Synthesis of some 2,3-dihydro-1,3,4-oxadiazoles and 4,5-dihydro-1,2,4-triazoles as anticancer agents

Article abstract of DOI:10.22159/ijpps.2020v12i8.36508

Objective: The main objective of this work was to synthesize and evaluate the novel 2,3-dihydro-1,3,4-oxadiazole and 4,5-dihydro-1,2,4-triazole derivatives for cytotoxic activities. Methods: The 2,3-dihydro-1,3,4-oxadiazole derivatives 4a-h were synthesized by cyclization of N'-(substituted-benzylidene) isonicotinohydrazide 3a-e in refluxing acetic anhydride. The 2,3-dihydro-1,3,4-oxadiazole derivatives 4a-h were converted into the corresponding 4,5-dihydro-1,2,4-triazoles 5a-h using ammonia. All the synthesized compounds were identified, depending on the physical and spectral data. Title compounds were assessed for their cytotoxic activity against human cancer cell line (MCF-7) by using Sulforhodamine B (SRB) colorimetric assay. Results: All the synthesized compounds showed characteristic peaks in FTIR, ¹HNMR and Mass spectral analysis. The results of the in vitro cytotoxic activity revealed that the compound 4c exhibited equipotent cytotoxic activity with an IC50 value of 8.04 μM when compared with that of standard drug doxorubicin (IC50= 8.02 μM). The reminder compounds have shown good to moderate cytotoxic activities when compared with that of a reference standard. Conclusion: We synthesized a series of title compounds in quantitative yields. Most derivatives showed moderate to good cytotoxic activity.

Full text of DOI:10.22159/ijpps.2020v12i8.36508

International Journal of Pharmacy and Pharmaceutical Sciences
Yahya et al.
Int J Pharm Pharm Sci, Vol 12, Issue 8, 92-99
Print ISSN: 2656-0097 | Online ISSN: 0975-1491
Vol 12, Issue 8, 2020
Original Article
SYNTHESIS OF SOME 2,3-DIHYDRO-1,3,4-OXADIAZOLES AND 4,5-DIHYDRO-1,2,4-
TRIAZOLES AS ANTICANCER AGENTS
TAWFEEK A. YAHYA1*, JALAL H. ABDULLAH1
1Department of Pharmaceutical Organic, Analytical and Medicinal Chemistry, Faculty of Pharmacy, Sana'a University, Sana'a 18084,
Yemen
Email: tawfik_93@yahoo.com
Received: 28 Nov 2019, Revised and Accepted: 16 Jun 2020
ABSTRACT
Objective: The main objective of this work was to synthesize and evaluate the novel 2,3-dihydro-1,3,4-oxadiazole and 4,5-dihydro-1,2,4-triazole
derivatives for cytotoxic activities.
Methods: The 2,3-dihydro-1,3,4-oxadiazole derivatives 4a-h were synthesized by cyclization of N'-(substituted-benzylidene) isonicotinohydrazide
3a-e in refluxing acetic anhydride. The 2,3-dihydro-1,3,4-oxadiazole derivatives 4a-h were converted into the corresponding 4,5-dihydro-1,2,4-
triazoles 5a-h using ammonia. All the synthesized compounds were identified, depending on the physical and spectral data. Title compounds were
assessed for their cytotoxic activity against human cancer cell line (MCF-7) by using Sulforhodamine B (SRB) colorimetric assay.
Results: All the synthesized compounds showed characteristic peaks in FTIR, 1HNMR and Mass spectral analysis. The results of the in vitro cytotoxic
activity revealed that the compound 4c exhibited equipotent cytotoxic activity with an IC50 value of 8.04 µM when compared with that of standard
drug doxorubicin (IC50= 8.02 µM). The reminder compounds have shown good to moderate cytotoxic activities when compared with that of a
reference standard.
Conclusion: We synthesized a series of title compounds in quantitative yields. Most derivatives showed moderate to good cytotoxic activity.
Keywords: 2,3-Dihydro-1,3,4-oxadiazole, 4,5-Dihydro-1,2,4-triazole, MCF-7, Anticancer
© 2020 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijpps.2020v12i8.36508. Journal homepage: https://innovareacademics.in/journals/index.php/ijpps.
INTRODUCTION
bromide discs. 1H-NMR spectra were recorded on a Bruker proton 300
MHz (Bruker, Munuch, Germany) spectrometer using DMSO-d6 as a
solvent and tetramethylsilane (TMS) as an internal standard. Chemical
shift values are listed in δ scale. Mass spectra were determined using a
GC/MS Mat 112 S at the 70ev spectrometer. Elemental analysis (C, H, N)
were performed on a Perkin-Elmer 2400 analyzer (Perkin-Elmer, Norwalk,
CT, USA) at the microanalytical laboratories of the Faculty of Science,
Cairo University. Completion of the reaction was monitored by thin-layer
chromatography (TLC) using precoated aluminum sheets silica gel (Merck,
60 F254). Visualization was accomplished with an ultraviolet UV lamp
(Merck, Darmstadt, Germany). Synthesized compounds were purified
by the re-crystallization process. The purity of the compounds was
checked by a single spot in TLC and the solvent system for TLC was
determined on a trial and error basis. All the chemicals and solvents
used were of commercial grade.
There are numerous literature reports confirming the multidirectional
effect of compounds containing the 1,3,4-oxadiazole ring in its
structure. 1,3,4-Oxadiazole derivatives showed numerous biological
activities [1-14]. In addition, the 1,3,4-oxadiazole derivatives showed
anti-proliferative properties against MCF-7 breast cancer cell Line [15-
17], ovarian cancer cell lines (ovcar-3 and Hela) [18, 19], human lung
cancer cell line (L2987) [20] and colorectal cancer [21]. These
compounds have different mechanisms of action, which is very
important in view of the observed resistance of tumors to standard
drug treatment. Moreover, some of the 1,3,4-oxadiazole derivatives
are inhibitors of growth factors, enzymes, kinases and receptors that
are mediated in cancer treatment [22-27].
On the other hand, compounds having triazole moieties, such as
vorozole, letrozole and anastrozole, appeared to be very effective
aromatase inhibitors, which in turn prevented cancer, especially
breast cancer [28-32]. Furthermore, certain 1,2,4-triazole
derivatives have been reported as antitumor agents [33-35].
Experimental procedures
Synthesis of N'-(substituted benzylidene) isonicotinohydrazide
(3a-h)
Inspired by these finding and in order to develop new anticancer
therapeutic agents, we were encouraged to synthesize series of 2,3-
dihydro-1,3,4-oxadiazoles and their bioisosters, 4,5-dihydro-1,2,4-
triazoles, with incorporation of pyridine moiety, halogens, methoxy
and methyl groups which are expected to allows simultaneous
modulation of electronic, lipophilic, and steric parameters. These
parameters can critically influence both the pharmacodynamic and
pharmacokinetic properties of the synthesized compounds and
expected to enhance their anticancer activities.
Isonicotinohydrazide 1 (0.001 mol), appropriate aromatic aldehyde
2 (0.001 mol), ethanol (30 ml) and a catalytic amount of acetic acid
were added to the round-bottomed flask (RBF) and the reaction
mixture was refluxed for 3 h. The completion of the reaction was
monitored by TLC. The reaction mixture was poured into crushed ice
to obtain a solid product. The obtained precipitate was filtered
under suction, washed thoroughly with water, dried and
recrystallized from methanol.
Synthesis of 1-(2-substituted phenyl-5-(pyridin-4-yl)-1,3,4-
oxadiazol-3(2H)-yl)ethanone (4 a-h)
MATERIALS AND METHODS
Melting points are uncorrected and were determined on a Stuart
melting point apparatus (Stuart Scientific, Redhill, UK). The FT-IR
spectra (KBr) were recorded on Shimadzu FT-IR 110
spectrophotometer (Shimadzu, Koyoto, Japan) by using 1% potassium
To arylidenearylhydrazides 3a-e (0.01 mol), acetic anhydride (40
ml) was added and the reaction mixture was refluxed for 2 h. The
crushed ice was added to the reaction mixture to obtain precipitate,
which was filtered off and, washed with 10% aqueous solution of
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Int J Pharm Pharm Sci, Vol 12, Issue 8, 92-99
NaHCO3 to remove the acetic acid. The obtained solid was
recrystalized from ethanol.
temperature during the addition was kept below 20 °C. Then the
reaction mixture was stirred for 2 h at room temperature. The
reaction mixture was poured into crushed ice and acidify with
hydrochloric acid to obtain precipitate, which was filtered off and,
washed with water. The obtained solid was recrystallized from
ethanol. IUPAC names and the molecular structures of the
synthesized compounds 3a-h, 4a-h and 5a-h are shown in table 1.
Synthesis of 1-(5-(4-substituted phenyl)-3-(pyridin-4-yl)-4,5-
dihydro-1,2,4-triazol-1-yl)ethanones (5a-h)
Compounds 4a-h (0.01 mol) was added during 10 min to stirred and
cooled solution of ammonia solution (10 ml) and water (10 ml). The
Table 1: List of the IUPAC name and the molecular structure of the synthesized compounds (3a-e, 4a-e and 5a-e)
Comp. No.
3a
Molecular structure
IUPAC name
N'-benzylideneisonicotinohydrazide
O
N
N
H
N
O
3b
N'-(4-methoxybenzylidene) isonicotinohydrazide
N
N
H
N
O
H3C
O
3c
N'-(4-methylbenzylidene) isonicotinohydrazide
N'-(4-chlorobenzylidene) isonicotinohydrazide
N
N
H
N
H3
C
O
3d
N
N
H
N
Cl
O
3e
3f
N'-(4-bromobenzylidene) isonicotinohydrazide
N'-(4-fluorobenzylidene) isonicotinohydrazide
N
N
H
N
Br
O
N
N
H
N
F
O
3g
3h
4a
N'-(3-chlorobenzylidene) isonicotinohydrazide
N
N
H
N
Cl
N
O
N'-(3-bromobenzylidene) isonicotinohydrazide
N
H
N
Br
N
1-(2-Phenyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)ethanone
O
N
N
O
H3C
N
4b
4c
1-(2-(4-Methoxyphenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)ethanone
1-(5-(Pyridin-4-yl)-2-p-tolyl-1,3,4-oxadiazol-3(2H)-yl)ethanone
O
N
N
O
H3
C
O
CH3
N
O
N
N
O
H3C
H3C
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Int J Pharm Pharm Sci, Vol 12, Issue 8, 92-99
4d
1-(2-(4-Chlorophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)ethanone
N
O
N
N
O
H3
C
Cl
4e
1-(2-(4-Bromophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)ethanone
1-(2-(4-Fluorophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)ethanone
N
O
N
N
O
H3
C
Br
O
4f
N
N
N
O
H3C
F
4g
4h
1-(2-(3-Chlorophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)ethanone
1-(2-(3-Bromophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)ethanone
N
O
N
N
O
H3
C
Cl
N
O
N
N
O
H3
C
Br
5a
5b
N
O
1-(5-Phenyl-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-triazol-1-yl)ethanone
N
N
NH
H3C
N
1-(5-(4-Methoxyphenyl)-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-triazol-1-yl)ethanone
O
N
N
NH
H3C
O
5c
1-(3-(Pyridin-4-yl)-5-p-tolyl-4,5-dihydro-1,2,4-triazol-1-yl)ethanone
N
O
N
N
NH
H3C
5d
1-(5-(4-Chlorophenyl)-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-triazol-1-yl)ethanone
N
O
N
N
NH
H3C
Cl
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Int J Pharm Pharm Sci, Vol 12, Issue 8, 92-99
5e
5f
1-(5-(4-Bromophenyl)-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-triazol-1-yl)ethanone
N
O
N
N
NH
H3C
Br
1-(5-(4-Fluorophenyl)-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-triazol-1-yl)ethanone
N
O
N
N
NH
H3
C
F
5g
5h
1-(5-(3-Chlorophenyl)-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-triazol-1-yl)ethanone
1-(5-(3-Bromophenyl)-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-triazol-1-yl)ethanone
N
O
N
N
NH
H3
C
Cl
N
O
N
N
NH
H3
C
Br
Anticancer activities
were transformed into the corresponding 4,5-dihydro-1,2,4-triazole
derivatives 5a-e via ring opening of the oxadiazole.
The Cytotoxic activity of the synthesized compounds was
measured against human mammary carcinoma cell line (MCF7)
in the National Cancer Institute, Cairo University. The screening
involves a calculation of the percentage growth or the surviving
fraction of the drug-treated cell lines compared with untreated
control using Sulforhodamine B (SRB) colorimetric assay [36].
Cells were plated in 96-multiwell plate (104 cells/well) for 24 h
before treatment with the compounds to allow attachment of
cells to the wall of the plate. Different concentrations of the
compound under test (0.0, 1.0, 2.5, 5.0 and 10.0 μg/ml) were
added to the cell monolayer. Triplicate wells were prepared for
each individual dose. Monolayer cells were incubated with the
compounds for 48 h at 37 °C and in an atmosphere of 5% CO2.
After 48 h, cells were fixed and stained for 30 min with 0.4%
(wt/vol) SRB dissolved in 1% acetic acid. Excess unbound dye
was removed by four washes with 1% acetic acid and the
attached stain was recovered with Tris–EDTA buffer. Color
intensity was measured in an ELISA reader. The relation
between surviving fraction and drug concentration is plotted to
get the survival curve of the tumor cell line after the specified
compound. The results were described in the table 2.
The synthesis of N'-(substitutedbenzylidene) isonicotinohydrazides 3a-h
shown to be simple and practical, achieving a good yield, as described in
previous studies [37-39]. On the other hand, for the series of 1-(2-
substituted phenyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl) ethanones
4a-h were synthesized according to the previously described procedures
[36-39]. Substitutions at the phenyl moiety, reaction time and
temperature of the reaction are the main parameters that identify the
yield of the products [38, 40]. In this study, the reaction time and
temperature of the reaction were adjusted to 3 h and 120 °C respectively
to achieve yield in the range from 70% to 82%. Finally, the 1-(2-
substituted phenyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl) ethanones
4a-h were reacted with ammonia to give 1-(5-(4-substituted phenyl)-3-
(pyridin-4-yl)-4,5-dihydro-1,2,4-triazol-1-yl)ethanones 5a-h in good
yield via ring-opening rearrangement of the oxadiazole.
During the synthesis procedure, thin layer chromatography (TLC)
analysis was carried out to verify the formation of the synthesized
compounds. The structural elucidation of these compounds was
confirmed through 1H NMR, IR and mas spectral data. The IR spectrum
for intermediate compounds 3a-h showed characteristic peaks of N-H
around (3420 cm-1) and of C-O-NH of amide in range of 1632-1635 cm-1.
The IR spectra for compounds 4a-h showed characteristic peaks of
carbonyl of CH3C-O in the range of 1690-1695 cm-1. The IR spectra for
final compounds 5a-h showed characteristic peaks of NH in the range of
3205-3212 cm-1. The 1H NMR spectrum of the compounds 3a-h contains
a multiplet in the range of 7.10-7.95 ppm for aromatic protons, a proton
of NH appeared as singlet in the around 8.01 ppm which exchanged with
D2O while a proton of CH=N appeared as singlet in the range of 8.18-
RESULTS AND DISCUSSION
Chemistry
In this study, N'-(substituted benzylidene) isonicotinohydrazides 3a-
h, 2,3-dihydro-1,3,4-oxadiazoles 4a-h and 4,5-dihydro-1,2,4-triazole
derivatives 5a-h (table 1) were synthesized, of which compounds 3a-
d and 4a-d have been reported before [37].
1
8.21 ppm. The H NMR spectra of the compounds 4a-h contains singlet
The synthesis of 1-(2-substituted phenyl-5-(pyridin-4-yl)-1,3,4-
oxadiazol-3(2H)-yl)ethanones was performed in two steps: the synthesis
of N'-(substituted benzylidene) isonicotinohydrazides 3a-h from the
substituted aromatic aldehyde 2a-h and synthesis of 1-(2-substituted
phenyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl) ethanones 4a-h from
the Schiff’s bases 3a-h using acetic anhydride (fig. 1). On the other
hand, the 2,3-dihydro-1,3,4-oxadiazole rings of compounds 4a-e
around 2.26 ppm for CH3 protons, protons of CH of oxadiazole ring
appeared as a singlet in the range of 5.53-5.67 ppm and aromatic
protons appeared in the range of 7.20-8.21 ppm. The 1H NMR spectra of
the final compounds 5a-h contains singlet around 6.15 and 2.40 ppm
attributed for CH and NH protons of triazole ring, respectively. Mass
spectra proved parent peaks of the synthesized compounds confirming
the molecular weight.
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Int J Pharm Pharm Sci, Vol 12, Issue 8, 92-99
Fig. 1: Synthesis of compounds 3a-e, 4a-e and 5a-e investigated in this work
Spectral characterization of synthesized compounds
5.51 (s, 1H, CH, oxadiazole), 7.10-7.85 (m, 9H, ArH). MS: (m/z) 267
(M+) observed for C15H13N3O2, Anal calcd: C, 67.40; H, 4.90; N, 15.72;
found: C, 67.80; H, 4.79; N, 15.58;
N'-benzylideneisonicotinohydrazide (3a): Yield 73%, mp 86-88 °
1
C. IR spectrum, ν, cm-1: 1633, 1650, 3052, 3420. H NMR (300 MHz,
DMSO-d6): 7.20-7.93 (m, 9H, ArH), 8.01 (s, 1H, NH, exch. With D2O),
8.20 (s, 1H, CH=N). MS: (m/z) 225 (M+) observed for C13H13N3O, Anal
calcd: C, 69.32; H, 4.92; N, 18.66; found: C, 69.59; H, 5.15; N, 18.92;
1-(2-(4-Methoxyphenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-
3(2H)-yl)ethanone (4b): Yield 77 %, mp 127-129 °C. IR spectrum,
1
ν, cm-1: 1691, 1620, 2980. H NMR (300 MHz, DMSO-d6): 2.27 (s, 3H,
CH3), 3.88 (s, 3H, OCH3), 5.53 (s, 1H, CH, oxadiazole), 7.20-7.91 (m,
8H, ArH). MS: (m/z) 297 (M+) observed for C16H15N3O3, Anal calcd: C,
64.64; H, 5.09; N, 14.13; found: C, 64.35; H, 5.27; N, 13.89;
N'-(4-methoxybenzylidene)isonicotinohydrazide (3b): Yield
80%, mp 102-104 °C. IR spectrum, ν, cm-1: 1632, 1650, 3061, 3424.
1H NMR (300 MHz, DMSO-d6): 3.85 (s, 3H, OCH3), 7.21-7.89 (m, 8H,
ArH), 8.08 (s, 1H, NH, exch. With D2O), 8.21 (s, 1H,-CH=N). MS: (m/z)
255 (M+) observed for C14H13N3O2, Anal calcd: C, 65.87; H, 5.13; N,
16.46; found: C, 65.39; H, 5.19; N, 16.58;
1-(5-(Pyridin-4-yl)-2-p-tolyl-1,3,4-oxadiazol-3(2H)-yl)ethanone
(4c): Yield 73%, mp 90-92 °C. IR spectrum, ν, cm-1: 1690, 1625,
2982. 1H NMR (300 MHz, DMSO-d6): 2.25 (s, 3H, CH3), 2.51(s, 3H,
CH3), 5.52 (s, 1H, CH, oxadiazole), 7.10-7.91 (m, 8H, ArH). MS: (m/z)
281 (M+) observed for C16H15N3O2, Anal calcd: C, 68.31; H, 5.37; N,
14.94; found: C, 68.61; H, 5.78; N, 14.79;
N'-(4-methylbenzylidene)isonicotinohydrazide (3c): Yield 77%,
mp 113-115 °C. IR spectrum, ν, cm-1: 1635, 1652, 3063, 3424. 1H
NMR (300 MHz, DMSO-d6): 2.51 (s, 3H, CH3), 7.31-7.95 (m, 8H, ArH),
8.10 (s, 1H, NH, exch. With D2O), 8.18 (s, 1H,-CH=N). MS: (m/z) 239
(M+) observed for C14H13N3O, Anal calcd: C, 70.28; H, 5.48; N, 17.56;
found: C, 70.49; H, 5.29; N, 17.88;
1-(2-(4-Chlorophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-
yl)ethanone (4d): Yield 78%, mp 121-123 °C. IR spectrum, ν, cm-1:
1
1695, 1620, 2985. H NMR (300 MHz, DMSO-d6): 2.26 (s, 3H, CH3),
5.52 (s, 1H, CH, oxadiazole), 7.30-7.96 (m, 8H, ArH). MS: (m/z) 301
(M+) observed for C15H12ClN3O2, Anal calcd: C, 59.71; H, 4.01; N,
13.93; found: C, 59.44; H, 4.38; N, 13.65;
(N'-(4-chlorobenzylidene)isonicotinohydrazide (3d): Yield 72%,
mp 105-107 °C. IR spectrum, ν, cm-1: 1634, 1651, 3059, 3422. 1H
NMR (300 MHz, DMSO-d6): 7.30-7.96 (m, 8H, ArH), 8.00 (s, 1H, NH,
exch. With D2O), 8.18 (s, 1H,-CH=N). MS: (m/z) 259 (M+) observed
for C13H10ClN3O, Anal calcd: C, 60.12; H, 3.88; N, 16.18; found: C,
60.41; H, 4.11; N, 16.52;
1-(2-(4-Bromophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-
yl)ethanone (4e): Yield 82%, mp 160-162 °C. IR spectrum, ν, cm-1:
1
1690, 1621, 2982. H NMR (300 MHz, DMSO-d6): 2.26 (s, 3H, CH3),
5.53 (s, 1H, CH, oxadiazole), 7.20-7.91 (m, 8H, ArH). MS: (m/z) 349
(M++2), 347 (M+) observed for C15H12BrN3O2, Anal calcd: C, 52.04; H,
3.49; N, 12.14; found: C, 52.34; H, 3.58; N, 12.52;
N'-(4-bromobenzylidene)isonicotinohydrazide (3e): Yield 74%,
mp 101-103 °C. IR spectrum, ν, cm-1: 1635, 1650, 3060, 3420. 1H
NMR (300 MHz, DMSO-d6): 7.10-7.95 (m, 8H, ArH), 8.02 (s, 1H, NH,
exch. With D2O), 8.19 (s, 1H,-CH=N). MS: (m/z) 305 (M++2), 303 (M+)
observed for C13H10BrN3O, Anal calcd: C, 51.34; H, 3.31; N, 13.82;
found: C, 51.49; H, 3.18; N, 13.56;
1-(2-(4-Fluorophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-
yl)ethanone (4f): Yield 77%, mp 125-127 °C. IR spectrum, ν, cm-1:
1
1695, 1620, 2985. H NMR (300 MHz, DMSO-d6): 2.25 (s, 3H, CH3),
5.67 (s, 1H, CH, oxadiazole), 7.45-8.21 (m, 8H, ArH). MS: (m/z) 285
(M+) observed for C15H12FN3O2, Anal calcd: C, 63.15; H, 4.24; N,
14.73; found: C, 62.91; H, 4.52; N, 14.88;
N'-(4-fluorobenzylidene)isonicotinohydrazide (3f): Yield 70%,
mp 109-111 °C. IR spectrum, ν, cm-1: 1633, 1653, 3064, 3421. 1H
NMR (300 MHz, DMSO-d6): 7.23-8.12 (m, 8H, ArH), 8.02 (s, 1H, NH,
exch. With D2O), 8.21 (s, 1H,-CH=N). MS: (m/z) 243 (M+) observed
for C13H10FN3O, Anal calcd: C, 64.19; H, 4.14; N, 17.28; found: C,
64.54; H, 3.96; N, 17.55;
1-(2-(3-Chlorophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-
yl)ethanone (4g): Yield 76%, mp 117-119 °C. IR spectrum, ν, cm-1:
1
1696, 1624, 2988. H NMR (300 MHz, DMSO-d6): 2.26 (s, 3H, CH3),
5.59 (s, 1H, CH, oxadiazole), 7.42-7.99 (m, 8H, ArH). MS: (m/z) 301
(M+) observed for C15H12ClN3O2, Anal calcd: C, 59.71; H, 4.01; N,
13.93; found: C, 59.84; H, 4.27; N, 14.16;
(N'-(3-chlorobenzylidene)isonicotinohydrazide (3g): Yield 72%,
mp 99-101 °C. IR spectrum, ν, cm-1: 1632, 1650, 3059, 3420. 1H NMR
(300 MHz, DMSO-d6): 7.28-7.92 (m, 8H, ArH), 8.01 (s, 1H, NH, exch.
With D2O), 8.19 (s, 1H,-CH=N). MS: (m/z) 259 (M+) observed for
C13H10ClN3O, Anal calcd: C, 60.12; H, 3.88; N, 16.18; found: C, 59.90;
H, 3.94; N, 16.23;
1-(2-(3-Bromophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-
yl)ethanone (4h): Yield 75%, mp 140-142 °C. IR spectrum, ν, cm-1:
1
1695, 1624, 2986. H NMR (300 MHz, DMSO-d6): 2.26 (s, 3H, CH3),
N'-(2-bromobenzylidene)isonicotinohydrazide (3h): Yield 69%,
5.62 (s, 1H, CH, oxadiazole), 7.40-8.08 (m, 8H, ArH). MS: (m/z) 349
(M++2), 347 (M+) observed for C15H12BrN3O2, Anal calcd: C, 52.04; H,
3.49; N, 12.14; found: C, 52.19; H, 3.82; N, 11.94;
1
mp 97-99 °C. IR spectrum, ν, cm-1: 1633, 1652, 3065, 3424. H NMR
(300 MHz, DMSO-d6): 7.19-7.98 (m, 8H, ArH), 8.00 (s, 1H, NH, exch.
With D2O), 8.18 (s, 1H,-CH=N). MS: (m/z) 305 (M++2), 303 (M+)
observed for C13H10BrN3O, Anal calcd: C, 51.34; H, 3.31; N, 13.82;
found: C, 51.21; H, 3.62; N, 13.93;
1-(5-Phenyl-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-triazol-1-
yl)ethanone (5a): Yield 62%, mp 110-112 °C. IR spectrum, ν, cm-1:
1
1699, 1625, 3010, 3210. H NMR (300 MHz, DMSO-d6): 2.31(s, 3H,
1-(2-Phenyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-
CH3), 2.41(s, 1H, NH, triazole), 6.20 (s, 1H, CH, triazole), 7.15-7.82 (m,
9H, ArH). MS: (m/z) 266 (M+) observed for C15H14N4O, Anal calcd: C,
67.65; H, 5.30; N, 21.04; found: C, 67.50; H, 5.54; N, 20.86;
yl)ethanone (4a): Yield 70%, mp 112-114 °C. IR spectrum, ν, cm-1:
1
1690, 1625, 2950. H NMR (300 MHz, DMSO-d6): 2.27 (s, 3H, CH3),
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Int J Pharm Pharm Sci, Vol 12, Issue 8, 92-99
1-(5-(4-Methoxyphenyl)-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-
triazol-1-yl)ethanone (5b): Yield 75%, mp 139-141 °C. IR
spectrum, ν, cm-1: 1701, 1625, 2997, 3208. 1H NMR (300 MHz,
DMSO-d6): 2.31(s, 3H, CH3), 2.39 (s, 1H, NH, triazole), 3.92 (s, 3H,
OCH3), 6.21 (s, 1H, CH, triazole), 7.32-8.12 (m, 8H, ArH). MS: (m/z)
296 (M+) observed for C16H16N4O2, Anal calcd: C, 64.85; H, 5.44; N,
18.91; found: C, 64.66; H, 5.65; N, 19.09;
1-(5-(3-Chlorophenyl)-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-
triazol-1-yl)ethanone (5g): Yield 74%, mp 135-137 °C. IR
spectrum, ν, cm-1: 1692, 1622, 2989, 3208. 1H NMR (300 MHz,
DMSO-d6): 2.27 (s, 3H, CH3), 2.39 (s, 1H, NH, triazole), 6.13 (s, 1H, CH,
triazole), 7.34-8.12 (m, 8H, ArH). MS: (m/z) 300 (M+) observed for
C15H13ClN4O, Anal calcd: C, 59.91; H, 4.36; N, 18.63; found: C, 59.64;
H, 4.63; N, 18.83;
1-(3-(Pyridin-4-yl)-5-p-tolyl-4,5-dihydro-1,2,4-triazol-1-
1-(5-(3-Bromophenyl)-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-
triazol-1-yl)ethanone (5h): Yield 79%, mp 139-141 °C. IR
spectrum, ν, cm-1: 1704, 1624, 3005, 3218. 1H NMR (300 MHz,
DMSO-d6): 2.28 (s, 3H, CH3), 2.42 (s, 1H, NH, triazole), 6.17 (s, 1H, CH,
triazole), 7.33-8.16 (m, 8H, ArH). MS: (m/z) 346 (M++2), 344 (M+)
observed for C15H13BrN4O, Anal calcd: C, 52.19; H, 3.80; N, 16.32;
found: C, 52.43; H, 3.52; N, 16.14;
yl)ethanone (5c): Yield 67%, mp 100-102 °C. IR spectrum, ν, cm-1:
1
1690, 1625, 2982, 3212. H NMR (300 MHz, DMSO-d6): 2.24 (s, 3H,
CH3), 2.52 (s, 3H, CH3), 2.40 (s, 1H, NH, triazole), 6.12 (s, 1H, CH,
triazole), 7.19-8.01 (m, 8H, ArH). MS: (m/z) 280 (M+) observed for
C16H15N4O, Anal calcd: C, 68.55; H, 5.75; N, 19.99; found: C, 68.81; H,
5.98; N, 19.81;
1-(5-(4-Chlorophenyl)-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-
triazol-1-yl)ethanone (5d): Yield 77%, mp 132-134 °C. IR
spectrum, ν, cm-1: 1695, 1620, 2985, 3205. 1H NMR (300 MHz,
DMSO-d6): 2.28 (s, 3H, CH3), 2.38 (s, 1H, NH, triazole), 6.15 (s, 1H, CH,
triazole), 7.38-8.13 (m, 8H, ArH). MS: (m/z) 300 (M+) observed for
C15H13ClN4O, Anal calcd: C, 59.91; H, 4.36; N, 18.63; found: C, 59.76;
H, 4.21; N, 18.40;
Cytotoxic activity
Cytotoxic activity results were summarized in table 2. All the
synthesized were evaluated to their cytotoxic activity against breast
cancer cell line MCF7. Most of the tested compounds exhibited
moderate to good cytotoxic activity with percentage inhibition in cell
proliferation at an IC50 value of 9.84 and 39.21 µM.
With regard to the benzylidene isonicotinohydrazides 3a-h, the
compounds 3a-h exhibited moderate to good cytotoxic activity with
IC50 ranges IC50 17.26-38.01 µM when compared to the reference
standard doxorubicin (IC50, 8.02 µM), while the compound 3d showed
the best activity among this series with IC50 value of 16.28 µM.
1-(5-(4-Bromophenyl)-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-
triazol-1-yl)ethanone (5e): Yield 79%, mp 136-138 °C. IR
spectrum, ν, cm-1: 1700, 1621, 2996, 3210. 1H NMR (300 MHz,
DMSO-d6): 2.29 (s, 3H, CH3), 2.40 (s, 1H, NH, triazole), 6.18 (s, 1H, CH,
triazole), 7.27-7.98 (m, 8H, ArH). MS: (m/z) 346 (M++2), 344 (M+)
observed for C15H13BrN4O, Anal calcd: C, 52.19; H, 3.80; N, 16.32;
found: C, 51.98; H, 3.98; N, 16.49;
Cyclization of 3a-h into the corresponding 2,3-dihydro-1,3,4-
oxadiazoles 4a-h resulted in an increased in cytotoxic activity with
IC50 ranges 8.04-27.08 µM. The compound 4d showed equipotent
activity (IC50, 8.04 µM) to that of the reference standard, doxorubicin
(IC50, 8.02 µM). Finally, the ring transformation of 2,3-dihydro-1,3,4-
oxadiazoles 4a-h into the corresponding 4,5-dihydro-1,2,4-triazoles
5a-h resulted in slightly decrease in cytotoxic activity with IC50
ranges 9.78-28.54 µM. The type and position of substituent on
phenyl moiety greatly affect anticancer activities.
1-(5-(4-Fluorophenyl)-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-
triazol-1-yl)ethanone (5f): Yield 77%, mp 141-143 °C. IR
spectrum, ν, cm-1: 1705, 1625, 2997, 3214. 1H NMR (300 MHz,
DMSO-d6): 2.32 (s, 3H, CH3), 2.41 (s, 1H, NH, triazole), 6.14 (s, 1H, CH,
triazole), 7.56-8.42 (m, 8H, ArH). MS: (m/z) 284 (M+) observed for
C15H13FN4O, Anal calcd: C, 63.37; H, 4.61; N, 19.71; found: C, 62.99; H,
4.86; N, 19.49;
Table 2: In vitro cytotoxic activity of the synthesized compounds against MCF-7 cell line
Compound concentration (µM)
Compound No
IC50 (µM)
5 µM 12.5 µM
25 µM
50 µM
Surviving fraction (mean±SEM)a
3a
0.983±0.057
0.721±0.031
0.765±0.051
0.397±0.031
0.333±0.051
0.745±0.182
0.866±0.060
0.882±0.038
0.373±0.033
0.352±0.012
0.299±0.110
0.682±0.017
0.452±0.018
0.681±0.182
0.853±0.013
0.841±0.022
0.378±0.070
0.713±0.038
0.589±0.16
0.695±0.041
0.364±0.041
0.381±0.029
0.445±0.027
0.229±0.015
0.121±0.035
0.393±0.065
0.582±0.030
0.568±0.011
0.152±0.032
0.291±0.045
0.279±0.024
0.096±0.034
0.365±0.021
0.321±0.065
0.379±0.043
0.454±0.027
0.158±0.050
0.352±0.008
0.254±0.081
0.212±0.011
0.312±0.045
0.391±0.072
0.329±0.071
0.389±0.070
0.251±0.023
0.376±0.043
0.181±0.031
0.385±0.021
0.295±0.004
0.110±0.001
0.192±0.068
0.397±0.008
0.422±0.076
0.141±0.013
0.425±0.043
0.289±0.042
0.099±0.021
0.280±0.015
0.121±0.068
0.345±0.091
0.235±0.015
0.145±0.021
0.117±0.003
0.146±0.065
0.289±0.021
0.189±0.043
0.102±0.034
0.342±0.015
0.325±0.093
0.266±0.032
19.52
18.22
16.28
17.26
17.43
18.65
36.45
38.01
15.21
11.20
8.04
12.01
10.22
14.73
25.62
27.08
16.23
12.54
9.78
3b
0.465±0.041
0.569±0.028
0.281±0.026
0.312±0.023
0.478±0.087
0.651±0.025
0.655±0.017
0.281±0.021
0.226±0.015
0.281±0.170
0.495±0.023
0.262±0.022
0.485±0.087
0.517±0.052
0.678±0.018
0.287±0.017
0.482±0.076
0.487±0.069
0.312±0.017
0.412±0.015
0.435±0.026
0.644±0.015
0.617±0.061
0.309±0.016
3c
3d
3e
3f
3g
3h
4a
4b
4c
4d
4e
4f
4g
4h
5a
5b
5c
5d
0.563±0.032
0.663±0.012
0.698±0.090
0.832±0.061
0.853±0.043
0.314±0.032
13.09
11.59
15.25
26.62
28.54
8.02
5e
5f
5g
5h
Doxorubicin
aEach value is the mean of three values±standard error.
yl) ethanones 5a-h have been synthesized and evaluated for their
antitumor activities. These compounds were characterized using
standard spectroscopic and spectrometric techniques, confirming
the integrity of these molecules. The biological activities of all of the
synthesized compounds were examined against breast cancer MCF7
CONCLUSION
In this study,
a series of benzylidene isonicotinohydrazide
derivatives 3a-h, 1,3,4-oxadiazol-3(2H)-yl) ethanones 4a-h and 1-(5-
(4-substituted phenyl)-3-(pyridin-4-yl)-4,5-dihydro-1,2,4-triazol-1-
97

Yahya et al.
Int J Pharm Pharm Sci, Vol 12, Issue 8, 92-99
cell lines. The results of in vitro anticancer activity indicated that
most of the tested compounds exhibited moderate to good activities.
On the other hand, compound 4c exhibited nearly similar cytotoxic
activity (IC50= 8.04 µM) to that of the standard drug doxorubicin
(IC50= 8.02 µM).
15. Akhtar MJ, Siddiqui AA, Khan AA, Ali Z, Dewangan RP, Pasha S,
et al. Design, synthesis, docking and qsar study of substituted
benzimidazole linked oxadiazole as cytotoxic agents, EGFR and
ErbB2 receptor inhibitors. Eur J Med Chem 2017;126:853-69.
16. Sun J, Zhu H, Yang ZM, Zhu HL. Synthesis, molecular modeling
and biological evaluation of 2-aminomethyl-5-(quinolin-2-yl)-
1,3,4-oxadiazole-2(3H)-thione quinolone derivatives as a novel
anticancer agent. Eur J Med Chem 2013;60:23-8.
ACKNOWLEDGMENT
The authors are grateful to the Faculty of Medical Sciences, National
University for their support and providing facilities.
17. Mosmann T. Rapid colorimetric assay for cellular growth and
survival: application to proliferation and cytotoxicity assays. J
Immunol Methods 1983;65:55-63.
FUNDING
18. Yadav N, Kumar P, Chhikara A, Chopra M. Development of 1,3,4-
oxadiazole thione based novel anticancer agents: design, synthesis
and in vitro studies. Biomed Pharmacother 2017;95:721-30.
19. He X, Li XY, Liang JW, Cao C, Li S, Zhang TJ, et al. Design,
synthesis and anticancer activities evaluation of novel 5H-
dibenzo[b,e]azepine-6,11-dione derivatives containing 1,3,4-
oxadiazole units. Bioorganic Med Chem Lett 2018;28:847-52.
20. Cai ZW, Wei D, Borzilleri RM, Qian L, Kamath A, Mortillo S, et al.
Synthesis, SAR and evaluation of 4-[2,4-difluoro-5-
Nil
AUTHORS CONTRIBUTIONS
All authors had equally contributed to the work.
CONFLICTS OF INTERESTS
Authors declare no conflicts of interest.
REFERENCES
(cyclopropylcarbamoyl)
phenylamino]pyrrolo[2,1-
f][1,2,4]triazine based VEGFR-2 kinase inhibitors. Bioorganic
Med Chem Lett 2008;18:1354-8.
21. Haque SU, Dashwood MR, Heetun M, Shiwen X, Farooqui N,
Ramesh B, et al. Efcacy of the specic endothelin a receptor
1. Jalhan S, Singh S, Saini R, Sethi Ns, Jain UK. Various biological
activities of coumarin and oxadiazole derivatives. Asian J
Pharm Clin Res 2017;10:38-43.
2.
Ahmed MN, Sadiq B, Al-Masoudi NA, Yasin KA, Hameed S,
Mahmood T, et al. Synthesis, crystal structures, computational
studies and antimicrobial activity of new designed bis((5-aryl-
1,3,4-oxadiazol-2-yl)thio)alkanes. J Mol Struct 2018;1155:403-13.
antagonist zibotentan (ZD4054) in colorectal cancer:
a
preclinical study. Mol Cancer Ther 2013;12:1556-67.
22. Abou Seri SM. Synthesis and biological evaluation of novel 2,4-
bis substituted diphenylamines as anticancer agents and
potential epidermal growth factor receptor tyrosine kinase
inhibitors. Eur J Med Chem 2010;45:4113-21.
23. Valente S, Trisciuoglio D, De Luca T, Nebbioso A, Labella D,
Lenoci A, et al. 1,3,4-Oxadiazole containing histone deacetylase
inhibitors: anticancer activities in cancer cells. J Med Chem
2014;57:6259-65.
24. Sun J, Li MH, Qian SS, Guo FJ, Dang XF, Wang XM, et al. Synthesis
and antitumor activity of 1,3,4-oxadiazole possessing 1,4-
benzodioxan moiety as a novel class of potent methionine
aminopeptidase type III inhibitors. Bioorganic Med Chem Lett
2013;23:2876-9.
25. Zhang YB, Wang XL, Liu W, Yang YS, Tang JF, Zhu HL. Design,
synthesis and biological evaluation of heterocyclic azoles
derivatives containing pyrazine moiety as potential telomerase
inhibitors. Bioorganic Med Chem 2012;20:6356-65.
26. Khan KM, Rani M, Ambreen N, Ali M, Hussain S, Perveen S, et al.
2,5-Disubstituted-1,3,4-oxadiazoles: thymidine phosphorylase
inhibitors. Med Chem Res 2013;22:6022-8.
27. Du QR, Li DD, Pi YZ, Li JR, Sun J, Fang F, et al. Novel 1,3,4-
oxadiazole thioether derivatives targeting thymidylate
synthase as dual anticancer/antimicrobial agents. Bioorganic
Med Chem 2013;21:2286-97.
28. Bekircana O, Kucuka M, Kahvecib B, Bektasa H. Synthesis and
anticancer evaluation of some new 4-amino-3-(p-
methoxybenzyl)-4,5-dihydro-1,2,4-triazole-5-one derivatives. Z
Naturforsch 2008;63b:1305-14.
29. Christov K, Shilkaitis A, Green A, Mehta RG, Grubbs C, Kelloff G,
et al. Cellular responses of mammary carcinomas to aromatase
inhibitors: effect of vorozole. Breast Cancer Res Treat
2000;60:117-28.
30. Delea TE, El-Ouagari K, Karnon J, Sofrygin O. Cost effectiveness
of letrozole versus tamoxifen as initial adjuvant therapy in
postmenopausal women with hormone-receptor positive early
breast cancer from a candian perspective. Breast Cancer Res
Treat 2008;108:375-87.
31. Kurosumi M, Takatsuka Y, Watanabe T, Imoto S, Inaji H, Tsuda H, et
al. Histopathological assessment of anastrozole and tamoxifen as
preoperative (neoadjuvant) treatment in postmenopausal
Japanese women with hormone-receptor positive breast cancer in
the proact trial. J Cancer Res Clin 2008;134:715-22.
32. Stephane P, Sook WY, Martyn J, Michael PC, Claire S. Synthesis and
CYP26A1 inhibitory activity of 1-[benzofuran-2-yl-(4-alkyl/aryl-
phenyl)-methyl]-1H-triazoles. Bioorg Med Chem 2006;14:3643-53.
33. Holla BS, Veerendra B, Shivananda MK, Boja P. Synthesis
characterization and anticancer activity studies on some
3. Singhai A, Gupta MK. Synthesis, characterization and biological
evaluation of substituted 1,3,4-oxadiazole derivative: derived
from ciprofloxacin. Asian J Pharm Clin Res 2019;12:205-9.
4. Verma G, Chashoo G, Ali A, Khan MF, Akhtar W, Ali I, et al.
Synthesis of pyrazole acrylic acid-based oxadiazole and amide
derivatives as antimalarial and anticancer agents. Bioorg Chem
2018;77:106-24.
5. Abd-Ellah HS, Abdel-Aziz M, Shoman ME, Beshr EAM, Kaoud TS,
Ahmed ASFF. New1,3,4-oxadiazole/oxime hybrids: design,
synthesis, anti-inflammatory, cox inhibitory activities and
ulcerogenic liability. Bioorg Chem 2017;74:15-29.
6. Bijander K, Raj V, Kumar A, Singh V. Anti-inflammatory activity
of 1, 3, 4-oxadiazole derivatives compound. Int J Curr Pharm
Res 2012;4:9-14.
7. Tantray MA, Khan I, Hamid H, Alam MS, Dhulap A, Kalam A.
Synthesis
of
benzimidazole
linked-1,3,4-oxadiazole
carboxamides as GSK-3 inhibitors with in vivo antidepressant
activity. Bioorg Chem 2018;77:393-401.
8. Yadagiri B, Gurrala S, Bantu R, Nagarapu L, Polepalli S, Srujana
G, et al. Synthesis and evaluation of benzosuberone embedded
with 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole
moieties as new potential anti-proliferative agents. Bioorg Med
Chem Lett 2015;25:2220-4.
9. Singh J, Rajapandi R, Maity TK. Evaluation of anticancer activity
of some 1,3,4-oxadiazole derivatives against Ehrlich ascites
carcinoma bearing mice. Asian J Chem 2010;22:4099-103.
10. Manjunatha K, Poojary B, Lobo PL, Fernandes J, Kumari NS.
Synthesis and biological evaluation of some 1,3,4-oxadiazole
derivatives. Eur J Med Chem 2010;45:5225-33.
11. Hajimahdi Z, Zarghi A, Zabihollahi R, Aghasadeghi MR.
Synthesis, biological evaluation, and molecular modeling
studies of new 1,3,4-oxadiazole-and 1,3,4-thiadiazole
substituted 4-oxo-4H-pyrido[1-a]pyrimidines as anti-HIV-1
agents. Med Chem Res 2013;22:2467-75.
12. Xu WM, Li SZ, He M, Yang S, Li XY, Li P. Synthesis and
bioactivities of novel thioether/sulfone derivatives containing
1,2,3-thiadiazole and 1,3,4-oxadiazole/thiadiazole moiety.
Bioorg Med Chem Lett 2013;23:5821-4.
13. Naga Sudha B, Sridhara C, Girija Sastry C, Reddy YSR, Sreevidya O,
Lavanya S, et al. Synthesis, characterization and anthelmintic
activity of 3-(4-acetyl-5-phenyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-
2H-chromen-2-one derivatives. Indian J Chem 2013;52B:422-7.
14. Patel K, Jayachandran E, Shah R, Javali V, Sreenivasa GM.
Synthesis, characterization and anthelmintic activity (perituma
posthuma) of new oxadiazole incorporated with imidazole and
pyrazole. Int J Pharm Bio Sci 2010;1:1-13.
98

Yahya et al.
Int J Pharm Pharm Sci, Vol 12, Issue 8, 92-99
mannich bases derived from 1,2,4-triazoles. Eur J Med Chem
2003;38:759-67.
scaffold for the selective inhibition of monoamine oxidase B. J
Med Chem 2011;54:6394-8.
34. Bekircan O, Kahveci B, Kucuk M. Synthesis and anticancer
evalution of some new unsymmetrical 3,5-diaryl-4H-1,2,4-
triazole derivatives. Turk J Chem 2006;30:29-40.
35. Genc M, Genc ZK, Tekin S, Sandal S, Sirajuddin M, Hadda TB,
Sekerci M. Design, synthesis, in vitro antiproliferative activity,
binding modeling of 1,2,4,-triazoles as new anti-breast cancer
agents. Acta Chim Slov 2016;63:726-37.
38. Alam MS, Lee DU. Synthesis, biological evaluation, drug-
likeness, and in silico screening of novel benzylidene hydrazone
analogues as small molecule anticancer agents. Arch Pharm Res
2016;39:191-201.
39. Desai NC, Trivedi A, Somani H, Jadeja KA, Vaja D, Nawale L, et
al. Synthesis, biological evaluation, and molecular docking
study of pyridine clubbed 1,3,4-oxadiazoles as potential
36. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica
D, et al. New colorimetric cytotoxicity assay for anticancer drug
screening. J Natl Cancer Inst 1990;82:1107-12.
antituberculars.
Doi:10.1080/00397911.2017.1410892.
40. Arora PK, Mittal A, Kaur G, Chauhan A. Synthesis of some novel
oxadiazole based chalcone derivatives as anti-bacterial agents.
IJPSR 2013;4:419-24.
Synth
Commun
2018.
37. Maccioni E, Alcaro S, Cirilli R, Vigo S, Cardia MC, Sanna ML, et al.
3-Acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoles:
a
new
99