Synthesis and Anticancer Evaluation of 1,2,4-Oxadiazole Linked Imidazothiadiazole Derivatives

Article abstract of DOI:10.1134/S1070363218050304

A series of 1,2,4-oxadiazole linked imidazothiadiazole derivatives 11a–11j have been synthesized. All derivatives were evaluated for anticancer activity against three human cancer cell lines (A375, MCF-7, and ACHN) and demonstrated activity comparable with that of doxorubicin. Three compounds 11b, 11c, and 11j exhibited higher anticancer activity than the positive control. The range of IC₅₀ for the compounds 11b, 11c, and 11j is determined to be from 0.11 to 2.98 μM.

Full text of DOI:10.1134/S1070363218050304

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 5, pp. 1020–1024. © Pleiades Publishing, Ltd., 2018.
Synthesis and Anticancer Evaluation
of 1,2,4-Oxadiazole Linked Imidazothiadiazole Derivatives1
B. Chakrapania, V. Ramesha, G. Pourna Chander Raoa, D. Ramachandrana,
T. Madhukar Reddyb, A. Kalyan Chakravarthyc*, and Gattu Sridhard
a Department of Chemistry, Acharya Nagarjuna University, Guntur, Andhra Pradesh, India
b Department of Physical Sciences, Kakatiya Institute of Technology and Science,
Hasanparthy, Warangal District, Telangana
c Dr. Reddy’s Laboratories, Integrated Product Development, Bachupally, Hyderabad, India
*e-mail: rk1org@yahoo.com
d Organic and Biomolecular Chemistry Division, Council of Scientific and Industrial Research,
Indian Institute of Chemical Technology, Hyderabad, 500107 India
Received March 1, 2018
Abstract—A series of 1,2,4-oxadiazole linked imidazothiadiazole derivatives 11a–11j have been synthesized.
All derivatives were evaluated for anticancer activity against three human cancer cell lines (A375, MCF-7, and
ACHN) and demonstrated activity comparable with that of doxorubicin. Three compounds 11b, 11c, and 11j
exhibited higher anticancer activity than the positive control. The range of IC50 for the compounds 11b, 11c,
and 11j is determined to be from 0.11 to 2.98 µM.
Keywords: levamisole, 1,2,4-oxadiazole and anticancer activity
DOI: 10.1134/S1070363218050304
INTRODUCTION
In view of the above facts and as part of our earlier
efforts to create novel biologically active agents, we
report herein synthesis of 1,2,4-oxadiazole linked
imidazothiadiazole derivatives and evaluation of their
anticancer action on human cancer cell lines.
Synthesis of heterocyclic fused rings led to develop-
ment of novel drugs with enhanced biological activities
[1, 2] including antitumor activity against diverse
human tumor cell lines [3–10]. Among such cyclic
systems is imidazole fused with 1,3,4-thiadiazole
moiety, imidazo[2,1-b]1,3,4-thiadiazoles [11], which
contains a bridgehead nitrogen atom. Imidazo[2,1-b]-
1,3,4-thiadiazoles exhibit a diverse array of biological
activities, such as anticancer [12], antitubercular [13],
antibacterial [14], antifungal [15], anticonvulsant, and
antitumor [16, 17]. Imidazo[2,1-b][1,3,4]thiadiazole is
somewhat structurally close to Levamisole (1) (see the
figure) [11], a well- known potential antitumor agents
and immunomodulator [18].
RESULTS AND DISCUSSION
Synthetic approach to 1,2,4-oxadiazole linked imida-
zothiadiazole derivatives 11a–11j is presented in
Scheme 1. Imidazothiadiazole precursor 6-chloro-2-
methylimidazo[2,1-b][1,3,4]thiadiazole-5-carbonitrile
9 was synthesized by the reaction of 5-methyl-1,3,4-
thiadiazol-2-amine 3 with bromoacetic acid 4 in
Cl
1,2,4-Oxadiazole is considered to be a privileged
nitrogen containing heterocyclic scaffold and is used
extensively in medicinal chemistry [19–22]. Among
oxadiazoles, 3,5-disubstituted-1,2,4-oxadiazoles (2)
(see the figure) are reported to demonstrate anticancer
potential [23, 24].
N
N
O
S
N
S
N
1
CF3
2
Structures of Levamisole (1) and 3,5-disubstituted-1,2,4-
oxadiazoles (2).
1 The text was submitted by the authors in English.
1020

SYNTHESIS AND ANTICANCER EVALUATION
1021
Scheme 1. Synthetic pathway to 1,2,4-oxadiazole linked imidazothiadiazole derivatives 11a–11j.
OH
O
N
S
N
N
S
O
N
POCl3
N
N
EtOH, POCl3
reflux, 7 h
.
H3C
NH HBr
Cl
+
Br
NH2
reflux, 2 h
H3C
S
OH
N
H3C
3
5
4
6
DMF, POCl3, CHCl3,
reflux, 12 h
OH
N
H
N
O
N
N
N
S
.
N
NH2OH HCl, pyridine
N
Ac2O
N
H3C
Cl
Cl
H3C
Cl
H3C
reflux, 6 h
reflux, 1 h
S
N
N
S
N
8
9
7
R
+
O
N
O
OH
N
N
o
.
NH2OH HCl, 100 C, 6 h
N
Cl
H3C
R
4-(dimethylamino)pyridinium acetate
N
S
11a−11j
10a−10j
R = H (10a, 11a), 3,4,5-trimethoxy (10b, 11b), 4-methoxy (10c, 11c), 4-chloro (10d, 11d), 4-bromo (10e, 11e), 4-fluoro
(10f, 11f), 4-nitro (10g, 11g), 3-nitro (10h, 11h), 4-methyl (10i, 11i), 4-trifluoromethyl (10j, 11j).
ethanol in the presence of POCl3. This was followed
by refluxing the salt 5 in POCl3 that gave 6-chloro-2-
methylimidazo[2,1-b][1,3,4]thiadiazole 6 with high
yield. Formylation of the byproduct 5 with DMF,
POCl3 in CHCl3, led to 6-chloro-2-methylimidazo[2,1-
b][1,3,4]thiadiazole-5-carbaldehyde 7. Its reaction with
NH2OH·HCl in pyridine afforded oxime 8. Oxime 8
reaction with Ac2O led to 6-chloro-2-methylimidazo
[2,1-b][1,3,4]thiadiazole-5-carbonitrile 9. This nitrile
intermediate 9 underwent cyclization with substituted
aromatic carboxylic acids 10a–10j in NH2OH·HCl and
in the presence of 4-(dimethylamino)pyridinium
acetate giving the target 1,2,4-oxadiazole linked
imidazothiadiazole derivatives 11a–11j.
employing the MTT assay (see the table). Here
doxorubicin was used as a reference drug. The
compound 11b demonstrated the most potent
anticancer activity higher than the positive control
doxorubicin. The compound 11j exhibit excellent
activity towards melanoma cancer cell line (A375) and
potent activities towards MCF-7 and ACHN.
EXPERIMENTAL
All chemicals and reagents were obtained from
Aldrich (Sigma–Aldrich, St. Louis, MO, USA),
Lancaster (Alfa Aesar, Johnson Matthey Company,
Ward Hill, MA, USA) and used without further
purification. Reactions were monitored by TLC, per-
formed on silica gel glass plates containing 60 F-254
In vitro cytotoxicity. The newly synthesized 1,2,4-
oxadiazole linked imidazothiadiazole compounds 11a–
11j were evaluated for their in vitro anticancer activity
against a panel of three human cancer cell lines, A375
(melanoma), MCF-7 (breast) and ACHN (renal), by
1
and visualized by UV light or iodine indicator. H and
13C NMR spectra were measured on a Bruker
UXNMR/XWIN-NMR spectrometer in CDCl3 for 7, 8
and DMSO-d6 for all other compounds using TMS as
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 5 2018

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CHAKRAPANI et al.
Cytotoxicity data for compounds 11a–11j
IC50 values, µM
IC50 values, µM
Compound
Compound
A375
11.4
1.22
2.98
14.6
8.20
2.70
MCF-7
10.2
0.23
0.70
19.1
11.2
8.41
ACHN
18.5
0.11
1.89
6.47
7.7
A375
17.7
2.20
9.56
0.37
5.51
MCF-7
9.7
ACHN
12.2
11a
11b
11c
11d
11e
11f
11g
11h
5.98
13.7
1.47
2.02
10.6
11i
2.44
11j
0.33
Doxorubicin
0.79
17.6
1
the internal standard. ESI spectra were recorded on a
Micro mass, Quattro LC using ESI+ software with
capillary voltage 3.98 kV and ESI mode positive ion
trap detector. Melting points were determined with an
electrothermal melting point apparatus.
pure compound 7. Yield 70%, mp 103–105°C. H
NMR spectrum, δ, ppm: 2.85 s (3H), 9.91 s (1H). MS
(ESI): m/z: 202 [M + H]+.
Synthesis of 6-chloro-2-methylimidazo[2,1-b][1,3,4]-
thiadiazole-5-carbaldehyde oxime (8). A mixture of
6-chloro-2-methylimidazo[2,1-b][1,3,4]thiadiazole-5-
carbaldehyde 7 (5 g, 24.8 mmol) with hydroxyl amine
hydrochloride (1.8 g, 24.8 mmol) was refluxed in
pyridine (15 mL) for 6 h. Upon completion of the
reaction, the mixture was cooled down then poured
onto crushed ice. The precipitate was filtered off,
washed with water, aqueous ethanol, and dried to
afford pure aldoxime 8. Yield 86%, mp 154–156°C. 1H
NMR spectrum, δ, ppm: 2.87 s (3H), 8.36 s (1H),
11.56 br.s (1H). MS (ESI): 217 [M + H]+.
Synthesis of 6-chloro-2-methylimidazo[2,1-b][1,3,4]-
thiadiazole (6). The appropriate 5-methyl-1,3,4-thia-
diazol-2-amine 3 (2 g, 17.3 mmol) was dissolved in
ethanol (30 mL) and treated with the equivalent of
2-bromoacetic acid 4 (2.4 g, 17.3 mmol). The reaction
mixture was refluxed for 7 h. The resulting salt 5 was
filtered off and without further purification refluxed
for 2 h with 15 mL of POCl3. After completion of the
reaction, the solvent was evaporated under vacuum and
the residue was poured onto crushed ice. The solution
was basified with 20% NH4OH. The residue was
filtered off and dried to obtain the crude compound.
The crude product was purified by column chromato-
graphy with hexanes–ethyl acetate (3 : 7) to afford
pure compound 6. Yield 69%, mp 129–131°C. 1H NMR
spectrum, δ, ppm: 2.82 s (3H), 7.26–7.30 m (1H). MS
(ESI): m/z: 174 [M + H]+.
Synthesis of 6-chloro-2-methylimidazo[2,1-b][1,3,4]-
thiadiazole-5-carbonitrile (9). 6-Chloro-2-methyl-
imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde oxime
8 (4 g, 18.5 mmol) was suspended in acetic anhydride
(15 mL) and refluxed for 1 h, then poured into cold
water and neutralized by sodium carbonate solution.
The precipitated solid was filtered off, washed
repeatedly with water, dried, and recrystallized from
ethanol to afford pure compound 9. Yield 74%, mp
Synthesis of 6-chloro-2-methylimidazo[2,1-b][1,3,4]-
thiadiazole-5-carbaldehyde (7). The Vilsmeier reagent
was prepared at 0–5°C by dropping POCl3 (13.5 mL,
144.5 mmol) into a stirred solution of DMF (8 mL) in
CHCl3. 6-Chloro-2-methylimidazo[2,1-b][1,3,4]thiadi-
azole 6 (2.5 g, 14.4 mmol) was suspended in CHCl3
(20 mL). The mixture thus obtained was added drop
wise to the Vilsmeier reagent while stirring and
cooling. The reaction mixture was stored for 3 h at
room temperature and then refluxed for 12 h.
Chloroform was removed under reduced pressure and
the resulting oily liquid was poured onto crushed ice.
The crude aldehyde was purified by column chromato-
graphy with hexanes–ethyl acetate (2 : 8) to obtain
1
166–168°C. H NMR spectrum, δ, ppm: 2.87 s (3H).
MS (ESI): 199 [M + H]+.
Synthesis of 6-chloro-2-methyl-5-(5-phenyl-1,2,4-
oxadiazol-3-yl)imidazo[2,1-b][1,3,4]thiadiazole (11a).
In a 5-mL round-bottom flask 6-chloro-2-methylimi-
dazo[2,1-b][1,3,4]thiadiazole-5-carbonitrile 9 (300 mg,
1.5 mmol), hydroxylamine hydrochloride (104 mg,
1.5 mmol) and benzoic acid 11a (183 mg, 1.5 mmol)
were added to 4-(dimethylamino) pyridinium acetate
(544 mg, 3 mmol). The reaction mixture was heated to
100°C for 6 h. Then the mixture was cooled down to
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SYNTHESIS AND ANTICANCER EVALUATION
1023
room temperature, ethanol (1 mL) was added, and
stirring continued for 30 min. Water (5 mL) was added
to the reaction mixture. The ionic liquid was dissolved
in water and filtered for separation of the products. The
solid product was collected and washed with water
(2×5 mL). The crude product was purified by column
chromatography with hexanes–ethyl acetate (3 : 7) to
afford pure compound 11a. Yield 61%, mp 170–172°C.
1H NMR spectrum: δ, ppm: 2.87 s (3H), 7.54–7.60 m
(3H), 7.76 d (2H, J = 8.23 Hz). 13C NMR spectrum: δ
18.7, 114.7, 126.9, 129.5, 132.5, 138.6, 142.5, 143.8,
149.6, 158.8, 159.6. MS (ESI): 318 [M + H]+.
117.6, 125.7, 133.8, 142.7, 143.8, 149.9, 158.7, 159.6,
160.5. MS (ESI): 336 [M + H]+.
6-Chloro-2-methyl-5-[5-(4-nitrophenyl)-1,2,4-
oxadiazol-3-yl]imidazo[2,1-b][1,3,4]thiadiazole (11g).
1
Yield 66%, mp 179–181°C. H NMR spectrum, δ,
ppm: 2.88 s (3H), 7.82 d (2H, J = 8.45 Hz), 7.93 d
(2H, J = 8.45 Hz). 13C NMR spectrum, δ, ppm: 18.8,
114.7, 123.8, 126.8, 142.6, 143.7, 143.9, 149.8, 150.6,
158.6, 159.8. MS (ESI): 363 [M + H]+.
6-Chloro-2-methyl-5-[5-(3-nitrophenyl)-1,2,4-
oxadiazol-3-yl]imidazo[2,1-b][1,3,4]thiadiazole (11h).
1
Yield 68%, mp 183–185°C. H NMR spectrum, δ,
The compounds 11b–11j were synthesized
according to the above method presented for 11a.
ppm: 2.88 s (3H), 7.77–7.83 m (2H), 7.90 d (1H, J =
8.34 Hz), 7.96 s (1H). 13C NMR spectrum, δ, ppm: 18.9,
114.8, 119.7, 128.7, 129.6, 130.5, 139.6, 142.5, 143.8,
149.7, 150.4, 158.7, 159.8. MS (ESI): 363 [M + H]+.
6-Chloro-5-[5-(3,4,5-trimethoxyphenyl)-1,2,4-oxa-
diazol-3-yl]-2-methylimidazo[2,1-b][1,3,4]thiadiazole
(11b). Yield 51%, mp 147–149°C. 1H NMR spectrum,
δ, ppm: 2.87 s (3H), 3.86 s (3H), 3.92 s (6H), 7.75 s
(2H). 13C NMR spectrum, δ, ppm: 18.7, 57.8, 61.7,
107.8, 114.6, 133.8, 142.6, 143.7, 144.6, 149.6, 158.6,
159.5. MS (ESI): 408 [M + H]+.
6-Chloro-2-methyl-5-(5-p-tolyl-1,2,4-oxadiazol-
3-yl)imidazo[2,1-b][1,3,4]thiadiazole (11i). Yield 64%,
1
mp 137–139°C. H NMR spectrum, δ, ppm: 2.76 s
(3H), 2.86 s (3H), 7.48 d (2H, J = 8.15 Hz), 7.75 d
(2H, J = 8.15 Hz). 13C NMR spectrum, δ, ppm: 18.6,
29.4, 114.6, 124.7, 129.6, 135.8, 141.6, 143.5, 144.4,
149.7, 158.6, 159.6. MS (ESI): 332 [M + H]+.
6-Chloro-5-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-
3-yl]-2-methylimidazo[2,1-b][1,3,4]thiadiazole (11c).
Yield 61%, mp 131–133°C. 1H NMR spectrum, δ, ppm:
2.87 s (3H), 3.87 s (3H), 7.24 d (2H, J = 8.12 Hz), 7.76
d (2H, J = 8.12 Hz). 13C NMR spectrum, δ, ppm: 18.6,
57.5, 114.6, 116.5, 118.6, 131.5, 142.6, 143.8, 149.7,
158.7, 159.5, 160.3. MS (ESI): 348 [M + H]+.
6-Chloro-5-{5-[4-(trifluoromethyl)phenyl]-1,2,4-
oxadiazol-3-yl}-2-methylimidazo[2,1-b][1,3,4]thia-
1
diazole (11j). Yield 55%, mp 155–157°C. H NMR
spectrum, δ , ppm: 2.88 s (3H), 7.76 d (2H, J = 8.35 Hz),
7.80 d (2H, J = 8.35 Hz). 13C NMR spectrum, δ, ppm:
18.7, 114.5, 122.4, 126.8, 128.6, 132.7, 143.5, 143.9,
144.6, 149.7, 158.6, 159.8. MS (ESI): 386 [M + H]+.
6-Chloro-5-[5-(4-chlorophenyl)-1,2,4-oxadiazol-
3-yl]-2-methylimidazo[2,1-b][1,3,4]thiadiazole (11d).
1
MTT assay. Cytotoxic activity of the compounds
was determined using the MTT assay. 1×104 Cells/well
were seeded in 200 mL DMEM, supplemented with
10% FBS in each well of 96-well microculture plates
and incubated for 24 h at 37°C in a CO2 incubator.
Compounds, diluted to the desired concentrations in
culture medium, were added to the wells with respec-
tive vehicle control. After 48 h of incubation, 10 mL of
MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetra-
zolium bromide] (5 mg/mL) were added to each well
and the plates were further incubated for 4 h. Then the
supernatant from each well was carefully removed,
formazan crystals were dissolved in 100 mL of DMSO
and absorbance at 540 nm wavelength was recorded.
Yield 62%, mp 176–178°C. H NMR spectrum, δ,
ppm: 2.87 s (3H), 7.74 d (2H, J = 8.17 Hz), 7.77 d
(2H, J = 8.17 Hz). 13C NMR spectrum, δ, ppm: 18.6,
114.8, 126.5, 129.8, 134.5, 136.8, 142.6, 143.8, 149.7,
158.7, 159.6. MS (ESI): 353 [M + H]+.
5-[5-(4-Bromophenyl)-1,2,4-oxadiazol-3-yl]-6-
chloro-2-methylimidazo[2,1-b][1,3,4]thiadiazole (11e).
Yield 55%, mp 180–182°C. 1H NMR spectrum, δ, ppm:
2.88 s (3H), 7.75 d (2H, J = 8.34 Hz), 7.80 d (2H, J =
8.34 Hz). 13C NMR spectrum, δ, ppm: 18.9, 114.7,
124.8, 126.8, 132.6, 136.4, 142.6, 143.6, 149.7, 158.9,
159.5. MS (ESI): 397 [M + H]+.
6-Chloro-5-[5-(4-fluorophenyl)-1,2,4-oxadiazol-
3-yl]-2-methylimidazo[2,1-b][1,3,4]thiadiazole (11f).
Yield 67%, mp 150–152°C. 1H NMR spectrum, δ, ppm:
2.86 s (3H), 7.45 d (2H, J = 8.26 Hz), 7.74 d (2H, J =
8.26 Hz). 13C NMR spectrum, δ, ppm: 18.7, 114.6,
CONCLUSIONS
Ten derivatives of 1,2,4-oxadiazole linked imidazo-
thiadiazoles 11a–11j have been synthesized and tested
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CHAKRAPANI et al.
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compounds exhibited variable in vitro anticancer
activity at micro molar (µM) concentration. The
compounds 11b, 11c and 11j demonstrated higher
anticancer activity than the positive control.
ACKNOWLEDGMENTS
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The authors are thankful to Acharya Nagarjuna
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Industrial Research (CSIR), New Delhi for constant
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