Synthesis, antioxidant activity and DFT study of some novel N-methylated indole incorporating isoxazole moieties

Article abstract of DOI:10.14233/ajchem.2020.22288

A novel series of indolyl isoxazole derivatives were synthesized and the structure of the products is confirmed on the basis of IR, ¹H NMR, MS and analytical data. The synthesized compounds were evaluated for their antioxidant and anticancer ac

Full text of DOI:10.14233/ajchem.2020.22288

Asian Journal of Chemistry; Vol. 32, No. 2 (2020), 244-248
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2020.22288
Synthesis, Antioxidant Activity and DFT Study of Some
Novel N-Methylated Indole Incorporating Isoxazole Moieties
1
2,*
J. JANI MATILDA and T.F. ABBS FEN REJI
1Manonmaniam Sundaranar University, Tirunelveli-627012, India
2Department of Chemistry and Research Centre, Nesamony Memorial Christian College, Marthandam-629165, India
*Corresponding author: E-mail: abbsfen@gmail.com
Received: 24 June 2019;
Accepted: 18 July 2019;
Published online: 30 December 2019;
AJC-19706
A novel series of indolyl isoxazole derivatives were synthesized and the structure of the products is confirmed on the basis of IR, 1H NMR,
MS and analytical data. The synthesized compounds were evaluated for their antioxidant and anticancer activities. The results revealed
clearly those compounds 4b and 4d exhibited better radical scavenging ability. The optimized structural parameters of all compounds was
carried out at the B3LYP/6-311++G (d, p) level of DFT basis set implemented in Gaussian 09 program package. Theoretical calculation
of the title compounds were carried out using density functional theory method (DFT).
Keywords: Acetyl indoles, Isoxazoles, Antioxidant activity, DFT.
pounds and medicinally important molecules. They are useful
as pharmaceuticals, since many antioxidant and anticancer
drugs are isoxazolyl derivatives.
INTRODUCTION
The life style related changes in the present day (sedentary
life style, wrong dietary practices, stress, smoking/alcohol con-
sumption/drug abuse) may cause overage of reactive oxygen
species and free radicals. A number of natural antioxidants
not only reduce oxidative stress, but also provides considerable
protection against several degenerative nerve diseases and thus
antioxidants play an important role in medical attendance. The
implementation and development of new and more efficient
synthetic or natural antioxidants are of great significance [1,2].
In addition, such compounds have also been used for the treat-
ment and prevention of stroke or coronary heart disease. In
last few decades, a search for better antioxidants led to the
synthesis and isolation of different organic molecules which
showed more effective antioxidant activity in comparison with
standard antioxidants, such as β-carotene, vitamin C, butylated
hydroxyanisole (BHA), lutein and vitamin A [3-5].
As a result, researchers are on a continuous search to design
and produce better heterocyclic compounds and also in order
to enhance its biological property, we combine indole and isox-
azole moieties in a single molecular framework to obtain a
new class of highly potent bioactive compounds [9-12]. Hence,
the present investigation aims to the synthesis and antioxidant
activity of indolyl isoxazole derivatives. Computational methods
predict relatively accurate molecular structure and molecular
vibrations of indolyl isoxazole molecules applying the density
functional theory (DFT) methods to derive information about
electronic effects and evaluate the interaction between these
molecules responsible for biological activity [13,14].
EXPERIMENTAL
Indole derivatives are common motifs in natural products
as well as drugs. Isoxazoles are aromatic five-membered hetero-
cycles containing adjacent nitrogen and oxygen atoms [6,7].
These heterocyclic compounds are useful synthetic building
blocks in medicinal and organic chemistry [8]. Indolyl isoxazole
ring systems are found in a variety of naturally occurring com-
All the reagents and solvents used were ofAR grade which
were purchased from Sigma-Aldrich and Merck Specialties
Pvt. Ltd. NMR spectra was recorded on recorded on Bruker
Avance III, 400 MHz NMR spectrometer (400 MHz for 1H and
400 MHz for 13C NMR spectra) and mass spectra on Waters
UPLC-TQD mass spectrometer (ESI-MS). Nicolet 400D FTIR
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Vol. 32, No. 2 (2020)
Synthesis and DFT Study of Some Novel N-Methylated Indole Incorporating Isoxazole Moieties 245
spectrometer was used for FTIR spectra. Melting points were
determined using Digital Program Rate melting point apparatus
and are uncorrected. Elemental analysis was carried out at
Central Drug Research Institute, Lucknow, India.
5-(2-Methylphenyl)-3-(1-methylindol-3-yl)isoxazole
(4d): Greenish yellow solid; yield 57 %; m.w.: 288.13, m.p.:
135-138 ºC; IR (KBr, νmax, cm-1): 3059 (C-H), 1564 (C=N),
1522 (C=C), 1074 (C-N). 1H NMR (DMSO-d6): δ 7.20-7.51
(m, 4H, ArH), 7.12 (d, 1H, ArH), 7.10 (m, 2H, ArH), 7.13 (m,
2H, ArH), 7.36 (d, 1H, ArH), 3.61 (s, 3H, N-CH3), 5.55 (s, 1H,
CH), 2.35 (s, 3H, CH3), 6.82 (s, 1H, CH). m/z: 288.13 (100.0
%), 289.13 (20.5 %), 290.13 (2.0 %). Elemental analysis of
C19H16N2O calcd. (found) %: C, 79.14 (79.25); H, 5.59 (5.62);
N, 9.72 (9.69).
5-(4-Methylphenyl)-3-(1-methylindol-3-yl)isoxazole
(4e): Greenish yellow solid; yield 53 %; m.w.: 288.13, m.p.:
133-136 ºC. IR (KBr, νmax, cm-1): 3071 (C-H), 1569 (C=N),
1612 (C=C), 1079 (C-N). 1H NMR (DMSO-d6): δ 7.22-7.53
(m, 4H, ArH), 7.12-7.39 (m, 4H, ArH), 3.63 (s, 3H, N-CH3),
5.67 (s, 1H, CH), 2.36 (s, 3H, CH3), 6.85 (s, 1H, CH). m/z:
288.13 (100.0 %), 289.13 (20.5 %), 290.13 (2.0 %). Elemental
analysis of C19H16N2O calcd. (found) %: C, 79.14 (79.21); H,
5.59 (5.57); N, 9.72 (9.73).
5-(2-Methoxyphenyl)-3-(1-methylindol-3-yl)isoxazole
(4f): Greenish yellow solid; yield 47 %, m.w.: 304.12, m.p.:
178-179 ºC; IR (KBr, νmax, cm-1): 3069 (C-H), 1679 (C=N),
1612 (C=C), 1074 (C-N). 1H NMR (DMSO-d6): δ 7.23-7.49
(m, 4H, ArH), 6.83(d, 1H, ArH), 7.11 (m, 2H, ArH), 6.88 (m,
2H, ArH), 7.37 (d, 1H, ArH), 3.60 (s, 3H, N-CH3), 5.42 (s, 1H,
CH),3.72 (s, 3H, OCH3), 6.80 (s, 1H, CH). m/z: 304.12 (100.0
%), 305.12 (20.5 %), 306.13 (2.0 %). Elemental analysis of
C19H16N2O2 calcd. (found) %: C, 74.98 (74.87);H, 5.30 (5.38);
N, 9.20 (9.33).
5-(4-Methoxyphenyl)-3-(1-methylindol-3-yl)isoxazole
(4g): Greenish yellow solid; yield 53 %; m.w.: 304.12, mp.:
175-178 ºC; IR (KBr, νmax, cm-1): 3019 (C-H), 1716 (C=N),
1555 (C=C), 1248,1287 (C-N). 1H NMR (DMSO-d6): δ 7.23-
7.49 (m, 4H, ArH), 6.83-7.39 (m, 4H, ArH), 3.60(s, 3H, N-CH3),
5.42 (s, 1H, CH), 3.73(s, 3H, OCH3), 6.82(s,1H,CH). m/z:
304.12 (100.0 %), 305.12 (20.5 %), 306.13 (2.0 %). Elemental
analysis of C19H16N2O2 calcd. (found) %: C, 74.98 (74.97); H,
5.30 (5.31); N, 9.20 (9.31).
Synthesis of 5-phenyl-3-(1-methylindol-3-yl)isoxazole
(IVa-h): The reaction of actyl indole with an aromatic aldehyde
in the presence of NaOH afforded 3-aryl-1-(1-methylindole-
3-yl)-2-propen-1-one.A mixture of 3-aryl-1-(1-methylindole-
3-yl)-2-propen-1-one (0.01 mol), hydroxylamine hydrochloride
(0.01 mol) in the presence of sodium acetate and exactly 50 mL
of ethanol with glacial acetic acid was added and refluxed for
8-10 h. The mixture was then poured into ice water. The product
obtained was filtered, dried and recrystallized from rectified
spirit (Scheme-I).
Antioxidant activity: Evaluation of antioxidant activity
of the synthesized compound was measured using, 1,1-diphenyl-
2-picryl hydrazyl radical (DPPH). The samples were made up
with methanol to different concentrations (50, 100, 250, 500
and 750 µM). Each sample (2 mL) was allowed to react with
2 mL of DPPH, an stable free radical, for 30 min in dark at
room temperature. The deep purple colour of DPPH solution
turns yellow in the presence of antioxidants. The disappearance
of this radical is measured at 517 nm in a methanolic solution.
Butylated hydroxyanisole (BHA) was used as a reference comp-
ound. From the absorbance values, the percentage inhibition
was calculated as follows:
Control absorbance − Sample absorbance
Inhibition (%) =
×100
Control absorbance
Spectral data
5-Phenyl-3-(1-methylindol-3-yl)isoxazole (4a): Greenish
yellow solid; yield 63 %; m.w.: 550.6, m.p.: 144-148 ºC; IR (KBr,
ν
max, cm-1): 3020 (C-H), 1697 (C=N), 1468(C=C), 1287, 1218,
1126, (C-N). 1H NMR (DMSO-d6): δ 7.22-7.51 (m, 4H,ArH),
7.22-7.51 (m, 5H, ArH), 3.63 (s, 3H, N-CH3), 5.42 (s, 1H,
isoxazole ring proton), 6.83 (s, 1H, indolyl proton), m/z: 274.11
(100.0 %), 275.11 (19.5 %), 276.12 (1.8 %). Elemental analysis
of C18H14N2O calcd. (found) %: C, 78.81 (78.79); H, 5.14 (5.19);
N, 10.21 (10.29).
5-(2-Hydroxyphenyl)-3-(1-methylindol-3-yl)isoxazole
(4h): Greenish yellow solid; yield 55 %; m.w.: 290.11, m.p.:
163-165 ºC; IR (KBr, νmax, cm-1): 3447(OH), 3024 (C-H), 1659
(C=N), 1540 (C=C), 1250, 1227 (C-N). 1H NMR (DMSO-d6):
δ 7.21-7.41(m, 4H, ArH), 6.79-7.31 (m, 4H, ArH), 3.63 (s,
3H, N-CH3), 5.48 (s, 1H, CH), 5.03 (s, 1H, Ar-OH), 6.88 (s,
1H, CH). m/z: 290.11 (100.0 %), 291.11 (19.5 %), 292.11
(1.8 %). Elemental analysis of C18H14N2O2 calcd. (found) %:
C, 74.47 (74.48); H, 4.86 (4.79); N, 9.65 (9.64).
5-(2-Chlorophenyl)-3-(1-methylindol-3-yl)isoxazole
(4b): Greenish yellow solid; yield 61 %; m.w.: 308.07, m.p.:
126-129 ºC; IR (KBr, νmax, cm-1): 3017 (C-H), 1721 (C=N),
1498 (C=C), 1086 (C-N). 1H NMR (DMSO-d6): δ 7.21-7.56
(m, 4H, ArH), 7.33 (d, 1H, ArH), 7.20 (m, 2H, ArH), 7.16 (m,
2H, ArH), 7.33 (d, 1H, ArH), 3.61 (s, 3H, N-CH3), 5.51 (s, 1H,
CH),6.83 (s, 1H, CH). m/z: 308.07 (100.0 %), 310.07 (32.0 %),
309.07 (19.5 %), 311.07 (6.2 %), 310.08 (1.8 %). Elemental
analysis of C18H13N2OCl calcd. (found) %: C, 70.02 (7.11);
H, 4.24 (4.28); N, 9.07 (9.11%.
RESULTS AND DISCUSSION
5-(4-Chlorophenyl)-3-(1-methylindol-3-yl)isoxazole
(4c): Greenish yellow solid; yield 60 %; m.w.: 308.07. m.p.:
123-127 ºC;IR (KBr, νmax, cm-1): 3019 (C-H), 1716 (C=N), 1521
(C=C), 1075 (C-N). 1H NMR (DMSO-d6): δ 7.25-7.58 (m, 4H,
ArH), 7.33-7.42 (m, 4H, ArH), 3.60 (s, 3H, N-CH3), 5.53 (s, 1H,
CH), 6.84 (s, 1H, CH). m/z: 308.07 (100.0 %), 310.07 (32.0
%), 309.07 (19.5 %), 311.07 (6.2 %), 310.08 (1.8 %). Elemental
analysis of C18H13N2OCl calcd. (found) %: C, 70.02 (7.14); H,
4.24 (4.21); N, 9.07 (9.17).
As seen in Scheme-I, the reaction of starting material, 3-acetyl
indole (1) with dimethyl sulphate in the presence of various
bases is a classical method to form N-methylated indole deri-
vatives. Methylation with dimethyl sulphate has been found
to be a practical method to develop N-methylated indole analo-
gues in good yields and purity. Therefore, development of efficient
synthetic methods for the synthesis of target compounds using
3-acetyl-1-methyl indole. Next, 3-acetyl-1-methyl (2) indole
treated with commercially available aromatic aldehydes, afforded

246 Matilda et al.
Asian J. Chem.
R
R
O
O
CH3
CH3
O
N
O
HC
HC
O
(i)
(ii)
(iii)
+
Ar
H
N
H
N
CH3
1
2
N
N
Reagents and conditions:
(i) (CH3)2SO4 and NaOH, (ii) EtOH, 10 % NaOH, (iii) NH2OH·HCl, NaOCOCH3, EtOH
CH3
CH3
3
4
4a: R = H; 4b: R = 2Cl; 4c: R = 4Cl; 4d: R = 2CH3; 4e: R = 4CH3; 4f: R = 2OMe; 4g: R = 4OMe; 4h: R = 2OH
Scheme-I: Synthetic route of some novel N-methylated indole containing isoxazole moieties
TABLE-1
3-aryl-1-(1-methylindole-3-yl)-2-propen-1-one (3).A mixture
of 3-aryl-1-(1-methylindole-3-yl)-2-propen-1-one (0.01 mol),
hydroxylamine hydrochloride (0.01 mol) in the presence of
sodium acetate and exactly 50 mL of ethanol with glacial acetic
acid was added and refluxed for 8-10 h to afford the target
compound (4). This reaction pathway shows that the nucleo-
philc attack of hydroxylamine hydrochloride at the β-carbon
of α,β-unsaturated carbonyl system leads ultimately to isoxazole.
The homogeneity of compounds was monitored by purified
by column chromatography (silica gel 60, 150 mesh) using
chloroform as the eluent to obtain pure colourless crystals of
compounds.
Antioxidant activity: Indolyl isoxazole derivatives were
investigated for their free radical scavenging activities using
DPPH assay. The antioxidant activity of synthesized comp-
ounds were also determined with measuring the IC50 (µM) values
in Table-1. The data revealed that the indolyl isoxazole hybrids
showed potent DPPH radical scavenging activity, comparable
to that of standard butylated hydroxyanisole. Compounds 4c
and 4f which exhibited good radical scavenging activity and
their IC50 values were found to be 92 and 78 µM, respectively
because compound having substitution with electron with-
drawing groups enhanced antioxidant activity against DPPH
free radicals. Moreover, compounds 4d and 4g showed mode-
rate scavenging activity with IC50 values 157 and 130 µM (Table-1).
Geometric optimization (molecular analysis): The opti-
mized structural parameters of all compounds was carried out
at the B3LYP/6-311++G (d, p) level of DFT basis set imple-
mented in Gaussian 09 program package. The optimized struc-
DPPH RADICAL SCAVENGING ACTIVITY OF 5-PHENYL-
3-(1-METHYLINDOL-3-YL)ISOXAZOLE (4a-h)
Compounds
IC50 (µM)
Compounds
IC50 (µM)
4a
4b
4c
4d
4e
564
321
92
157
307
4f
4g
4h
BHA
–
78
130
188
624
–
ture of compound (4a) with numbering of the atoms is depicted
in Fig. 1 and the important geometrical parameters are listed
inTable-2.The atomic orbital components of HOMO and LUMO
distribution pattern of indolyl derivatives 4a are shown in Fig. 2.
Fig. 1. Structure of 5-phenyl-3-(1-methylindol-3-yl)isoxazole (4a)
Frontier molecular orbitals of compound 4a shows that
the electrons are transferring from the indole moiety towards
HOMO
LUMO
Fig. 2. HOMO and LUMO of 5-phenyl-3-(1-methylindol-3-yl)isoxazole (4a)

Vol. 32, No. 2 (2020)
Synthesis and DFT Study of Some Novel N-Methylated Indole Incorporating Isoxazole Moieties 247
TABLE-2
OPTIMIZED GEOMETRICAL PARAMETERS OF 5-PHENYL-3-(1-METHYLINDOL-3-YL)ISOXAZOLE (4a)
Atom
Bond length (Å)
1.4576
1.3837
1.3709
1.0758
1.4336
1.3405
1.4521
1.3834
1.0784
1.3838
1.3942
1.4276
1.4073
1.0842
1.3939
1.0852
Atom
O1–C3–C4
C3–C4–H15
C4–C5–H15
C4–C5–C6
Bond angle (°)
108.81
127.44
126.45
128.28
124.63
128.57
121.21
107.77
121.51
117.56
120.92
119.52
119.49
119.24
121.23
25.35
Atom
Dihedral angle (°)
179.95
O1–N2
O1–C3
C3–C4
O1–C3–C21–C26
C4–C3–C21–C22
C7–C6–C5–C4
179.56
-157.56
-177.76
179.18
-178.12
-179.99
-179.59
-159.05
179.95
C4–H15
C4–C5
C13–C14–C12–H20
H19–C11–C10–C9
N2–C5–C4–H15
H27–C22–C23–C24
H16–C7–C6–C14
N2–C5–C6–C14
H18–C10–C11–C12
N8–C13–C14–C12
C9–C13–C14–C6
C21–C22–C23–H28
C32–N8–C7–C6
C21–C26–C25–H30
C13–N8–C32–H33
C5–C6–C7
N2–C5
C5–C6
C6–C7
C6–C7–H16
N8–C7–H16
C9–C13–C14
C13–C9–H17
C13–C9–C10
C9–H17–C10
C9–C10–H18
C10–C11–H18
C10–C11–H19
C10–C11–C12
C12–C14–H20
C7–H16
N8–C7
N8–C13
C13–C14
C14–C12
C12–H20
C11–C12
C11–H19
178.51
-179.87
-179.96
-179.34
-179.99
-60.18
isoxazole moiety due to HOMO-LUMO excitation. The comp-
arison between frontier molecular orbitals of indolyl derivatives
at the ground state, HOMO is delocalized over the indole ring
whereas the LUMO is placed over the isoxazole ring. HOMO
and LUMO energies of compounds 4a-h along with their gaps
and the reactivity indices of compounds (4a-h) were calculated
and are listed in Table-3. Among all compounds, compound
4a showed the lowest HOMO-LUMO energy gap, i.e. -0.2387
eV, while 4b and 4c showed the largest energy gap i.e. 0.2360
eV. In the Mulliken analysis, half the overlap population is
assigned to each contributing orbital, giving the total popu-
lation of each atomic orbital. Summing over all the atomic
orbitals on a specific atom gives the gross atomic population.
From the Mulliken population analysis, atomic charge values
were obtained (Fig. 3).The Mulliken atomic charges of 5-
phenyl-3-(1-methylindol-3-yl)isoxazole (4a) are presented in
Table-3. The Mulliken atom charge is positive for all hydrogen
atoms. Oxygen and nitrogen atoms possess negative charge
and chlorine atoms carry positive charge.
Fig. 3. Mulliken charge distribution of 5-phenyl-3-(1-methylindol-3-yl)-
isoxazole (4a)
value of hardness (η), i.e. 0.1125eV, whereas 4d has the highest
value of hardness (0.2301 eV).Compound 4d has the highest
ionization potential (I) value (0.2958 eV) among the other
compounds, while 4g has the lowest chemical potential value
(0.2336 eV). The results indicate that the compound 4a has
the lowest electron affinity (A) value -0.0009 eV, whereas com-
pound 4b has the highest value is 0.0055 eV. In addition, among
the set of the synthesized compounds, compound 4b has the
highest electronegativity (χ) value (0.1236 eV) while com-
pound 4d has the lowest value (0.0656 eV). Compound 4c
(4.2371 eV) has the highest value of softness of the compound
and the lowest value is 2.1723 eV for compound 4d (Table-4).
The proton transfer of indolyl isoxazole compounds has
been investigated here using reactivity indices. From Table-3,
it is clear that among all the compounds, 4g has the lowest
TABLE-3
MULLIKEN CHARGE DISTRIBUTION OF 5-PHENYL-
3-(1-METHYLINDOL-3-YL)ISOXAZOLE (4a)
Conclusion
Mulliken
atomic charge
Mulliken
atomic charge
Atom
Atom
In conclusion, a new series of 5-phenyl-3-(1-methylindol-
3-yl)isoxazole derivatives were successfully synthesized by
the reaction of 3-acetyl-1-methyl indole with different aromatic
aldehydes. All the synthesized compounds were screened for
their antioxidant activity. The compound with highest anti-
oxidant activity was 4d, whose IC50 value is found to be 78 µM.
The optimized geometrical parameters calculated at B3LYP/
6-31G (d,p) basis set. Compounds with lower HOMO-LUMO
band gap has higher biological activities. The feasibilities of
hydrogen bonding were explained by Mulliken charge analysis.
O1
N2
C3
C4
C5
C6
C7
N8
C9
C10
C11
C12
C13
C14
H15
-0.454
-0.185
0.234
-0.105
0.077
0.002
0.120
-0.691
-0.085
-0.150
-0.135
-0.136
0.255
0.020
0.159
H16
H17
H18
H19
H20
C21
C22
C23
C24
C25
C26
H27
H28
H29
H30
0.187
0.128
0.120
0.118
0.129
0.076
-0.129
-0.138
-0.109
-0.142
-0.121
0.170
0.133
0.131
0.131
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.

248 Matilda et al.
Asian J. Chem.
TABLE-4
ENERGIES OF HOMO-LUMO OF 5-PHENYL-3-(1-METHYLINDOL-3-YL)ISOXAZOLE (4a-h)
B3LYP/631G
Parameters (a.u)
4a
4b
4c
4d
4e
4f
4g
4h
HOMO
LUMO
HOMO-LUMO
-0.2377
0.0009
-0.2387
0.2377
-0.0009
0.1183
0.1193
4.1893
-0.2416
-0.0055
0.2360
0.2416
0.0055
0.1236
0.1180
4.2362
-0.2391
-0.0031
0.2360
0.2391
0.0031
0.1211
0.1180
4.2371
-0.2958
0.1644
-0.4603
0.2958
-0.1644
0.0656
0.2301
2.1723
-0.2373
0.0019
-0.2392
0.2373
-0.0019
0.1176
0.1196
4.1795
-0.2357
0.0045
-0.2402
0.2357
-0.0045
0.1156
0.1201
4.1618
-0.2336
0.0085
-0.2421
0.2336
-0.0085
0.1210
0.1125
4.1295
-0.2342
0.0074
-0.2416
0.2342
-0.0074
0.1133
0.1208
4.1378
I
A
χ
η
S
I-Ionisation potential; A-Electron affinity; χ-Electronegativity; η-Hardness; S-Softness
8. W.S. Hamama, M.E. Ibrahim,A.A. Gooda and H.H. Zoorob, J. Heterocycl.
Chem., 55, 2623 (2018);
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