Synthesis and Anticancer Evaluation of Amide Derivatives of 1,3,4-Oxadiazole Linked with Benzoxazole

Article abstract of DOI:10.1134/S1070363219050219

A novel series of amide 1,3,4-oxadiazole linked benzoxazole derivatives 12a–12j are synthesized and their anticancer activity is screened against four human cancer cell lines including A549 (Lung cancer), MCF7 (Breast cancer), A375 (Melanoma cancer), HT-29 (Colon cancer) using Combretastatin-A4 as a control drug. Among the synthesized compounds, 12c and 12g demonstrate potent anticancer activity against HT-29 cancer cell line with IC₅₀ values of 0.018 and 0.093 μM, respectively, which is higher than the standard drug.

Full text of DOI:10.1134/S1070363219050219

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 5, pp. 1003–1008. © Pleiades Publishing, Ltd., 2019.
Synthesis and Anticancer Evaluation of Amide Derivatives
of 1,3,4-Oxadiazole Linked with Benzoxazole
B. Ravinaika, D. Ramachandranb*, and M. V. Basaveswara Raoc
a Department of Chemistry, Krishna University, Machilipatnam, Andhra Pradesh, 521001 India
b Department of Chemistry, Acharya Nagarjuna University, Nagarjuna Nagar, Andhra Pradesh, 522510 India
*e-mail: dittakavirc@gmail.com
c Department of Chemistry, Dr. MRAR. PG Centre, Krishna University, Nuzvid, Andhra Pradesh, 521201 India
Received October 10, 2018; revised March 3, 2019; accepted May 28, 2019
Abstract—A novel series of amide 1,3,4–oxadiazole linked benzoxazole derivatives 12a–12j are synthesized
and their anticancer activity is screened against four human cancer cell lines including A549 (Lung cancer),
MCF7 (Breast cancer), A375 (Melanoma cancer), HT-29 (Colon cancer) using Combretastatin-A4 as a control
drug. Among the synthesized compounds, 12c and 12g demonstrate potent anticancer activity against HT-29
cancer cell line with IC50 values of 0.018 and 0.093 µM, respectively, which is higher than the standard drug.
Keywords: benzoxazole, AJI9561, zibotentan, amide, 1,3,4-oxadiazole and anticancer activity
DOI: 10.1134/S1070363219050219
INTRODUCTION
isolated from Streptomyces sp. AJ956 [31] which
exhibited promising growth inhibitory activity against
murine cancer cell line P388.
A big number of recent publications is devoted to
synthesis of heterocyclic compounds as important com-
ponents in construction of anticancer agents (drugs)
against a panel of different human cancer cell lines, to
mention a few [1–15]. Benzoxazole derivatives are
highly recognized by medicinal chemists as biolo-
gically active compounds, that demonstrate antitumor
[17-20], DNA-topoisomerase [21], antitubercular [22],
antimicrobial [23], antiviral [24], antibacterial,
antifungal [25, 26], antihistaminic [27], antiallergic
[28], herbicidal [29], and antiparasitic [30] activities.
Compound AJI9561 (Fig. 1a) is a bis-benzoxazole
1,3,4-Oxadiazole derivatives are considered to be
active bioisosteres of amides and esters due to forma-
tion of hydrogen bonds with receptors [32] charac-
terized by various types of biological properties. For
example, Zibotentan (Fig. 1b) is one of the most
important anticancer drugs available on the market [33].
In view of the above information and in continua-
tion of our earlier efforts, we have synthesized a novel
series of amide derivatives of benzoxazole. Their
1
structures were supported by H and 13C NMR, and
(a)
O
(b)
MeO
N
OH
HN
Me
O
N
O S O N
HO
N
O
N
O
N
N
Me
2
1
Fig. 1. Structures of (a) AJI9561 1 and (b) Zibotentan 2.
1003

1004
RAVINAIK et al.
Scheme 1. Synthesis of amide derivatives of 1,3,4-oxadiazole linked with benzoxazole.
CHO
N
O
NH2
OH
a. EtOH, reflux, 4 h
b. Pb(OAc)4, AcOH
CO2Me
+
CO2Me
4
5
3
EtOH, N2H4·H2O
reflux, 6 h
O
N
O
N
O
N
O
CS2, KOH
NH
Cl
CONHNH2
+
OMe
EtOH, HCl
reflux, 12 h
8
S
6
7
MeCN, TEA
room temperature, 5 h
N
O
N
O
N
OMe
S
O
9
room temperature, 2 h
MeOH, NaOH
N
O
N
N
O
S
OH
O
10
NH2
EDCI, HOBt
R
DCM, room temperature, 12 h
11a−11j
N
N
N
H
R
O
O
N
S
12a−12j
O
R = H (11a, 12a), 3,4,5-trimethoxy (11b, 12b), 4-methoxy (11c, 12c), 4-chloro (11d, 12d), 4-bromo (11e, 12e), 4-fluoro (11f,
12f), 4-nitro (11g, 12g), 4-methyl (11h, 12h), 4-cyano (11i, 12i), 3,5-dimethoxy (11j, 12j).
mass spectral data. The synthesized compounds were
tested for their anticancer activity against four human
cancer cell lines.
condensation of compound 3 with methyl 4-formyl-
benzoate 4 upon refluxing in ethanol medium. The
following addition of Pb(OAc)4 and acetic acid led to
compound 5 at room temperature. Refluxing of the
intermediate 5 with hydrazine hydrate in ethanol
afforded acid hydrazide 6. The subsequent cyclization
of compound 6 with CS2 in alkali medium led to com-
pound 7, which was reacted with methyl chloroacetate
RESULTS AND DISCUSSION
Synthetic approach to the series of ten amide
derivatives of benzoxazoles (Scheme 1) started with
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SYNTHESIS AND ANTICANCER EVALUATION OF AMIDE DERIVATIVES
1005
Anticancer activity of compounds 12a–12j
8 in presence of TEA with formation of compound 9.
The ester 9 was hydrolyzed with aq NaOH in methanol
at room temperature to give the corresponding acid
intermediate 10, coupling of which with substituted
aromatic amines 11a–11j in presence of EDCI, HOBt
in CH2Cl2 at room temperature afforded the corres-
ponding target compounds 12a–12j.
a
IC50 , µM
Compound
A549 MCF-7 A375
HT-29
12a
12b
12c
12d
12e
12f
12g
12h
12i
2.78
0.13
1.56
2.77
4.90
0.77
0.67
10.40
0.24
1.09
0.11
3.670
0.100
0.330
3.600
5.100
0.018
0.076
8.290
0.130
0.980
0.180
2.33
–
4.780
0.220
0.018
–
1.77
–
Biological evaluation. In vitro cytotoxicity. The
newly synthesized compounds 12a–12j were tested for
their anticancer activity against four human cancer cell
lines including A549 (Lung cancer), MCF7 (Breast cancer),
A375 (Melanoma cancer), HT-29 (Colon cancer) by
MTT assay (see the table). The CA4 was used as a
positive control. All the compounds exhibited significant
anticancer activity with IC50 values ranging from 0.01
to 10.40 µM, while for the positive control IC50 was in
the range of 0.11–0.93 µM. The compounds 12c, 12g,
and 12b demonstrated most potent anticancer activity
against HT-29 cancer cell line with IC50 values of
0.018, 0.093, and 0.22 µM, respectively, while the
compounds 12f, 12g, 12b, and 12i were determined to
be the most potent anticancer agents against MCF-7
cell line. The compounds 12b and 12i showed good
anticancer activity against A549 cell line. So, the most
active products can be considered as drug lead compounds.
7.56
1.39
1.55
–
2.110
–
0.093
9.340
0.900
8.900
0.930
1.90
2.10
0.21
12j
Combretastatin-A4
a (–) Not active.
and stirred at room temperature for 1 h. The reaction
mixture was then diluted with 30 mL of H2O, extracted
with ethyl acetate and dried over anhydrous Na2SO4.
The solvent was removed in vacuum, and the crude
product was purified by column chromatography with
ethyl acetate–hexane (3 : 7) to afford pure compound
5, yield 77%. 1H NMR spectrum, δ, ppm: 3.87 s (3H),
7.10 d (1H, J = 8.04 Hz), 7.33–7.37 m (3H), 7.56 br.s
(1H), 7.69 br.s (2H), 7.83 d (2H, J = 8.10 Hz), 8.07 d
(2H, J = 8.10 Hz). MS (ESI): 254 [M + H]+.
EXPERIMENTAL
All chemicals and reagents were obtained from
Aldrich (Sigma–Aldrich, St. Louis, MO, USA) and
Lancaster (Alfa Aesar, Johnson Matthey Company,
Ward Hill, MA, USA), and were used without further
purification. Reactions were monitored by TLC, per-
formed on silica gel glass plates containing 60 F-254,
and visualized under UV light or by iodine indicator.
4-(1,3-Benzoxazol-2-yl)-1-benzenecarbohydrazide
(6). A mixture of methyl 4-(1,3-benzoxazol-2-yl)-
benzoate 5 (25 g, 98.8 mmol) with hydrazine hydrate
(92 mL, 296 mmol) in ethanol was refluxed for 3 h.
The crude product was obtained after distilling off the
excess ethanol, cooling down, filtering, and washing
with small quantity of cold water. Thus obtained
product 6 (yield 74%) was introduced in the next step
without further purification. 1H NMR spectrum, δ,
ppm: 7.09 d (1H, J = 8.05 Hz), 7.32–7.38 m (3H), 7.56
br.s (1H), 7.69 br.s (2H), 7.84 d (2H, J = 8.13 Hz),
8.08 d (2H, J = 8.13 Hz). MS (ESI): 254 [M + H]+.
13
1H and C NMR spectra were measured on a Gemini
Varian-VXR-unity (300 and 400 MHz) spectrometer
using TMS as a standard and DMSO-d6 as a solvent.
ESI spectra were recorded on Micro mass, Quattro LC
using ESI+ software with capillary voltage 3.98 kV
and ESI mode positive ion trap detector. Melting
points were determined on an electrothermal melting
point apparatus, and are uncorrected.
Methyl 4-(1,3-benzoxazol-2-yl)benzoate (5). A
mixture of 2-aminophenol (3) (19 g, 174 mmol) with
methyl 4-formylbenzoate 4 (28 g, 174 mmol) was
refluxed in 70 mL of ethanol for 3 h. Then it was
cooled down, and ethanol was removed in vacuum.
The resulting Schiff base was dissolved in 100 mL of
acetic acid, mixed with lead tetraacetate (77 g, 174 mmol)
5-[4-(1,3-Benzoxazol-2-yl)phenyl]-2,3-dihydro-
1,3,4-oxadiazole-2-thione (7).
A
mixture of
compound 6 (17 g, 67 mmol) with potassium hyd-
roxide (3.7 g, 67 mmol), carbon disulfide (4.6 mL,
67 mmol) and absolute ethanol (50 mL) was refluxed
upon stirring for 12 h. The solvent was evaporated
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1006
RAVINAIK et al.
under vacuum. The residue was dissolved in water and
acidified with hydrochloric acid (10%). The formed
precipitate was filtered off, washed with water, dried,
and recrystallized from absolute ethanol to give
NMR spectrum, δ, ppm: 40.5, 111.6, 119.6, 121.4,
124.8, 125.3, 125.8, 126.3, 127.6, 128.7, 134.3, 134.8,
139.6, 143.3, 150.8, 156.7, 159.4, 161.3, 164.8. MS
(ESI): 429 [M + H]+.
1
compound 7. Yield 72%, mp 230–232°C. H NMR
The compounds 12b–12j were synthesized according
to the method presented above for compound 12a
using the corresponding substituted anilines.
spectrum, δ, ppm: 7.09 d (1H, J = 8.05 Hz), 7.32 –7.38
m (3H), 7.84 d (2H, J = 8.13 Hz), 8.02 s (1H), 8.08 d
(2H, J = 8.13 Hz). MS (ESI): 296 [M + H]+.
N1-(3,4,5-Trimethoxyphenyl)-2-{5-[4-(1,3-benz-
Methyl 2-{5-[4-(1,3-benzoxazol-2-yl)phenyl]-1,3,4-
oxadiazol-2-ylsulfanyl}acetate (9). To a stirred mixture
of the appropriate oxadiazole 7 (13 g, 44 mmol) with
methyl chloroacetate 8 (4.1 mL, 44 mmol) in CH3CN
(30 mL), triethylamine (18 mL, 132 mmol) was added.
The mixture was stirred at room temperature for 5 h
and the immediately formed precipitate was filtered
off, washed with methanol, and recrystallized from
oxazol-2-yl)phenyl]-1,3,4-oxadiazol-2-ylsulfanyl}-
1
acetamide (12b). Yield 86%, mp 245–247°C. H
NMR spectrum, δ, ppm: 3.87 s (6H), 3.90 s (3H), 4.10
s (2H), 6.99 s (2H), 7.10 d (1H, J = 8.03 Hz), 7.40–
7.49 m (3H), 7.85 d (2H, J = 8.11 Hz), 8.10 d (2H, J =
8.11 Hz), 9.21 s (1H). 13C NMR spectrum, δ, ppm: 40.4,
57.6, 61.8, 101.6, 111.7, 119.4, 124.7, 125.6, 126.4,
127.4, 134.2, 134.7, 137.6, 138.5, 143.7, 150.5, 152.3,
156.4, 159.6, 161.8, 164.8. MS (ESI): 519 [M + H]+.
1
absolute ethanol, yield 92%. H NMR spectrum, δ,
ppm: 3.84 s (3H), 4.09 s (2H), 7.09 d (1H, J =
8.02 Hz), 7.35–7.41 m (3H), 7.85 d (2H, J = 8.09 Hz),
8.09 d (2H, J = 8.09 Hz). MS (ESI): 368 [M + H]+.
N1-(4-Methoxyphenyl)-2-{5-[4-(1,3-benzoxazol-2-
yl)phenyl]-1,3,4-oxadiazol-2-ylsulfanyl}acetamide
1
(12c). Yield 80%, mp 237–239°C. H NMR spectrum,
2-{5-[4-(1,3-Benzoxazol-2-yl)phenyl]-1,3,4-oxa-
diazol-2-ylsulfanyl}acetic acid (10). A solution of
50% NaOH (20 mL) was added to a solution of 9
(13 g, 35.4 mmol) in methanol (50 mL), and the
mixture was stirred at room temperature for 2 h. Upon
evaporation of most of ethanol the aqueous phase was
acidified with 6 N HCl to pH 7 and extracted with
ethyl acetate (50 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated
under vacuum to afford pure compound 10, yield 82%.
1H NMR spectrum, δ, ppm: 4.09 s (2H), 7.10 d (1H,
J = 8.01 Hz), 7.34–7.40 m (3H), 7.85 d (2H, J =
8.10 Hz), 8.09 d (2H, J = 8.10 Hz), 11.55 br.s (1H).
MS (ESI): 354 [M + H]+.
δ, ppm: 3.90 s (3H), 4.10 s (2H), 6.92 d (2H, J =
8.10 Hz), 7.09 d (1H, J = 8.03 Hz), 7.41–7.50 m (3H),
7.68 d (2H, J = 8.10 Hz), 7.86 d (2H, J = 8.13 Hz),
8.11 d (2H, J = 8.13 Hz), 9.21 s (1H). 13C NMR
spectrum, δ, ppm: 40.7, 56.7, 111.8, 117.4, 119.5, 122.4,
124.6, 125.7, 126.4, 127.8, 134.2, 134.7, 135.2, 143.6,
150.5, 154.6, 156.5, 159.7, 161.5, 164.8. MS (ESI): 459
[M + H]+.
N1-(4-Chlorophenyl)-2-{5-[4-(1,3-benzoxazol-2-
yl)phenyl]-1,3,4-oxadiazol-2-ylsulfanyl}acetamide
(12d). Yield 90%, mp 249–251°C. 1H NMR spectrum,
δ, ppm: 4.11 s (2H), 7.10 d (1H, J = 8.04 Hz), 7.28 d
(2H, J = 8.16 Hz), 7.42–7.51 m (3H), 7.65 d (2H, J =
8.16 Hz), 7.88 d (2H, J = 8.18 Hz), 8.12 d (2H, J =
8.18 Hz), 9.21 s (1H). 13C NMR spectrum, δ, ppm:
40.6, 111.8, 119.7, 122.4, 124.6, 125.7, 126.3, 127.5,
127.9, 129.7, 134.5, 134.7, 139.8, 143.4, 150.5, 156.8,
159.8, 161.7, 164.8. MS (ESI): 463 [M + H]+.
N1-Phenyl-2-{5-[4-(1,3-benzoxazol-2-yl)phenyl]-
1,3,4-oxadiazol-2-ylsulfanyl}acetamide (12a). To the
solution of compound 10 (500 mg, 1.41 mmol) in
10 mL of dry CH2Cl2, aniline 11a (0.13 mL, 1.41 mmol),
EDCI (270 mg, 1.41 mmol) and HOBt (19 mg,
0.141 mmol) were added. The reaction mixture was
stirred at room temperature for 6 h, washed with
saturated solution of NaHCO3, extracted with CH2Cl2,
and dried over anhydrous Na2SO4. The crude product
was purified by column chromatography with ethyl
acetate–hexane (1 : 1) to afford the pure compound
12a. Yield 87%, mp 230–232°C. 1H NMR spectrum, δ,
ppm: 4.10 s (2H), 7.09 d (1H, J = 8.02 Hz), 7.32–7.53
m (6H), 7.65 d (2H, J = 8.20 Hz), 7.86 d (2H, J =
N1-(4-Bromophenyl)-2-{5-[4-(1,3-benzoxazol-2-
yl)phenyl]-1,3,4-oxadiazol-2-ylsulfanyl}acetamide
1
(12e). Yield 85%, mp 254–256°C. H NMR spectrum,
δ, ppm: 4.11 s (2H), 6.98 d (1H, J = 8.05 Hz), 7.29 d
(2H, J = 8.17 Hz), 7.41–7.50 m (3H), 7.54 d (2H, J =
8.17 Hz), 7.89 d (2H, J = 8.19 Hz), 8.13 d (2H, J =
8.19 Hz), 9.21 s (1H). 13C NMR spectrum, δ, ppm:
40.6, 111.7, 112.8, 119.5, 121.5, 124.3, 125.7, 126.5,
127.5, 131.2, 134.5, 134.7, 139.5, 143.5, 150.7, 156.7,
159.7, 161.8, 164.8. MS (ESI): 508 [M + H]+.
13
8.12 Hz), 8.10 d (2H, J = 8.12 Hz), 9.20 d (1H). C
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SYNTHESIS AND ANTICANCER EVALUATION OF AMIDE DERIVATIVES
1007
N1-(4-Fluorophenyl)-2-{5-[4-(1,3-benzoxazol-2-
MTT assay. Cytotoxic activity of the compounds
was tested using 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
respective vehicle control. After 48 h of incubation,
10 mL (5 mg/mL) of MTT [3-(4,5-dimethylthiazol-2-
yl)-2,5-diphenyl tetrazolium bromide] 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 wavelength of 540 nm
was recorded.
yl)phenyl]-1,3,4-oxadiazol-2-ylsulfanyl}acetamide
1
(12f). Yield 88%, mp 240–242°C. H NMR spectrum,
δ, ppm: 4.10 s (2H), 6.97 d (1H, J = 8.03 Hz), 7.14 d
(2H, J = 8.14 Hz), 7.42–7.54 m (5H), 7.87 d (2H, J =
8.17 Hz), 8.11 d (2H, J = 8.17 Hz), 9.21 s (1H). 13C
NMR spectrum, δ, ppm: 40.5, 111.5, 115.6, 119.6, 123.5,
124.7, 125.8, 126.5, 127.8, 134.3, 134.8, 137.6, 138.7,
143.5, 150.7, 156.8, 160.7, 161.9, 164.9. MS (ESI): 447
[M + H]+.
N1-(4-Nitrophenyl)-2-{5-[4-(1,3-benzoxazol-2-yl)-
phenyl]-1,3,4-oxadiazol-2-ylsulfanyl}acetamide (12g).
1
Yield 89%, mp 259–261°C. H NMR spectrum, δ,
ppm: 4.12 s (2H), 6.97 d (1H, J = 8.06 Hz), 7.42–7.54
m (3H), 7.88 d (2H, J = 8.20 Hz), 8.12 d (2H, J =
8.17 Hz), 8.17–8.23 m (4H), 9.21 s (1H). 13C NMR
spectrum, δ, ppm: 40.7, 111.8, 119.5, 120.6, 123.5, 124.6,
125.7, 126.4, 127.5, 134.2, 134.7, 143.6, 144.3, 150.7,
156.8, 160.5, 161.8, 164.9. MS (ESI): 474 [M + H]+.
CONCLUSIONS
A series of amides of benzoxazole derivatives 12a–
12j is synthesized. Their structures are confirmed by
1H and 13C NMR, and mass spectra. The synthesized
compounds are tested for their anticancer activity
against four human cancer cell lines, A549 (Lung
cancer), MCF7 (Breast cancer), A375 (Melanoma
cancer), and HT-29 (Colon cancer). The compounds
12b, 12c, 12f, 12g, 12i, and 12j demonstrated activity
more potent than the control CA4.
N1-(4-Methylphenyl)-2-{5-[4-(1,3-benzoxazol-2-
yl)phenyl]-1,3,4-oxadiazol-2-ylsulfanyl}acetamide (12h).
1
Yield 87%, mp 239–241°C. H NMR spectrum, δ,
ppm: 2.29 s (3H), 4.10 s (2H), 6.96 d (1H, J =
8.03 Hz), 7.09 d (2H, J = 8.14 Hz), 7.41–7.51 m (5H),
7.85 d (2H, J = 8.18 Hz), 8.10 d (2H, J = 8.18 Hz),
9.21 s (1H). 13C NMR spectrum, δ, ppm: 22.4, 40.6,
111.7, 119.6, 121.5, 124.3, 125.6, 126.4, 127.4, 127.8,
134.2, 134.8, 135.3, 139.6, 143.5, 150.6, 156.7, 159.6,
161.8, 164.9. MS (ESI): 443 [M + H]+.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
REFERENCES
N1-(4-Cyanophenyl)-2-{5-[4-(1,3-benzoxazol-2-
yl)phenyl]-1,3,4-oxadiazol-2-ylsulfanyl}acetamide
1
(12i). Yield 90%, mp 260–262°C. H NMR spectrum,
δ, ppm: 4.12 s (2H), 6.98 d (1H, J = 8.05 Hz), 7.42–
7.49 m (3H), 7.64 d (2H, J = 8.20 Hz), 7.78 d (2H, J =
8.20 Hz), 7.87 d (2H, J = 8.19 Hz), 8.12 d (2H, J =
8.19 Hz), 9.21 s (1H). 13C NMR spectrum, δ, ppm:
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126.4, 127.5, 133.5, 134.5, 134.8, 142.3, 143.8, 150.6,
156.9, 160.5, 162.4, 165.2. MS (ESI): 454 [M + H]+.
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2-yl)phenyl]-1,3,4-oxadiazol-2-ylsulfanyl}acetamide
1
(12j). Yield 81%, mp 244–246°C. H NMR spectrum,
δ, ppm: 3.86 s (6H), 3.90 s (3H), 4.10 s (2H), 6.28 s
(1H), 6.78 s (2H), 7.42–7.49 m (3H), 7.85 d (2H, J =
13
8.16 Hz), 8.10 d (2H, J = 8.16 Hz), 9.21 s (1H). C
NMR spectrum, δ, ppm: 40.3, 56.8, 98.5, 101.5, 111.8,
119.6, 124.5, 125.7, 126.4, 127.8, 134.3, 134.8, 141.3,
143.5, 150.7, 156.7, 159.8, 161.6, 164.9. MS (ESI):
489 [M + H]+.
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RAVINAIK et al.
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