Vol. 31, No. 11 (2019)
Synthesis and Antioxidant Activity Evaluation of Isoindoline-1,3-dione Derivatives 2549
receptor complex with upgraded adjustment and with the
objective of having less confining free energy [10]. Various
proteins and impetuses are used as targets or receptors in atomic
docking.
DMSO (125 MHz, Bruker) using tetramethylsilane (TMS) as
an internal standard. Mass spectra were measured by the Electron
Impact (EI) method (Jeol GC-Mate 2).Absorbance of antioxidants
was measured by spectrophotometer (ELICO SL 207 mini spec).
in vitro Cytotoxicity of all the compounds was studied by cell
viability assay method. Cytotoxicity assay evaluated using the
cell culture facilities, which includes a laminar flow hood and
a 37 ºC CO2 incubator. Molecular docking studies were performed
using Hex 8.0.0 docking software.
Synthesis of isoindoline-1,3-dione derivatives (3a-k):
To a solution of isobenzofuran-1,3-dione (1.48 g, 10 mmol)
in methanol (4 mL/1 mmol) at room temperature was added
aliphatic or aromatic amine (10 mmol) and the reaction mixture
was refluxed at 65 ºC for 4 h. After completion of the reaction
as indicated by the TLC, the reaction was cooled to room temp-
erature and purified by column chromatography using petroleum
ether:ethyl acetate (7:3).
The discovery and evaluation of organic compounds with
a specific pharmacological activity is a necessary task in the
drug development process.Among the large variety of organic
compounds, heterocyclic compounds have been extensively
studied due to their important pharmacological properties and
applications [11]. Heterocyclic compounds display an array of
interesting properties [12] and exploration of their potency is
always worth investigating.Among divergent varieties of hetero-
cyclic compounds, N-heterocyclic compounds [13] occupy
centre stage due to their proven bioactivity. Isoindoline-1,3-
diones [14] are a group of typical annulated N-heterocyclic
compounds which have attracted much attention, in the recent
past. They have been widely studied for their anticancer [15],
antimicrobial [16], antioxidant [17], anti-inflammatory [18],
antipsychotic [19], anticonvulsive [20] and antihypertensive
[21] properties. Reports are also available on isoindoline-1,3-
diones as enzyme inhibitor towards RSK2 [22], cytotoxic activity
[23] towards T47D cancer cell line and as a possible 15-lipoxy-
genase-1-inhibitor [24]. Owing to their interesting properties,
isoindoline-1,3-diones are considered as the promising chemical
entities whose potential is worth investigating.
2-(4-(4-Aminobenzyl)phenyl)isoindoline-1,3-dione (3a):
White solid; m.p.: > 300 °C, yield: 1.968 g, 60 %; IR (KBr,
ν
max, cm-1): 717 (C-H), 1373 (C-N), 1512 (C=C), 1720 (C=O);
1H NMR (500 MHz, DMSO-d6): 7.91-8.10 (2H, Ar-phthalic),
7.6-7.7 (2H,Ar-phthalic), 6.3-7.8 (8H,Ar-benzene), 4.00 (2H,
-NH2), 3.33 (2H, CH2); 13C NMR (125 MHz, DMSO-d6): 127,
131 (6C, Ar-phthalic), 137, 130, 125 (3C, CN, C-CH2, CH2C),
128.8, 128.4, 128.2, 124 (8C, Ar-benzene), 148 (1C, CNH2),
54.1 (1C, CH2), 167.5 (3C, C=O); MS (EI): m/z [M+H]+: Calcd.
for C21H15N2O2: 328.3639; found:328.3601.
All the synthesized isoindoline-1,3-dione derivatives were
thoroughly analyzed and their structures are confirmed using
13
FTIR, NMR (1H and C) and mass spectroscopy techniques.
4-(1,3-dioxoisoindolin-2-yl) benzoic acid (3b): White
solid; m.p.: 290 °C, yield: 1.78 g, 67 %; IR (KBr, νmax, cm-1):
713 (C-H), 1300 (C-N), 1378 (C=C), 1714 (C=O); 1H NMR
(500 MHz, DMSO-d6): 7.61-7.62 (2H,Ar-phthalic), 7.91-8.00
(2H,Ar-phthalic), 7.92-7.93 (2H,Ar-benzene), 8.00-8.10 (2H,
For all the synthesized compounds, molecular docking, anti-
oxidant and cytotoxicity studies were carried out to evaluate
their bioactivity.
13
Ar-benzene), 10.8 (1H, OH); C NMR (125 MHz, DMSO-
EXPERIMENTAL
d6): 127, 131, 130 (6C, Ar-phthalic), 146 (1C, CN), 121, 124,
135 (5C, Ar-benzene), 171, 167.12 (3C, C=O); MS (EI): m/z
[M+H]+: Calcd. for C15H9NO4: 267.0531; found: 267.0012.
2-(2-Aminoethyl)isoindoline-1,3-dione (3c):White solid;
m.p.: 190 °C, yield: 1.31 g, 69 %; IR (KBr, νmax, cm-1): 719
(C-H), 1316 (C-N), 1397 (C=C), 1709 (C=O), 3064 (C-H);
1H NMR (500 MHz, DMSO-d6): 1.71 (2H, NH2), 3.35, 3.85
(4H, CH2CH2), 7.8-8.2 (4H,Ar-phthalic); 13C NMR (125 MHz,
DMSO-d6): 36.7, 54.1 (2C, CH2CH2), 123.5, 131.8, 134.9 (6C,
Ar-phthalic), 168.2 (2C, C=O); MS (EI): m/z [M+H]+: Calcd.
for C10H10N2O2: 190.1986; found: 190.4626.
All the chemicals and reagents employed for the synthesis
of isoindoline-1,3-dione derivatives (3a-k) were purchased
from Sigma-Aldrich.All the reagents and solvents were obtained
from Aldrich and used without further purification. Doxoru-
bicin was purchased from Pfizer Pharma, India. ABTS was
purchased from Nice chemicals Ltd., India. 1H and 13C NMR
spectra were recorded on a Bruker FT-500 using tetramethyl-
silane (TMS) as an internal standard. The IR spectra were
recorded on a Shimadzu FTIR spectrophotometer using KBr
(4000-400 cm-1). The compounds were purified by column
chromatography using silica gel (100-200 mesh) and petroleum
ether:ethyl acetate. TLC was performed using silica gel 60
F254 pre-coated on aluminum sheets, obtained from Merck.
Visualization of spots on TLC plate was done with UV light
(254 nm). in vitro Cytotoxicity of all the compounds was studied
by cell viability assay method. Molecular docking studies of
all the synthesized compounds were studied by Hex 8.0.0
docking software.
2-(2-Methyl-5-nitrophenyl)isoindoline-1,3-dione (3d):
White solid; m.p.: 213 °C, yield: 1.80 g, 64 %; IR (KBr, νmax
,
cm-1): 788 (C-H), 1345 (C-N), 1544 (C=C), 1710 (C=O); 1H
NMR (500 MHz, DMSO-d6): 7.9-8.0 (2H, Ar-phthalic), 7.6-
7.7 (2H, Ar-phthalic), 7.52-7.79 ( 2H, Ar-benzene), 8.4 (1H,
Ar-benzene), 2.35 (3H, CH3); 13C NMR (125 MHz, DMSO-
d6): 129, 131, 132 (6C, Ar-phthalic), 141 (1C, C-NO2), 137
(1C, CN), 18.5 (1C, CH3), 128, 130.0, 130.1 (3C,Ar-benzene),
139 (1C, CCH3), 167 (2C, C=O); MS (EI): m/z [M+H]+: Calcd.
for C15H10N2O4: 282.2509; found: 282.2504.
Completion of all the reactions were checked by thin layer
chromatography (TLC silica gel 0.25 mm, 60G F254 and the
eluting solvents were ethyl acetate:hexane). All the compounds
were characterized by FT-IR spectrometer (IR Prestige-21,
2-(4-(4-Aminophenylsulfonyl) phenyl)isoindoline-1,3-
dione (3e): White solid; m.p.: > 300 °C, yield: 1.82 g, 64 %;
IR (KBr, νmax, cm-1): 744 (C-H), 1376 (C-N), 1592 (C=C),
1
Shimadzu, Japan) using KBr pellets, H NMR spectroscopy
in DMSO (500 MHz, Bruker) and 13C NMR spectroscopy in
1
1709 (C=O); H NMR (500 MHz, DMSO-d6): 8.0-8.2 (2H,