 %.
o
Yield 82 %; m.p. 215–217 C; IR (KBr, cm–1): 3153, 3062,
2938, 1669, 1587, 1560, 1473, 1443, 1202, 1101, 936, 858,
1
702; H NMR (400 MHz, DMSO-d6) δ / ppm: 2.35 (s, 3H,
CH3), 4.06 (s, 2H, CH2), 5.43 (s, 2H, N-CH2), 6.82–6.88 (m,
2H, ArH), 7.04–7.06 (m, 1H, ArH), 7.20–7.32 (m, 2H, ArH),
7.43 (d, J = 8.8 Hz, 1H, ArH), 7.70 (s, 1H, ArH), 7.74–7.80 (m,
2H, ArH), 8.06 (d, J = 4.0 Hz, 1H, ArH), 8.22 (s, 1H, N=CH),
11.07 (s, 1H, NH), 11.36 (s, 1H, CONH); ESI-MS: m / z 568.15
(M+) (79 Br).
N'-((5-Bromo)-1-(2,4-difluorobenzyl)-1H-indol-3-yl)-
methylene)-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-
yl)acetohydrazide (9i)
o
Yield 88 %; m.p. 195–197 C; IR (KBr, cm–1): 3156, 3065,
2945, 1667, 1589, 1558, 1445, 1407, 1259, 1141, 973, 880,
1
670; H NMR (400 MHz, DMSO-d6) δ / ppm: 2.39 (s, 3H,
CH3), 4.12 (s, 2H, CH2), 5.49 (s, 2H, N-CH2), 6.85–6.92 (m,
2H, ArH), 7.04–7.06 (m, 1H, ArH), 7.21–7.30 (m, 2H, ArH),
7.45 (d, J = 8.8Hz, 1H, ArH), 7.73 (s, 1H, ArH), 7.79–7.85 (m,
2H, ArH), 8.04 (d, J = 4.0 Hz, 1H, ArH), 8.20 (s, 1H, N=CH),
11.05 (s, 1H, NH), 11.32 (s, 1H, CONH); ESI-MS: m / z 536.19
(M+) (79 Br).
N'-((5-Bromo)-1-(4-cyanobenzyl)-1H-indol-3-yl)-
methylene)-2-(2-methyl-1H-pyrrolo[2,3-b] pyridin-3-
yl)acetohydrazide (9j)
o
Yield 84 %; m.p. 216–218 C; IR (KBr, cm–1): 3154, 3063,
2936, 2842, 2228, 1667, 1609, 1541, 1461, 1389, 1258,
1167, 1113, 880, 787, 660; 1H NMR (400 MHz, DMSO-d6) δ
/ ppm: 2.40 (s, 3H, CH3), 4.06 (s, 2H, CH2), 5.58 (s, 2H, N-
CH2), 6.91–6.98 (m, 1H, ArH), 7.32–7.36 (m, 3H, ArH), 7.81–
7.86 (m, 4H, ArH), 8.03–8.06 (m, 2H, ArH), 8.21 (s, 1H,
N=CH), 8.36–8.41 (m, 1H, ArH), 11.13 (s, 1H, NH), 11.34 (s,
1H, CONH); ESI-MS: m / z 525.24 (M+) (79Br).
RESULTS AND DISCUSSION
Chemistry
Synthesis of the 2-methyl-7-azaindolyl hydrazide 5 has
been accomplished by the chemical reactions outlined in
Scheme 1. Mannich reaction of 2-methyl-7-azaindole with
N,N-dimethyl amine hydrochloride and paraformaldehyde
gave N,N-dimethyl-1-(2-methyl-1H-pyrrolo[2,3-b] pyridin-
3-yl)methanamine 1 which on treatment with methyl io-
dide in alcohol followed by substitution with sodium cya-
nide in DMF furnished 2-methyl-7-azaindole-3-acetonitrile
2. The acid hydrolysis of 2 gave 2-(2-methyl-1H-pyrrolo[2,3-
b]pyridin-3-yl)acetic acid 3 which on esterification with
methanol and catalytic amount of concentrated H2SO4,
gave corresponding ester 4. Methyl ester 4 on treatment
with hydrazine hydrate in methanol offered 2-methyl-7-
azaindolyl hydrazide 5 in excellent yield (Scheme 1).
Anticancer Activity
PROCEDURE OF THE SRB-ASSAY
Anticancer evaluation was performed as per the procedure
reported in literature.[9] Tumor cells (human breast cancer
cell line MCF-7) were grown in tissue culture flasks in
growth medium (RPMI-1640 with 2 mM glutamine, pH 7.4,
10 % fetal calf serum, 100 μg/mL streptomycin, and 100
units / mL penicillin) at 37 oC under the atmosphere of 5 %
CO2 and 95 % relative humidity employing a CO2 incubator.
The cells at subconfluent stage were harvested from the
flask by treatment with trypsin (0.05 % trypsin in PBS con-
taining 0.02 % EDTA) and placed in growth medium. The
cells with more than 97 % viability (trypan blue exclusion)
were used for cytotoxicity studies. An aliquot of 100 μL of
cells were transferred to a well of 96-well tissue culture
The 2-methyl-7-azaindolyl hydrazide
5 initially
reacted with various substituted aromatic aldehydes
6a–l in ethanol at room temperature and later with
DOI: 10.5562/cca3418
Croat. Chem. Acta 2019, 92(1), 1–9

6
S. B. DONGARE et al.: Design, Synthesis, and Spectroscopic Study …
(a)
90 °C
70 °C
50 °C
Scheme 1. Synthesis of 2-methyl-7-azaindolyl hydrazide;
Reagents and conditions: a) HN(CH3)2.HCl, HCHO, MeOH;
b) EtOH, CH3I, NaCN, DMF; c) Aq. HCl, d) MeOH, H2SO4;
e) NH2NH2.H2O.
25 °C
(b)
25 °C
50 °C
70 °C
90 °C
Figure 2. Effect of temperature on isomerization: (a) heating;
(b) cooling.
isomers (rotation around N-C(O)) or geometrical isomers
(E / Z, N=CH). 13C NMR spectrum of compound 8a also
showed two sets of signals for most of its carbon nuclei. In
1H NMR spectra of compound 8a, we observed a mixture of
cis/trans isomers in unequal proportions in solution phase
at room temperature. Thus, we studied the possibility of
isomerization in solution phase by analyzing sample at var-
ious temperatures while heating and cooling. The temper-
ature study revealed that with the rise in temperature up
to 90 °C only one isomer exists predominantly but at 50 °C
and 70 °C, mixture of isomers observed and similarly during
cooling conversion of single isomer to mixture of isomers
was observed (Figure 2).
Scheme 2. Synthesis of 7-azaindolyl hydrazones; Reagents
and conditions: a) DMF, POCl3; b) NaH, Dry THF 0 oC-RT;
c) EtOH, glacial AcOH; d) EtOH, glacial AcOH, Reflux.
N-1-substituted indole-3-carboxyaldehydes 7a–j in ethanol
at reflux for 3-5 h in the presence of catalytic amount of
acetic acid resulted in the formation of hydrazones 8a–l and
9a–j, respectively. The various N-1-substituted-indole-
3-carboxyaldehydes 7a–j selected as starting material
were prepared by the Vilsmeier-Hack formylation of
5-substituted indoles followed by N-protection with various
substituted alkyl halides in presence of sodium hydride in
THF as reaction medium (Scheme 2). The structures of all
the synthesized compounds 8a–l and 9a–j were established
by 1H NMR, IR and mass spectroscopy techniques.
BIOLOGICAL EVALUATION
In vitro Anticancer Activity
The in vitro anti-proliferative activity of the synthesized
compounds was evaluated against human breast cancer
cell line MCF-7 and normal Vero monkey cell line by em-
ploying sulforhodamine B (SRB) protein assay method.[13]
Adriamycin a potent anticancer drug was used as reference
standard. The anticancer activity of tested compounds is
given by three parameters, GI50 (molar concentration of the
compound that inhibits 50 % net cell growth), TGI (molar
concentration of the compound leading to total inhibition)
and LC50 (molar concentration of the compound leading to
Spectroscopy Study
It is previously well documented that N-acylhydrazones
may exist as geometrical isomers (E/Z) with respect to the
imine bonds and as conformational (cis/trans) isomers
around the amide N−C(O) bond.[12] In 1H NMR spectrum of
compound 8a, we observed two signals for imine protons
(N=CH), -CH2-C(O) and some of the benzylidene protons,
which is believed to be due to its existence as conformational
Croat. Chem. Acta 2019, 92(1), 1–9
DOI: 10.5562/cca3418

S. B. DONGARE et al.: Design, Synthesis, and Spectroscopic Study …
7
50 % net cell death) and the results are summarized in Table
1. From the results obtained (Table 1), it is clear that all the
hydrazones reduce the cancer cell viability significantly
with GI50 values ranging from 22.3 - 81.0 μM. SRB assay
reveals that most of the hydrazones of N-1-substituted
indole-3-carboxyaldehydes 9f, 9g, 9h, 9c, and 9j are potent
against MCF-7 cell line with GI50 values less than 40 μM.
Remaining compounds have shown moderate to weak
cytotoxicity against MCF-7 cell line ranging from 58.5–
81 μM.
A comparison of the TGI concentrations of the com-
pounds with adriamycin was also done. Most of the com-
pounds were inactive and a few displayed weak activity
against the MCF-7 cell line. Compounds 9f, 9g, 9h, 9c and
9j exhibited weak activity (TGI = 56.6, 59.5, 65.5, 70.7, and
94.6 µM respectively) against MCF-7 cell line. All the other
compounds found inactive (TGI > 100 μM) as compared to
standard drug adriamycin (TGI = 25.9 μM).
The LC50 concentrations of the compounds were also
compared to that of adriamycin to get a sign of the cyto-
toxic effects of these compounds against the MCF-7 cell
line. Most of the compounds were found to be inactive
(LC50 > 100 µM) except compound 9f and 9g as like
adriamycin (LC50 = 92.8 µM) against the MCF-7 cell line.
Most of the marketed drugs affect the normal cell
growth, which serves to be a major disadvantage in the
evolution of anticancer drug development. Therefore, we
have ensured the selectivity of active compounds by in
vitro screening against the normal Vero Monkey cell line
(Table 1). These results demonstrate that the synthesized
Table 1. Anticancer activity profile of synthesized hydrazone derivatives against MCF-7 breast cancer cell line.
Substitutions
MCF-7
Vero (Normal)
Entry
TGI(c)
NT
(a)
(b)
(a)
(b)
R
R1
–
–
–
–
–
–
–
–
–
–
–
–
R2
GI50
LC50
TGI(c)
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
70.7
GI50
LC50
8a
8b
8c
8d
8e
8f
–
2,4-(Cl)2C6H3
75.0
73.5
72.5
69.8
78.7
68.9
75.2
70.4
58.5
76.2
62.6
60.1
72.1
80.2
30.2
77.8
73.2
22.3
24.9
29.6
81.0
37.8
< 0.1
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
90.3
NT
NT
NT
NT
–
3,4-(F)2C6H3
NT
–
3,4,5-(MeO)3C6H2
NT
NT
NT
–
3,4-(O-CH2-O)C6H3
NT
NT
NT
–
2,4-(F)2C6H3
NT
NT
NT
–
3-NO2-C6H4
NT
NT
NT
8g
8h
8i
–
2,4,6-(MeO)3C6H2
NT
NT
NT
–
3-Br-C6H4
NT
NT
NT
–
4-OH-C6H4
NT
NT
NT
8j
–
3-F-4-OMe-C6H3
NT
NT
NT
8k
8l
–
–
3-OMe-4-OH-C6H3
NT
NT
NT
4-CN-C6H4
NT
NT
NT
9a
9b
9c
9d
9e
9f
H
4-ClC6H4CH2
–
–
–
–
–
–
–
–
–
–
–
NT
NT
NT
H
4-FC6H4CH2
2,4-(Cl)2C6H3CH2
2,4-(F)2C6H3CH2
2,4-(Cl)2C6H3CH2
2,4-(F)2C6H3CH2
4-BrC6H4CH2
2,4-(Cl)2C6H3CH2
2,4-(F)2C6H3CH2
4-CNC6H4CH2
–
NT
NT
NT
H
59.4
NT
> 100
NT
> 100
NT
H
> 100
> 100
56.6
5-OMe
5-OMe
5-OMe
5-Br
5-Br
5-Br
–
NT
NT
NT
23.8
18.2
25.1
NT
75.9
86.8
99.4
NT
68.2
45.5
52.3
NT
9g
9h
9i
94.0
59.5
> 100
> 100
> 100
92.8
65.5
> 100
94.6
9j
22.5
19
> 100
52.5
77.6
> 10
ADR
25.9
(a)
Concentrations in µM; Growth inhibition of 50 % (GI50) calculated from [(Ti – Tz) / (C – Tz)] × 100 = 50.
Concentration of drug resulting in a 50 % reduction in the measured protein at the end of the drug treatment as compared to that at the beginning) calculated
from [(Ti – Tz) / Tz] × 100 = –50.
(b)
(c)
Drug concentration resulting in total growth inhibition (TGI) will calculated from Ti = Tz.
ADR = adriamycin.
DOI: 10.5562/cca3418
Croat. Chem. Acta 2019, 92(1), 1–9

8
S. B. DONGARE et al.: Design, Synthesis, and Spectroscopic Study …
7-azaindolyl hydrazine derivatives 9f, 9g, 9h, 9c, and 9j
show moderate selectivity against cancer lines over normal
cell line.
[4]
(a) J-Y. Merour, S. Routier, F. Suzenet, B. Joseph,
Tetrahedron 2013, 69, 4767.
https://doi.org/10.1016/j.tet.2013.03.081
(b) F. Popowycz, S. Routier, B. Josepha, J-Y. Merour,
Tetrahedron 2007, 63, 1031–1064.
https://doi.org/10.1016/j.tet.2006.09.067
CONCLUSION
In conclusion, a series of 7-azaindolyl hydrazones were
prepared and their structures were analyzed by FT-IR, H
[5]
(a) W. Zhu, C. Chen, C. Sun, S. Xu, C. Wu, F. Lei, H.
Xia, Q. Tu, P. Zheng, Eur. J. Med. Chem. 2015, 93, 64–
73. https://doi.org/10.1016/j.ejmech.2015.01.061
(b) R. G. Strachan, M. A. P. Meisinger, W. V. Ruyle, R.
Hirschmann, T. Y. Shen, J. Med. Chem. 1964, 7, 799–
800. https://doi.org/10.1021/jm00336a026
(c) D. Kumar, N. M. Kumar, S. Ghosh, K. Shah, Bioorg.
Med. Chem. Lett. 2012, 22, 212–215.
https://doi.org/10.1016/j.bmcl.2011.11.031
(d) S. Schmidt, L. Preu, T. Lemcke, F. Totzke, C.
Schächtele, M. H. G. Kubbutat, C. Kunick, Eur. J. Med.
Chem. 2011, 46, 2759–2769.
1
NMR and mass spectral data. All the compounds were
screened for their anticancer potential against MCF-7
induced breast carcinoma. All the compounds screened
were found to possess notable anticancer potential.
Compounds 9f, 9g, 9h, 9c, and 9j were significantly active
against MCF-7 cell line with GI50 values ranging from 22.3–
37.8 µM and TGI values 56.6–94.6 µM. Thus, these
compounds constitute an interesting template and may be
helpful for the design and development of new therapeutic
tools against cancer.
https://doi.org/10.1016/j.ejmech.2011.03.065
(e) O. Ünsal-Tana, K. Özdenc, A. Raukb, A. Balkana,
Eur. J. Med. Chem. 2010, 45, 2345–2352.
https://doi.org/10.1016/j.ejmech.2010.02.012
(a) S. Hong, J. Kim, J. Hyeon Seo, K. Hee Jung, S.-S.
Hong, S. Hong, J. Med. Chem. 2012, 55, 5337–5349.
https://doi.org/10.1021/jm3002982
(b) H.-R. Tsou, G. MacEwan, G. Birnberg, N. Zhang,
N. Brooijmans, L. Toral-Barza, I. Hollander, S. Ayral-
Kaloustian, K. Yu, Bioorg. Med. Chem. Lett. 2010, 20,
2259–2263.
https://doi.org/10.1016/j.bmcl.2010.02.012
(c) D. Simard, Y. Leblanc, C. Berthelette, M.H.
Zaghdane, C. Molinaro, Z. Wang, M. Gallant, S. Lau,
T. Thao, M. Hamel, R. Stocco, N. Sawyer, S. Sillaots,
F. Gervais, R. Houle, J.-F. Levesque, Bioorg. Med.
Chem. Lett. 2011, 21, 841–845.
Acknowledgment. We offer thanks to ACTREC Mumbai for
providing anticancer activity determinations. We also thank
Instrumentation Centre, Solapur University for providing
facility of spectral analysis.
[6]
REFERENCES
[1]
(a) S. Sibu, P. Jan, Plant Science 2011, 180, 454–460.
https://doi.org/10.1016/j.plantsci.2010.12.007
(b) S. Wu, L. Wang, W. Guo, X. Liu, J. Liu, X. Wei, B.
Fang, J. Med. Chem. 2011, 54, 2668–2679.
https://doi.org/10.1021/jm101417n
(c) N. I. Park, J. K. Kim, W. T. Park, J. W. Cho, Y. P. Lim, S.
U. Park, Molecular Biology Reports 2010, 38, 4947–4953.
https://doi.org/10.1007/s11033-010-0638-5
R. Singla, V. Singh, A. Negi, Adv. J. Pharma Life. Sci.
Res. 2013, 1, 7–15.
[2]
[3]
https://doi.org/10.1016/j.bmcl.2010.11.084
(a) A. Carbone, M. Pennati, B. Parrino, A. Lopergolo, P.
Barraja,A. Montalbano,V. Spanò,S. Sbarra,V. Doldi,M. De
Cesare, G. Cirrincione,P. Diana,N. Zaffaroni,J. Med. Chem.
2013,56,7060–7072. https://doi.org/10.1021/jm400842x
(b) H. R. Bokesch, L. K. Pannell, T. C. McKeea, M. R.
Boyd, Tetrahedron Letters 2000, 41, 6305–6308.
https://doi.org/10.1016/S0040-4039(00)01062-5
(c) A. Wienecke, G. Bacher, Cancer Res. 2009, 69, 171–
177. https://doi.org/10.1158/0008-5472.CAN-08-1342.
(d) H .R. Pettit, J. C. Knight, D. L. Herald, R. Davenport, R.
K. Pettit, B. E. Tucker, J. M. Schmidt, J. Nat. Prod. 2002,
65, 1793–1797. https://doi.org/10.1021/np020173x
(e) G. Wylie, T. Appelboom, W. Bolten, F. C.
Breedveld, J. Feely, M. R. Leeming, X. Le Loët, R.
Manthorpe, R. Marcolongo, J. Smolen, British
Journal of Rheumatology 1995, 34, 554–563.
https://doi.org/10.1093/rheumatology/34.6.554
(d) M. Kritsanida, P. Magiatis, A.-L. Skaltsounis, Y.
Peng, P. Li, L. P. Wennogle, J. Nat. Prod. 2009, 72,
2199–2202. https://doi.org/10.1021/np9003905
(e) J.-Y. Merour, F. Buron, K. Ple, P. Bonnet, S.
Routier, Molecules 2014, 19, 19935–19979.
https://doi.org/10.3390/molecules191219935
(f) J. F. Kadow, Y. Ueda, N. A. Meanwell, T. P.
Connolly, T. Wang, C.-P. Chen, K.-S. Yeung, J. Zhu, J.
A. Bender, Z. Yang, D. Parker, P.-F. Lin, R. J. Colonno,
M. Mathew, D. Morgan, M. Zheng, C. Chien, D.
Grasela, J. Med. Chem. 2012, 55, 2048–2056.
https://doi.org/10.1021/jm201218m
S. Rollas, S. Guniz Kucukguzel, Molecules 2007, 12,
1910–1939. https://doi.org/10.3390/12081910
(a) S. G. Küçükgüzel, A. Mazi, F. Sahin, S. Öztürk, J.
Stables, Eur. J. Med. Chem. 2002, 38, 1005–1013.
https://doi.org/10.1016/j.ejmech.2003.08.004
[7]
[8]
Croat. Chem. Acta 2019, 92(1), 1–9
DOI: 10.5562/cca3418

S. B. DONGARE et al.: Design, Synthesis, and Spectroscopic Study …
9
(b) S. M. Sondhi, M. Dinodia, A. Kumar, Bioorg. Med.
Chem. 2006, 14, 4657–4663.
https://doi.org/10.1016/j.bmc.2006.02.014
(c) Z. Garkani-Nejad, B. Ahmadi-Roudi, Eur. J. Med.
Chem. 2010, 45, 719–726.
https://doi.org/10.1016/j.ejmech.2009.11.019
(d) L. Savini, L. Chiasserini, A. Gaeta, C. Pellerano,
Bioorg. Med. Chem. 2002, 10, 2193–2198.
https://doi.org/10.1016/S0968-0896(02)00071-8
(e) P. Vicini, M. Incerti, I. A. Doytchinova, P. La Colla, B.
Busonera, R. Loddo, Eur. J. Med. Chem. 2006, 41, 624–
632. https://doi.org/10.1016/j.ejmech.2006.01.010
(f) N. Terzioglu, A. Gürsoy, Eur. J. Med. Chem. 2003,
38, 781; (g) A. H. Abadi, A. A. H. Eissa, G. S. Hassan,
Chem. Pharm. Bull. 2003, 51, 838–844.
https://doi.org/10.1248/cpb.51.838
(a) J.-M. Lehn, Chem. Soc. Rev. 2007, 36, 151–160.
https://doi.org/10.1039/B616752G
(b) F. J. Uribe-Romo, C. J. Doonan, H. Furukawa, K.
Oisaki, and O. M. Yaghi, J. Am. Chem. Soc. 2011, 133,
11478–11481. https://doi.org/10.1021/ja204728y
(c) Y. Jin, C. Yu, R. J. Denman, W. Zhang, Chem. Soc.
Rev. 2013, 42, 6634–6654.
(d) B. P. Bandgar, S. S. Jalde, B. L. Korbad, S. A. Patil,
H. V. Chavan, S. N. Kinkar, L. K. Adsul, S. N. Shringare,
S. H. Nile, J. Enz. Inhib. Med. Chem. 2012, 27, 267–274.
https://doi.org/10.3109/14756366.2011.587416
(e) H. V. Chavan, L. K. Adsul, A. S. Kotmale, V. D.
Dhakane, V. N. Thakare, B. P. Bandgar, J. Enz. Inhib.
Med. Chem. 2015, 30, 22–31.
https://doi.org/10.3109/14756366.2013.873037
(f) B. P. Bandgar, R. J. Sarangdhar, F. Khan, J.
Mookkan, S. Chaudhary, H. V. Chavan, S. B. Bandgar,
V. Y. Kshirsagar, Eur. J. Med. Chem. 2012, 57, 217–224.
https://doi.org/10.1016/j.ejmech.2012.08.036
(g) P. S. Bhale, H. V. Chavan, S. B. Dongare, S. N.
Shringare, Y. B. Mule, S. S. Nagane, B. P. Bandgar,
Bioorg. Med. Chem. Lett. 2017, 27, 1502–1507.
https://doi.org/10.1016/j.bmcl.2017.02.052
[11] D. A. Sandham, C. Adcock, K. Bala, L. Barker, Z.
Brown, G. Dubois, D. Budd, B. Cox, R. A. Fairhurst, M.
Furegati, C. Leblanc, J. Manini, R. Profit, J. Reilly, R.
Stringer, A. Schmidt, K. L. Turner, S. J. Watson, J.
Willis, G. Williams, C. Wilson, Bioorg. Med. Chem.
Lett. 2009, 19, 4794–4798.
[9]
https://doi.org/10.1016/j.bmcl.2009.06.042
[12] (a) M. Zhou, Y.-J. Eun, I. A. Guzei, D. B. Weibel, ACS
Med. Chem. Lett. 2013, 4, 880–885.
https://doi.org/10.1039/c3cs60044k
[10] (a) V. H. Masand, D. T. Mahajan, T. B. Hadda, R. D.
Jawarkar, H. Chavan, B. P. Bandgar, H. Chauhan,
Med. Chem. Res. 2014, 23, 417–425.
https://doi.org/10.1021/ml400234x
(b) O. Unsal-Tan, K. Ozden, A. Rauk, A. Balkan, Eur. J.
Med. Chem. 2010, 45, 2345–2352.
https://doi.org/10.1016/j.ejmech.2010.02.012
(c) V. V. Syakaev, S. N. Podyachev, B. I. Buzykin, S. K.
Latypov, W. D. Habicher, A. I. Konovalov, J. Mol.
Struct. 2006, 788, 55–62.
https://doi.org/10.1007/s00044-013-0647-8
(b) B. P. Bandgar, S. A. Patil, J. V. Totre, B. L. Korbad,
R. N. Gacche, B. S. Hote, S. S. Jalde, H. V. Chavan,
Bioorg. Med. Chem. Lett. 2010, 20, 2292–2296.
https://doi.org/10.1016/j.bmcl.2010.02.001
(c) B. P. Bandgar, L. K. Adsul, S. V. Lonikar, H. V.
Chavan, S. N. Shringare, S. A: Patil, S. S. Jalde, B. A.
Koti, N. A. Dhole, R. N. Gacche, A. Shirfule, J. Enz.
Inhib. Med. Chem. 2013, 28, 593–600.
https://doi.org/10.1016/j.molstruc.2005.11.018
[13] P. Skehan, R. Strong, D. Scadiaro, A. Monks, J.
McMahon, D. Vistica, J. T. Warren, H. Bokesch, S.
Kenney, M. R. Boyed, J. Natl. Cancer Inst. 1990, 82,
1107–1112. https://doi.org/10.1093/jnci/82.13.1107
https://doi.org/10.3109/14756366.2012.663365
DOI: 10.5562/cca3418
Croat. Chem. Acta 2019, 92(1), 1–9