Synthesis and biological potentials of some new 1,3,4-oxadiazole analogues

Article abstract of DOI:10.1007/s00044-017-2109-1

In continuation of our research to explore new antiproliferative agents, we report herein the synthesis and antiproliferative activity of two new series of N-(substituted phenyl)-5-aryl-1,3,4-oxadiazol-2-amine (4a–j) and N-{[5-aryl-1,3,4-oxadiazol-2-yl]me

Full text of DOI:10.1007/s00044-017-2109-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-2109-1
ORIGINAL RESEARCH
Synthesis and biological potentials of some new 1,3,4-oxadiazole
analogues
1 ●
1 ●
1 ●
1 ●
Mohamed Jawed Ahsan
Rachana Meena Swati Dubey Vasim Khan
1
2 ●
1 ●
3 ●
●
Sunita Manda Surender Singh Jadav Piush Sharma Mohammed H. Geesi
Mohd. Zaheen Hassan Mohammad Afroz Bakht Yassine Riadi
Md. Habban Akhter Salahuddin Rambabu Gundla
4 ●
3 ●
5 ●
6 ●
7 ●
2
Received: 5 August 2017 / Accepted: 2 November 2017
©
Springer Science+Business Media, LLC, part of Springer Nature 2017
Abstract In continuation of our research to explore new
antiproliferative agents, we report herein the synthesis and
antiproliferative activity of two new series of N-(substituted
phenyl)-5-aryl-1,3,4-oxadiazol-2-amine (4a–j) and N-{[5-
aryl-1,3,4-oxadiazol-2-yl]methyl}-substituted aniline (4k–t)
analogs. The antiproliferative activity of fifteen compounds
and 4-{5-[(2-Methoxyphenyl)amino]-1,3,4-oxadiazol-2-yl}
phenol (4c) showed maximum antiproliferative activity
among the series with a mean growth percents (GPs) of
45.20 and 56.73, respectively. The compound 4b showed
significant percent growth inhibitions (GIs) on nearly 47
cancer cell lines and were found to have higher sensitivity
towards HL-60(TB), MDA-MB-435, OVCAR-3, and K-
562 with percent GIs (GIs) of 109.62, 105.90, 91.94, and
88.30, respectively. Similarly the compound, 4c showed
significant percent GIs on nearly 42 cancer cell lines and
were found to have higher sensitivity towards UO-31,
MDA-MB-435, KM12, and K-562 with %GIs of 84.31,
(
4a–h, and 4n) was tested against nine different panels of
nearly 60 NCI human cancer cell lines. N-(2-Methox-
yphenyl)-5-(4-chlorophenyl)-1,3,4-oxadiazol-2-amine (4b)
Electronic supplementary material The online version of this article
80.52, 78.65, and 77.06, respectively. Both the compounds
(https://doi.org/10.1007/s00044-017-2109-1) contains supplementary
4b and 4c showed better antiproliferative activity than the
material, which is available to authorized users.
standard drug Imatinib while the antiproliferative activity of
compound 4b was found to be nearly comparable to the
standard drug 5-flurouracil (5-FU). The antiproliferative
activity of five compounds (4o-s) was tested against the
breast cancer cell lines (MCF-7 and MDA-MB-231) as per
Sulforhodamine B assay (SRB assay). N-{[5-(4-Methox-
yphenyl)-1,3,4-oxadiazol-2-yl]methyl}-4-methylaniline (4p)
was found to have significant antiproliferative activity against
MCF-7 and MDA-MB-231 with GI50 of 12.9 and 59.3 µM,
respectively. Further, the free radical scavenging activity
results were significant for the most active compounds, 4b
*
Mohamed Jawed Ahsan
jawedpharma@gmail.com
1
Department of Pharmaceutical Chemistry, Maharishi Arvind
College of Pharmacy, Ambabari Circle, Jaipur, Rajasthan 302 039,
India
2
3
Department of Chemistry, School of Technology, GITAM
University, Hyderabad, Telangana 502 102, India
Department of Chemistry, College of Science & Humanities,
Prince Sattam Bin Abdul Aziz University, P.O. Box 11323, Al
Kharj, Saudi Arabia
4
5
Department of Pharmaceutical Chemistry, College of Pharmacy,
King Khalid University, Abha 62529, Saudi Arabia
(
IC = 21.07 µM) and 4c (IC = 15.58 µM). The docking
50 50
studies was also carried against tubulin enzyme and the most
active compound (4b) showed good interaction with the
residues Lys254, Ala250, Cys241, Val318, Ala316, Asn258,
and Lys352 present in the hydrophobic cavity of tubulin.
Department of Pharmaceutical Chemistry, College of Pharmacy,
Prince Sattam Bin Abdul Aziz University, P.O. Box 11323, Al
Kharj, Saudi Arabia
6
7
Department of Pharmaceutics, School of Pharmaceutical
Education & Research (SPER), Jamia Hamdard University, New
Delhi 110062, India
●
●
Keywords Antiproliferative activity Antioxidants One
●
●
●
dose assay SRB assay Oxadiazoles Imatinib
Department of Pharmaceutical Chemistry, Noida Institute of
Technology (Pharmacy Institute), Knowledge Park-2, Greater
Noida, Uttar Pradesh 201 306, India

Med Chem Res
Introduction
The methylene linkage (–CH2–) was introduced in the
series two oxadiazoles (4k–s) to alter the biological profile.
The structure of oxadiazoles (4k–s) was based on the
structures of our previous reported work which contained
the core aryl linked oxadiazole of IMC-039525, with an
incorporation methylene linkage. The oxadiazoles NSC
781633 and NSC 783624 showed promising anti-
proliferative activity and had an inhibitory action on tubulin
(Fig. 2) (Ahsan et al. 2014, 2017). The formation of free
radicals by oxidative stress induce damage to the biological
macromolecules and lead to many health related disorders
such as cancer, inflammation, cardiovascular and neurode-
generative disorders (Pham-Huy et al. 2008; Birben et al.
2012). Since cancer and imbalance of oxidative stress share
aspects of their underlying pathophysiology therefore, some
antioxidants are equally effective antiproliferative agents.
Hence the antioxidant potentials of all the oxadiazoles (4a–t)
were also evaluated by the DPPH assay.
Cancer is one among the leading causes of death and taking
second position after cardiovascular disorder (Noolvi et al.
2
011). With more than 100 types of different cancer, it
became a serious global public health problem (Siegel et al.
012). More or less 14 million new cases of cancer and 8.2
million cancers’ related death tolls were reported in the year
012. It is envisaged that the new cases of cancer will rise
up from 14 million to 22 million in the next two decades
WHO Cancer statistics). Chemotherapy is the major strat-
2
2
(
egy to treat cancers, despite its drawbacks of limited effi-
cacy, safety and selectivity mainly on cancer cells. Higher
costs, toxicity, emergence of drug resistant cancer and
genotoxicity are other complications of chemotherapy
(
Aydemir and Bilaloglu 2003). Therefore development of
synthetic compounds of medicinal importance is a major
focus for scientists and researchers across the world. In the
present work two series of oxadiazoles were synthesized
and fifteen oxadiazole analogs (4a–n and 4t) were evaluated
for their antiproliferative activity on nine different panels of
nearly 60 NCI cancer cell lines. The antiproliferative
activity of the remaining five oxadiazoles (4o–s) was
evaluated on two breast cancer cell lines (MCF-7 and
MDA-MB-231) because breast cancer is the leading cause
of cancer related deaths among the female worldwide
O
OH
HO
O
N
N
N
N
NH
S
O
HN
F
NH
IMC-038525
R1
FABT
N
N
N
NH
4a-j
O
(
WHO Cancer statistics).
R2
Last few decades witnessed the development of antic-
O
ancer drugs from chemically synthesized compounds. The
heterocyclic 1,3,4-oxadiazoles being good bioisosteres of
amides and esters, can interact with the receptors by
forming hydrogen bonding and perhaps increase the bio-
logical profile significantly (Zhang et al. 2014). A number
of potential activities of oxadizoles were reported earlier
O
N
N
NH
O
N
N
N
NH
NH
O
IMC-094332
N
O
NSC 777948
(
Vaidya et al. 2016; Salahuddin et al. 2017). Biological
Fig. 1 Design of oxadiazole analogs (4a–j) on the basis of reported
potentials of oxadiazoles were also reported in the litera-
tures as antitubercular (Dhumal et al. 2016), anticancer
antiproliferative oxadiazoles
(
Abdel-Aziz et al. 2016; Agarwal and Singh et al. 2016;
Ahsan 2016), antioxidant (Mihailovic et al. 2017), anti-
microbial (Mohamed et al. 2015), anticonvulsant (Tabatabai
et al. 2013), anti-HIV (Khan et al. 2012), anti-inflammatory
N
N
H
N
O
HO
O
Cl
O
NSC 781633
(
Rathore et al. 2017) agents, and many more. Earlier we
reported the anticancer activity of some newer oxadiazoles
Ahsan 2016; Ahsan et al. 2014, 2016, 2017; Agarwal and
NH
N
N
R1
N
(
H
N
N
O
O
Singh et al. 2016). Encouraged by all these facts we syn-
thesized and report herein the antiproliferative and free
radical scavenging activities of some new oxadiazoles (4a–t).
The oxadiazole linked aryl core of IMC-038525, IMC-
R2
H
N
4
k-s
IMC-038525
N
N
N
Cl
0
1
94332, 2-(4-fluorophenylamino)-5-(2,4-dihydroxyphenyl)-
,3,4-thiadiazole (FABT), and NSC 777948 was taken to
O
OH
O
O
Cl
NSC 783624
design the title compounds (4a-k).The design of series one
oxadiazoles (4a-k) is shown in Fig. 1 (Ahsan et al. 2014;
Tuma et al. 2010; Lukas et al. 2014; Rzeski et al. 2007).
Fig. 2 Design of oxadiazole analogs (4k–s) on the basis of reported
antiproliferative oxadiazoles

Med Chem Res
Materials and methods
Experimental
the reported method (Agarwal and Singh et al. 2016; Ahsan
016; Finger et al. 1965).
2
General method for the synthesis of 2,5-disubstituted-1,3,4-
All the chemicals were procured from SD fine, CDH and
chemcodyes and were used without being further purified.
The open tube capillary method was used to record the
melting points and is uncorrected. Fourier transform infra-
red (FT-IR), nuclear magnetic resonance (NMR), and mass
spectral data were recorded on Bruker Alpha-E spectro-
meter, Bruker AC 400 MHz spectrometer and Bruker
Esquire LCMS, respectively. The microanalysis was carried
out on Perkin-Elmer 2400 Elemental Analyzer.
oxadiazole analogs (4a–t)
An equimolar mixture of substituted phenyl semicarbazide
(0.005 mol) (3a–b)/2-[(substituted phenyl)amino]acetohy-
drazide (0.005 mol) (3c–e) and aromatic aldehydes (0.005
mol) in ethanol-water system (1:2, v/v) solvent was refluxed
for 10–12 h with addition of 20 mol% solution of NaHSO3
(Sangshetti et al. 2011). The progress of the reaction was
monitored throughout by preparatory thin layer chromato-
graphy (TLC silica gel 60 F254) using eluent n-hexane/ethyl
acetate/formic acid (5:4:1) and benzene/acetone (8:2). The
reaction mixture was worked up as per the reported protocol
by pouring into the crushed ice, to obtain the final com-
pounds N-(substituted phenyl)-5-aryl-1,3,4-oxadiazol-2-
amine (4a–j) and N-{[5-aryl-1,3,4-oxadiazol-2-yl]methyl}-
substituted aniline (4k–t).
Method for the synthesis of substituted phenyl urea (2a–b)
A solution sodium cyanate (0.05 ml; 3.25 g) in hot water
was added to a solution of aromatic aniline (0.05 mol) in 10
ml glacial acetic acid and 75 ml hot water with continuous
stirring on magnetic stirrer to obtain precipitate of sub-
stituted phenyl urea (2a–b) which was further recrystallized
with hot water (Agarwal and Singh et al. 2016; Ahsan
N-(2-Methoxyphenyl)-5-(4-fluorophenyl)-1,3,4-oxadiazol-
2-amine (4a) Yield: 62%; creamy solid; mp 160–162 °C;
2
016).
−1 1
infraed (IR) (KBr): 3216, 1517, 1256, 788 cm ; H NMR
(
(
400 MHz, DMSO-d ): δ 3.83 (3H, s, OCH ), 6.81–7.05
6 3
Method for the synthesis of substituted N-(substituted
phenyl)hydrazinecarboxamide (3a–b)
4H, m, ArH, H-3, H-4, H-5 H-6), 7.99–8.21 (4H, m, ArH,
1
3
H-2′, H-3′, H-5′, H-6′), 8.49 (1H, s, ArNH); C NMR (100
MHz, DMSO-d ): δ 160.33 (C=N, C-5), 159.01 (C=N, C-
6
N-(Substituted phenyl)hydrzinecarboxamide (3a–b) was
obtained by refluxing substituted phenyl urea (2a–b) (0.04
mol) and hydrazine hydrate (0.08 mol; ~4 ml) in ethanol for
2
1
3
), 152.11 (C, C-4′), 147.03 (C, C-2), 132.61 (C, C-1),
32.01 (C, C-1′), 129.12 (CH, C-2′, C-6′), 121.81 (CH, C-
′, C-5′), 121.61 (CH, C-5), 119.81 (CH, C-4), 118.91 (CH,
2
2
4 h as per the reported method (Agarwal and Singh et al.
016; Ahsan 2016).
C-6), 115.11 (CH, C-3), 55.24 (OCH ); anal. calc. for
3
C H FN O : C, 63.15; H, 4.24; N, 14.73; found: C,
1
5
12
3 2
+
6
3.18; H, 4.23; N, 14.75%. EIMS m/z = 286.00 [M + 1] .
Method for the synthesis of ethyl[(substituted phenyl)
amino]acetate (2c–e)
N-(2-Methoxyphenyl)-5-(4-chlorophenyl)-1,3,4-oxadiazol-
-amine (4b) Yield: 88%; creamy solid; mp 210–212 °C;
IR (KBr): 3214, 1511, 1251, 698 cm ; H NMR (400
2
Ethyl[(substituted phenyl)amino]acetate (2c–e) was
obtained by stirring a mixture of aromatic aniline (1) (0.1
mol), ethylbromoacetate (0.2 mol; ~33.0 ml) and anhydrous
potassium carbonate (5 g) suspended in acetone at 80 °C for
−1
1
MHz, DMSO-d ): δ 3.81 (3H, s, OCH ), 6.62–6.88 (4H, m,
6
3
ArH, H-3, H-4, H-5, H-6), 7.46 (2H, d, J = 8.1 Hz, ArH, H-
′, H-5′), 7.61 (2H, d, J = 8.1 Hz, ArH, H-2′, H-6′), 7.78
3
6
h, as a creamy solid. This method of synthesis is some-
13
(
(
(
(
(
1H, s, ArNH), C NMR (100 MHz, DMSO-d ): δ 160.59
6
what faster than the reported method mentioned earlier in
which ethylchloroacetate was taken (Agarwal and Singh
et al. 2016; Ahsan 2016; Finger et al. 1965).
C=N, C-5), 132.58 (C=N, C-2), 147.21 (C, C-2), 130.00
C, C-1), 129.07 (C, C-4′), 128.99 (CH, C-3′, C-5′), 121.85
CH, C-1′), 120.59 (CH, C-5), 120.38 (CH, C-4), 119.09
CH, C-6), 118.11 (CH, C-3), 110.72 (CH, C-2′, C-6′),
Method for the synthesis of 2-[(substitutedphenyl)amino]
55.62 (OCH ); anal. calc. for C H ClN O : C, 59.71; H,
3 15 12 3 2
acetohydrazide (3c–e)
4.01; N, 13.93; found: C, 59.75; H, 4.04; N, 13.95%. EIMS
m/z = 302.00 [M] , 304.01 [M + 2] .
+
+
2
-[(Substituted phenyl)amino]acetohydrazide (3c–e) was
obtained by refluxing a mixtures of ethyl[(substituted phe-
nyl)amino]acetate (2c–e) (0.05 mol) and hydrazine hydrate
4-{5-[(2-Methoxyphenyl)amino]-1,3,4-oxadiazol-2-yl}phe-
nol (4c) Yield: 74%; creamy solid; mp 176–178 °C; IR
−
1 1
(
0.10 mol; ~ 5 ml) in ethanol for 22 h as creamy solid as per
(KBr): 3412, 3214, 1513, 1252 cm ; H NMR (400 MHz,

Med Chem Res
1
3
DMSO-d ): δ 3.85 (3H, s, OCH ), 6.81–6.97 (4H, m, ArH,
s, ArNH); C NMR (100 MHz, DMSO-d ): δ 153.31
6
3
6
H-3, H-4, H-5, H-6), 7.01 (2H, d, J = 8.0 Hz, ArH, H-3′, H-
′), 7.43 (2H, d, J = 8.0 Hz, ArH, H-2′, H-6′), 7.77 (1H, s,
ArNH), 10.72 (1H, s, ArOH), C NMR (100 MHz, DMSO-
(C=N, C-5), 152.15 (C=N, C-2), 151.33 (C, C-4′), 150.11
(C, C-5), 142.03 (C, C-1), 139.60 (C, C-2), 133.07 (CH, C-
2′, C-6′), 128.57 (CH, C-3′, C-5′), 118.53 (CH, C-1′),
116.31 (CH, C-3), 114.30 (CH, C-4), 100.86 (CH, C-6),
56.47 (OCH , C-5), 55.91 (OCH , C-4′), 55.24 (OCH , C-
5
1
3
d6): δ 160.57 (C=N, C-5), 152 (C=N, C-2), 147.01 (C, C-
2
6
1
), 132.51 (C, C-4′), 130.09 (C, C-1), 128.06 (CH, C-2′, C-
′), 121.99 (CH, C-5), 119.09 (CH, C-4), 118.31 (CH, C-
′), 117.81 (CH, C-6), 116.57 (CH, C-3′, C-5′), 115.39 (CH,
3
3
3
2); anal. calc. for C H N O : C, 62.38; H, 5.23; N, 12.84;
1
7 17 3 4
found: C, 62.41; H, 5.21; N, 12.85%. EIMS m/z = 328.10
+
C-3), 55.63 (OCH ); anal. calc. for C H N O : C, 63.60;
[M] .
3
15 13 3 3
H, 4.63; N, 14.83; found: C, 63.63; H, 4.61; N, 14.85%.
+
EIMS m/z = 284.00 [M] .
4-{5-[(2,5-Dimethoxyphenyl)amino]-1,3,4-oxadiazol-2-yl}
phenol (4g) Yield: 58%; creamy solid; mp 160–162 °C; IR
−
1 1
N-(2-Methoxyphenyl)-5-(4-methoxyphenyl)-1,3,4-oxadia-
zol-2-amine (4d) Yield: 72%; creamy solid; mp 166–
(KBr): 3409, 3213, 1514, 1257 cm ; H NMR (400 MHz,
DMSO-d ): δ 3.67 (3H, s, OCH , C-5), 3.85 (3H, s, OCH ,
6
3
3
−1 1
1
68 °C; IR (KBr): 3218, 1519, 1251 cm ; H NMR (400
C-2), 6.50 (1H, d, J = 8.7 Hz, ArH, H-3), 6.83 (2H, d, J =
8.4 Hz, ArH, H-3′, H-5′), 6.94 (1H, d, J = 8.8 Hz, ArH, H-
4), 7.66 (2H, d, J = 8.3 Hz, ArH, H-2′, H-6′), 7.81 (1H, s,
ArH, H-6), 7.85 (1H, s, ArNH), 10.73 (1H, s, ArOH);
NMR (100 MHz, DMSO-d ): δ 153.33 (C=N, C-5), 152.10
MHz, DMSO-d ): δ 3.77 (3H, s, OCH , C-4′), 3.81 (3H, s,
6
3
OCH , C-2), 6.84–7.03 (4H, m, ArH, H-3, H-4, H-5, H-6),
3
1
3
7
7
.60 (2H, d, J = 7.9 Hz, ArH, H-3′, H-5′), 7.79 (2H, d, J =
.9 Hz, ArH, H-2′, H-6′), 7.93 (1H, s, ArNH); C NMR
C
1
3
6
(
(
100 MHz, DMSO-d ): δ 160.51 (C=N, C-5), 152.11
C=N, C-5), 147.12 (C, C-2), 132.59 (C, C-1), 130.11 (C,
(C=N, C-2), 151.31 (C, C-4′), 150.13 (C, C-5), 142.01 (C,
C-1), 139.62 (C, C-2), 133.17 (C, C-1′), 128.77 (CH, C-2′,
C-6′), 118.57 (CH, C-3), 116.32 (CH, C-3′, C-5′), 114.31
6
C-4′), 129.09 (CH, C-2′, C-6′), 121.94 (CH, C-5), 119.06
(
(
CH, C-4), 118.51 (C, C-1′), 117.82 (CH, C-6), 115.59
(CH, C-4), 100.86 (CH, C-6), 56.47 (OCH , C-5), 55.24
3
CH, C-3), 114.31 (CH, C-3′, C-5′), 56.24 (OCH , C-4′),
(OCH , C-2); anal. calc. for C H N O : C, 61.34; H,
3
3
16 15 3 4
5
5.61 (OCH , C-2); anal. calc. for C H N O : C, 64.64;
4.83; N, 13.41; found: C, 61.36; H, 4.81; N, 13.45%. EIMS
m/z = 313.10 [M] .
3
16 15 3 3
+
H, 5.09; N, 14.13; found: C, 64.67; H, 5.11; N, 14.10%.
EIMS m/z = 298.10 [M] .
+
N-(2,5-Dimethoxyphenyl)-5-(3,4-dimethoxyphenyl)-1,3,4-
oxadiazol-2-amine (4h) Yield: 69%; creamy solid; mp
N-(2,5-Dimethoxyphenyl)-5-(4-chlorophenyl)-1,3,4-oxadia-
zol-2-amine (4e) Yield: 82%; white solid; mp 216–
2
−
1 1
178–180 °C; IR (KBr): 3212, 1511, 1255 cm ; H NMR
(400 MHz, DMSO-d ): δ 3.68 (3H, s, OCH , C-2), 3.77
18 °C; IR (KBr): 3216, 1512, 1256, 698 cm− ; H NMR
1
1
6
3
(
400 MHz, DMSO-d ): δ 3.68 (3H, s, OCH , C-5), 3.86
(3H, s, OCH , C-4′), 3.82 (6H, s, OCH , C-5, C-3′), 6.51
3 3
6
3
(
6
3H, s, OCH , C-2), 6.53 (1H, d, J = 8.0 Hz, ArH, H-4),
.94 (1H, d, J = 8.0 Hz, ArH, H-3), 7.52 (2H, d, J = 8.3 Hz,
(1H, d, J = 5.7 Hz, ArH, H-4), 6.94 (1H, d, J = 8.8 Hz,
ArH, H-3), 7.01 (1H, d, J = 8.4 Hz, ArH, H-5′), 7.13 (1H, d,
J = 6.6 Hz, ArH, H-6′), 7.31 (1H, s, ArH, H-6), 7.84 (1H, s,
3
ArH, H-3′, H-5′), 7.67 (2H, d, J = 8.3 Hz, ArH, H-2′, H-6′),
7
1
3
13
.78 (1H, s, ArH, H-6), 7.95 (1H, s, ArNH); C NMR (100
ArH, H-2′), 7.93 (1H, s ArNH); C NMR (100 MHz,
MHz, DMSO-d ): δ 153.31 (C=N, C-5), 152.15 (C=N, C-
DMSO-d ): δ 153.31 (C=N, C-5), 152.15 (C=N, C-2),
6
6
2
1
2
), 142.03 (C, C-5), 139.60 (C, C-2), 134.02 (C, C-1),
33.07 (C, C-4′), 128.97 (CH, C-3′, C-5′), 128.53 (CH, C-
′, C-6′), 127.98 (C, C-1′), 111.30 (CH, C-3), 105.86 (CH,
151.12 (C, C-5), 142.03 (C, C-3′), 139.60 (C, C-2), 134.02
(C, C-4′), 133.07 (C, C-1), 128.97 (CH, C-6′), 128.53 (C,
C-1′), 127.98 (CH, C-5′), 112.36 (CH, C-3), 111.30 (CH, C-
C-4), 104.88 (CH, C-6), 56.47 (OCH , C-5), 55.24 (OCH ,
2′), 105.86 (CH, C-4), 104.88 (CH, C-6), 56.47 (OCH , C-
3
3
3
C-2); anal. calc. for C H ClN O : C, 57.93; H, 4.25; N,
5), 56.46 (OCH , C-3), 55.56 (OCH , C-4′), 55.24 (OCH ,
1
6
14
3
3
3
3
3
1
3
2.67; found: C, 57.96; H, 4.23; N, 12.65%. EIMS m/z =
32.00 [M] , 334.02 [M + 2] .
C-2); anal. calc. for C H N O : C, 60.50; H, 5.36; N,
18 19 3 5
+
+
11.76; found: C, 60.53; H, 5.33; N, 11.77%. EIMS m/z =
+
3
58.10 [M] .
N-(2,5-Dimethoxyphenyl)-5-(4-methoxyphenyl)-1,3,4-oxa-
diazol-2-amine (4f) Yield: 77%; creamy solid; mp
4-{5-[(2,5-Dimethoxyphenyl)amino]-1,3,4-oxadiazol-2-yl}-
−
1 1
1
68–170 °C; IR (KBr): 3215, 1517, 1253 cm ; H NMR
2-methoxyphenol (4i) Yield: 72%; creamy solid; mp
−
1 1
(
(
400 MHz, DMSO-d ): δ 3.68 (3H, s, OCH , C-5), 3.78
180–182 °C; IR (KBr): 3214, 1513, 1251 cm ; H NMR
(400 MHz, DMSO-d ): δ 3.68 (6H, s, OCH , C-2, C-3′),
6
3
3H, s, OCH , C-4′), 3.86 (3H, s, OCH , C-2), 6.51 (1H, d,
3
3
6
3
J = 7.9 Hz, ArH, H-4), 6.94 (1H, d, J = 8.7 Hz, ArH, H-3),
3.82 (3H, s, OCH , C-5), 6.50 (1H, d, J = 8.0 Hz, ArH, H-
3
7
7
.02 (2H, d, J = 7.4 Hz, ArH, H-3′, H-5′), 7.60 (2H, d, J =
.9 Hz, ArH, H-2′, H-6′), 7.81 (1H, s, ArH, H-6), 7.90 (1H,
4), 6.81 (1H, d, J = 8.3 Hz, ArH, H-3), 6.94 (1H, d, J = 8.8
Hz, ArH, H-5′), 7.01 (1H, d, J = 7.6 Hz, ArH, H-6′), 7.27

Med Chem Res
(
2H, s, ArH, H-6, H-2′), 7.84 (1H, s, ArNH) 10.51 (1H, s,
(C, C-1), 129.09 (CH, C-2′, C-6′), 128.97 (CH, C-5),
128.08 (C, C-1′), 121.81 (CH, C-4), 120.59 (CH, C-3′, C-
1
3
ArOH); C NMR (100 MHz, DMSO-d ): δ 153.34 (C=N,
6
C-5), 152.36 (C=N, C-2), 148.57 (C, C-5), 148.01 (C, C-
5′), 120.36 (CH, C-3), 114.16 (CH, C-6), 56.24 (OCH , C-
3
3
1
1
1
′), 141.82 (C, C-4′), 141.41 (C, C-2), 128.77 (C, C-1),
25.51 (CH, C-1′), 121.26 (CH, C-6′), 115.48 (CH, C-5′),
11.25 (CH, C-2′), 108.24 (CH, C-3), 105.54 (CH, C-4),
04.62 (CH, C-6), 56.43 (OCH , C-5, C-3′), 55.22 (OCH ,
2), 55.64 (OCH , C-4′), 52.14 (CH , ArNHCH ); anal. calc.
3
2
2
for C H N O : C, 65.58; H, 5.50; N, 13.50; found: C,
1
9 21 3 5
+
65.55; H, 5.53; N, 13.53%. EIMS m/z = 311.40 [M] .
3
3
C-2); anal. calc. for C H N O : C, 59.47; H, 4.99; N,
N-{[5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-
2,5-dimethoxyaniline (4m) Yield: 76%; creamy solid; mp
1
7 17 3 5
1
3
2.24; found: C, 59.47; H, 4.97; N, 12.25%. EIMS m/z =
44.10 [M] .
+
−1 1
112–114 °C; IR (KBr): 3215, 1517, 1253 cm ; H NMR
400 MHz, DMSO-d ): δ 3.68 (3H, s, OCH , C-2), 3.77
(
6
3
N-(2,5-Dimethoxyphenyl)-5-(2,3,4-trimethoxyphenyl)-1,3,
(3H, s, OCH , C-4), 3.83 (6H, s, OCH , C-5, C-3′), 4.18
3 3
4
2
-oxadiazol-2-amine (4j) Yield: 72%; creamy solid; mp
(2H, s, CH ), 6.53 (1H, d, J = 7.7 Hz, ArH, H-4), 6.93 (1H,
2
08–210 °C; IR (KBr): 3213, 1514, 1258 cm− ; H NMR
1
1
d, J = 7.7 Hz, ArH, H-3), 7.01 (1H, d, J = 8.1 Hz, ArH, H-
5′), 7.13 (1H, d, J = 8.1 Hz, ArH, H-6′), 7.33 (1H, s, ArH,
(
400 MHz, DMSO-d ): δ 3.68 (6H, s, OCH , C-2, C-4′),
6 3
1
3
3
6
.81 (3H, s, OCH , C-5), 3.84 (6H, s, OCH , C-3′, C-5′),
H-6, H-2′), 7.88 (1H, s, ArNH); C NMR (100 MHz,
3
3
.51 (1H, d, J = 7.1 Hz, ArH, H-4), 6.95 (1H, d, J = 8.8 Hz,
DMSO-d ): δ 153.30 (C=N, C-5), 152.18 (C=N, C-2),
6
ArH, H-3), 6.99 (2H, s, ArH, H-2′, H-6′), 7.84 (1H, s, ArH,
151.11 (C, C-5), 142.05 (C, C-3′), 139.61 (C, C-2), 134.06
(C, C-4′), 133.17 (C, C-1), 128.91 (CH, C-3), 128.43 (CH,
C-6′), 127.99 (CH, C-1′), 112.31 (CH, C-2′), 111.35 (CH,
C-3), 105.81 (CH, C-4), 104.86 (CH, C-6), 56.46 (OCH3,
C-2, C-5), 56.22 (OCH , C-3′, C-4′), 52.14 (CH ,
1
3
H-6), 7.88 (1H, s, ArNH), C NMR (100 MHz, DMSO-
d6): δ 153.33 (C=N, C-5), 152.11 (C=N, C-2), 142.03 (C,
C-5), 139.61 (C, C-2), 134.01 (C, C-4′), 133.06 (C, C-3′, C-
5
1
6
′), 128.91 (C, C-1), 128.57 (C, C-1′), 127.99 (CH, C-3),
11.31 (CH, C-4), 105.76 (CH, C-6), 104.78 (CH, C-2′, C-
′), 56.55 (OCH , C-4′), 56.45 (OCH , C-5), 56.24 (OCH ,
3
2
ArNHCH ); anal. calc. for C H N O : C, 61.45; H, 5.70;
2
19 21 3 5
N, 11.31; found: C, 61.43; H, 5.74; N, 11.33%. EIMS m/z
3
3
3
+
C-3′, C-5′), 55.24 (OCH , C-2); anal. calc. for C H N O :
= 372.04 [M] .
3
19 21 3 6
C, 58.91; H, 5.46; N, 10.85; found: C, 58.93; H, 5.43; N,
+
1
0.87%. EIMS m/z = 387.10 [M] .
N-{[5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-4-
methylaniline (4n) Yield: 89 %; light brown solid; mp
−1 1
N-{[5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-2-
methoxyaniline (4k) Yield: 76%; creamy solid; mp
18–120 °C; IR (KBr): 3213, 1518, 1258, 699 cm ; H
140–142 °C; IR (KBr): 3216, 1519, 1252, 695 cm ; H
NMR (400 MHz, DMSO-d ): δ 2.12 (3H, s, ArCH ), 4.16
6
3
−1 1
1
(2H, s, CH ), 6.52 (2H, d, J = 8.4 Hz, ArH, H-2, H-6), 6.89
2
NMR (400 MHz, DMSO-d ): δ 3.84 (3H, s, OCH ), 4.48
(2H, d, J = 5.7 Hz, ArH H-3, H-5), 7.48 (2H, d, J = 8.4 Hz,
ArH, H-3′, H-5′), 7.73 (2H, d, J = 8.3 Hz, ArH, H-2′, H-6′),
6
3
(
2H, s, CH ), 7.21–7.58 (4H, m, ArH, H-3, H-4, H-5, H-6),
2
1
3
7
7
.63 (2H, d, J = 7.9 Hz, ArH, H-3′, H-5′), 7.84 (2H, d, J =
.9 Hz, ArH, H-2′, H-6′), 8.68 (1H, s, ArNH); C NMR
7.97 (1H, s, ArNH); C NMR (100 MHz, DMSO-d ): δ
6
1
3
164.41 (C=N, C-5), 152.22 (C=N, C-2), 144.60 (C, C-1),
134.41 (C, C-4′), 129.91 (CH, C-3, C-5), 129.64 (CH, C-3′,
C-5′), 128.91 (CH, C-2′, C-6′), 126.82 (C, C-4), 124.47 (C,
C-1′), 113.86 (CH, C-3, C-5), 51.72 (CH , ArNHCH ),
(
(
100 MHz, DMSO-d ): δ 160.55 (C=N, C-5), 152.11
C=N, C-2), 144.21 (C, C-2), 132.53 (C, C-1), 130.01 (C,
6
C-4′), 129.09 (CH, C-3′, C-5′), 128.99 (CH, C-2′, C-6′),
2
2
1
1
21.89 (CH, C-5), 120.58 (C, C-1′), 120.34 (CH, C-4),
24.31 (CH , ArCH ); anal. calc. for C H ClN O: C,
3 3 16 14 3
19.07 (CH, C-3), 118.11 (CH, C-6), 56.24 (OCH ), 52.16
64.11; H, 4.71; N, 14.02; found: C, 64.15; H, 5.68; N,
3
+
+
(
CH , ArNHCH ); anal. calc. for C H N O : C, 60.86; H,
14.05%. EIMS m/z = 300.01 [M] , 302.00 [M + 2] .
2
2
19 21 3 5
4
.47; N, 13.31; found: C, 60.83; H, 4.50; N, 13.33%. EIMS
+
+
m/z = 316.00 [M] , 318.10 [M + 2] .
4-(5-{[(4-Methylphenyl)amino]methyl}-1,3,4-oxadiazol-2-
yl)phenol (4o) Yield: 76%; light brown solid; mp 112–114
−
1 1
N-{[5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2-
methoxyaniline (4l) Yield: 72%; creamy solid; mp
1
°C; IR (KBr): 3414, 3219, 1516, 1257 cm ; H NMR (400
MHz, DMSO-d ): δ 2.12 (3H, s, ArH), 4.16 (2H, s, CH ),
6
2
26–128 °C; IR (KBr): 3219, 1517, 1253 cm−1; 1H NMR
6.32 (2H, d, J = 8.0 Hz, ArH, H-2, H-6), 6.79 (2H, d, J =
8.1 Hz, ArH, H-3′, H-5′), 6.85 (2H, d, J = 8.0 Hz, ArH, H-
3, H-5), 7.33 (2H, d, J = 8.1 Hz, ArH, H-2′, H-6′), 7.95 (1H,
s, ArNH), 11.31 (1H, s, ArOH); C NMR (100 MHz,
DMSO-d ): δ 164.41 (C=N, C-5), 158.53 (C=N, C-2),
(
(
400 MHz, DMSO-d ): δ 3.68 (3H, s, OCH , C-4′), 3.83
6 3
3H, s, OCH , C-2), 4.46 (2H, s, CH ), 7.23–7.56 (4H, m,
3
2
1
3
ArH, H-3, H-4, H-5, H-6), 7.61 (2H, d, J = 8.1 Hz, ArH, H-
′, H-5′), 7.68 (2H, d, J = 8.1 Hz, ArH, H-2′, H-4′), 8.72
3
6
1
3
(
1H, s, ArNH); C NMR (100 MHz, DMSO-d ): δ 160.63
152.21 (C, C-4′), 144.59 (C, C-1), 129.91 (CH, C-3, C-5),
6
(
C=N, C-5), 152.11 (C=N, C-2), 152.04 (C, C-4′), 130.15
128.93 (CH, C-2′, C-6′), 126.74 (C, C-4), 118.91 (C, C-1′),

Med Chem Res
1
16.72 (CH, C-3′, C-5′), 113.50 (CH, C-2, C-6), 51.72
112.31 (CH, C-1′), 56.62 (OCH , C-3′), 51.73 (CH , ArNH
3
2
(
CH , ArNHCH ), 24.33 (CH , ArCH ); anal. calc. for
CH ), 24.32 (CH , ArCH ); anal. calc. for C H N O : C,
2 3 3 17 17 3 3
2
2
3
3
C H N O : C, 68.31; H, 5.37; N, 14.94; found: C, 68.36;
H, 5.35; N, 14.92%. EIMS m/z = 282.09 [M] .
65.58; H, 5.50; N, 13.50; found: C, 65.55; H, 5.53; N,
13.53%. EIMS m/z = 312.10 [M] .
1
6 15 3 2
+
+
N-{[5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-4-
methylaniline (4p) Yield: 72%; light brown solid; mp
1
N-{[5-(2,3,4-Trimethoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-
4-methylaniline (4s) Yield: 78%; light brown solid; mp
58–160 °C; IR (KBr): 3217, 1519, 1259 cm− ; H NMR
1
1
−1 1
110–112 °C; IR (KBr): 3219, 1517, 1259 cm ; H NMR
(400 MHz, DMSO-d ): δ 2.12 (3H, s, ArCH ), 3.79 (3H, s,
(
400 MHz, DMSO-d ): δ 2.12 (3H, s, ArCH ), 3.78 (3H, s,
6 3
6
3
OCH ), 4.13 (2H, s, CH ), 6.47 (2H, d, J = 7.9 Hz, ArH, H-
OCH , C-4′), 3.81 (6H, s, OCH , C-3′, C-5’), 4.17 (2H, s,
3 3
3
2
2
, H-6), 6.87 (2H, d, J = 7.9 Hz, ArH, H-3, H-5), 6.98 (2H,
CH ), 6.50 (2H, d, J = 8.8 Hz, ArH, H-2, H-6), 6.87 (2H, d,
2
d, J = 8.8 Hz, ArH, H-3′, H-5′), 7.64 (2H, d, J = 8.8 Hz,
ArH, H-2′, H-6′), 7.93 (1H, s, ArNH); C NMR (100 MHz,
J = 8.8 Hz, ArH, H-3, H-5), 6.96 (2H, s, ArH), 7.90 (1H, s,
1
3
13
ArNH); C NMR (100 MHz, DMSO-d ): δ 164.61 (C=N,
6
DMSO-d ): δ 164.40 (C=N, C-5), 160.51 (C, C-4′), 152.22
C-5), 152.72 (C=N, C-2), 151.60 (C, C-3′, C-5’), 144.71
(C, C-1), 139.92 (C, C-4′), 129.89 (CH, C-3, C-5), 126.82
(C, C-4), 120.91 (C, C-1′), 113.83 (CH, C-2, C-6), 104.91
6
(
C=N, C-2), 144.63 (C, C-1), 129.92 (CH, C-3, C-5),
28.51 (CH, C-2′, C-6′), 126.81 (C, C-4), 118.60 (C,
C-1′), 114.71 (CH, C-3′, C-5′), 113.54 (CH, C-2, C-6),
6.62 (C, OCH ), 51.71 (CH , ArNHCH ), 24.31 (CH ,
1
(CH, C-2′, C-6′), 56.52 (OCH , C-4′), 56.25 (OCH3, C-3′,
3
5
C-5′), 51.62 (CH , ArNHCH ), 24.31 (CH , ArCH ); anal.
3
2
2
3
2
2
3
3
ArCH ); anal. calc. for C H N O : C, 69.14; H, 5.80; N,
calc. for C H N O : C, 64.21; H, 5.96; N, 11.82; found:
19 21 3 4
3
17 17
3
2
1
2
4.23; found: C, 69.17; H, 5.78; N, 14.21%. EIMS m/z =
95.80 [M] .
C, 6sza 4.19; H, 5.98; N, 11.85%. EIMS m/z = 356.10
[M] .
+
+
N-{[5-(3,4-Dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-
N-{[5-(Furan-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-4-methy-
laniline (4t) Yield: 67%; light brown solid; mp 108–
110 °C; IR (KBr): 3218, 1513, 1254 cm ; H NMR (400
4
7
-methylaniline (4q) Yield: 67%; light brown solid; mp
0–72 °C; IR (KBr): 3219, 1513, 1249 cm ; H NMR
−
1
1
−1 1
(
400 MHz, DMSO-d ): δ 2.12 (3H, s, ArCH ), 3.77 (3H, s,
MHz, DMSO-d ): δ 2.12 (3H, s, ArCH ), 4.13 (2H, s, CH ),
6
3
6
3
2
OCH , C-4′), 3.79 (3H, s, OCH , C-3′), 4.12 (2H, s, CH ),
6.31 (2H, d, J = 8.0 Hz, ArH, H-2, H-6), 6.39–6.43 (3H, s,
ArH, H-3′, H-4′, H-5′), 6.85 (2H, d, J = 8.0 Hz, ArH, H-3,
3
3
2
6
8
6
.31 (2H, d, J = 8.1 Hz, ArH, H-2, H-6), 6.85 (2H, d, J =
.1 Hz, ArH, H-3, H-5), 6.72 (1H, d, J = 8.0 Hz, ArH, H-
′), 6.88 (1H, s, ArH, H-1′), 6.93 (1H, d, J = 8.0 Hz, ArH,
1
3
H-5), 7.92 (1H, s, ArNH); C NMR (100 MHz, DMSO-
d6): δ 157.92 (C=N, C-5), 152.71 (C=N, C-2), 147.90 (C,
C-1′), 144.42 (C, C-1), 142.81 (CH, C-3′), 129.91 (CH, C-
3, C-5), 126.41 (C, C-4), 113.42 (CH, C-2, C-6), 107.93
(CH, C-5′), 105.52 (CH, C-4′), 51.62 (CH , ArNHCH ),
1
3
H-5′), 7.98 (1H, s, ArNH); C NMR (100 MHz, DMSO-
d6): δ 164.42 (C=N, C-5), 150.51 (C, C-3′), 149.90 (C, C-
4′), 144.71 (C, C-1), 129.94 (CH, C-3, C-5), 126.91 (C, C-
4), 120.80 (CH, C-6′), 119.79 (C, C-1′), 115.94 (CH, C-5′),
113.42 (CH, C-2, C-6), 112.31 (CH, C-1′), 56.62 (OCH3,
2
2
24.32 (CH , ArCH ); anal. calc. for C H N O : C, 65.87;
3
3
19 21 3 4
H, 5.13; N, 16.46; found: C, 65.89; H, 5.11; N, 16.46%.
+
C-3′, C-4′), 51.73 (CH , ArNHCH ), 24.34 (CH , ArCH );
EIMS m/z = 256.11 [M] .
2
2
3
3
anal. calc. for C H N O : C, 66.45; H, 5.89; N, 12.91;
1
8 19 3 3
found: C, 66.42; H, 5.90; N, 12.93%. EIMS m/z = 326.09
+
[
M] .
Antiproliferative activity
2
-Methoxy-4-(5-{[(4-methylphenyl)amino]methyl}-1,3,4-
The antiproliferative activity of the oxadiazoles was carried
out as per the standard protcols reported elsewhere (http://
dtp.nci.nih.gov; Boyd and Paull 1995; Monks et al. 1991;
Shoemaker 2006; Vichai and Kirtikara 2006). The method
for the evaluation of antiproliferative activity was provided
as supplementary information.
oxadiazol-2-yl)phenol (4r) Yield: 62%; light brown solid;
−
1
mp 120–122 °C; IR (KBr): 3408, 3216, 1511, 1256 cm
;
1
H NMR (400 MHz, DMSO-d ): δ 2.12 (3H, s, ArCH ),
6
3
3
.80 (3H, s, OCH ), 4.14 (2H, s, CH ), 6.40 (2H, d, J = 7.9
3 2
Hz, ArH, H-2, H-6), 6.68 (1H, d, J = 8.8 Hz, ArH, H-5′),
.82 (1H, s, ArH, H-2′), 6.85 (2H, d, J = 7.9 Hz, ArH, H-3,
H-5), 6.87 (1H, d, J = 8.8 Hz, ArH, H-6′), 7.95 (1H, s,
6
Molecular docking studies
1
3
ArNH), 11.31 (1H, s, ArOH); C NMR (100 MHz,
DMSO-d ): δ 164.41 (C=N, C-5), 152.71 (C=N, C-5),
The present molecular studies were carried out using
Maestro 8.5 (Schrodingers LLC) installed in RHEL 5.0
platform. Maestro 10.1 (Academic version) was utilized for
docking interpretation. 3-D X-ray crystallographic tubulin
6
1
51.22 (C, C-3′), 145.71 (C, C-4′), 144.82 (C, C-1), 129.92
(
(
CH, C-3, C-5), 126.93 (C, C-4), 121.30 (CH, C-6′), 119.81
CH, C-1′), 117.90 (CH, C-5′), 113.43 (CH, C-2, C-6),

Med Chem Res
complexed with colchicine as ligand (PDB: 1SA0) at
resolution 3.58 Å with r value 0.233 (obs.) was obtained
from the protein data bank (https://www.rcsb.org/) (Ravelli
et al. 2004; Wallace et al. 1995).
517 nm) which turns into yellow after accepting hydrogen
from the antioxidants.
Results and discussion
Chemistry
DPPH free radical scavenging assay
The antioxidant activity of compounds was assessed by
DPPH free radical assay (Koleva et al. 2002). This assay is
based on the theory that hydrogen donors are antioxidants.
DPPH (1,1-Diphenyl-2-picrylhydrazyl) is a commercially
available stable free radical with purple color (absorbed at
The synthetic routes for the synthesis of oxadiazole analogs
(4a–t) are outlined in the Schemes 1 and 2. The oxadiazoles
(4a–j and 4k–t) were prepared starting from substituted
aniline (1a–b) by adopting two different routes. For the
Scheme 1 Synthetic route for
the preparation of N-(substituted
phenyl)-5-aryl-1,3,4-oxadiazol-
H
N
H
N
H
N
NH
2
R1
NaCNO
AcOH
NH2 NH
NH .H O
2 2 2
R1
R1
NH2
O
EtOH
Reflux, 22 h
O
Stirring, 30 min, Rt
2
-amine analogs (4a-j)
3a-b
1a-b
2a-b
EtOH/H O (1:2, v/v)
2
ArCHO
2
0% mol NaHSO3
Reflux, 10-12 h
H
N
O
R1
N
R2
N
4
a-j
1
R = 2-OCH , 2,5-(OCH )
3
3 2
2
R = 4-F, 4-Cl, 4-OH, 4-OCH , 3,4-(OCH )
3
3 2
=
4-OH-3-OCH , 2,3,4-(OCH )
3
3 3
Scheme 2 Synthetic route for
the preparation of N-(substituted
phenyl)[5-aryl/alkyl-1,3,4-
oxadiazol-2-yl]methyl amine
analogs (4k-t)
O
N
H
O
N
N
4t
EtOH/H2O, (1:2, v/v)
O
O
NaHSO , 20% mol.
3
H
Reflux, 10 h
H
O
H O
NH2 BrCH COOEt
N
NH2
2
N
NH NH .H O
2 2 2
R1
R1
O
R1
N
H
K CO /Acetone
EtOH
Reflux, 6 h
2
3
6
h, Stirring at 60 °C
3c-e
1
a-c
2c-e
EtOH/H2O, (1:2, v/v)
NaHSO , 20% mol. ArCHO
3
Reflux, 10-12 h
R1
R2
O
N
H
N
N
4
k-s
1
R = 2-OCH , 2,5-(OCH ) , 4-CH
3
3
3 2
2
R = 4-Cl, 4-OH, 3-OCH , 3,4-(OCH ) , 3-OCH -4-OH, 3,4,5-(OCH )
3 3
3
3 2
3

Med Chem Res
series one oxadizoles (4a–j), the intermediate substituted
phenyl urea (2a–b) was prepared by stirring a solution of
substituted anilines (1a–b) in glacial acetic acid and warm
water with a solution of sodium cyanate in hot water, while
the intermediate substituted N-(substituted phenyl)hydra-
zine-carboxamide (3a–b) was prepared by refluxing a
mixture of substituted phenyl urea (2a–b) and hydrazine
hydrate in ethanol for 24 h, as per the reported method
singlet at 7.84–7.98 ppm for the corresponding aromatic
NH (ArNH) and a singlet at 10.72–11.31 ppm for the cor-
responding phenolic (OH) group. The aromatic protons
(ArH) were observed as singlet/doublet/multiplet depending
on the nature of protons at δ 6.31–7.84 ppm. The coupling
constants (J value in Hz) were also calculated for the
doublet peak of aromatic protons. The nature of the carbon
1
3
atoms was characterized and verified by C NMR, recor-
(
2
Agarwal and Singh et al. 2016; Ahsan 2016; Ahsan et al.
017; Azam et al. 2010). For series two oxadiazoles (4k–t),
the intermediates ethyl[(substituted phenyl)amino]acetate
2c–e) was obtained by stirring and refluxing a mixture of
ded in DMSO-d at 100 MHz. The mass spectra of the
6
+
+
compounds showed molecular ion peak M , (M + 1) and
+
(M + 2).
(
substituted aniline (1a–c) and bromoethylacetate in acetone
Antiproliferative activity evaluation
for 6 h with an addition of K CO , while 2-[(substituted
2
3
phenyl)amino]acetohydrazide (3c–e) was obtained by
refluxing ethyl [(substituted phenyl)amino]acetate (2c–e)
and hydrazine hydrate in ethanol for 22 h as per the reported
method (Agarwal and Singh et al. 2016; Ahsan 2016;
Ahsan et al. 2017; Finger et al. 1965). The preparation of
ethyl[(substituted phenyl)amino]acetate (2c–e) from bro-
moethylacetate was found to be less time consuming as
compared to the earlier reported method (Agarwal and
Singh et al. 2016; Ahsan 2016; Ahsan et al. 2017). In the
final step for both series oxadiazoles were synthesized by
refluxing an equimolar quantities of N-(substituted phenyl)
hydrazinecarboxamide (3a-b)/ 2-[(substituted phenyl)
amino]acetohydrazide (3c–e) and aromatic aldehyde for
Fifteen oxadiazole analogs (4a-n and 4t) were evaluated for
their antiproliferative activity on nine different panels
(leukemia, non small lung cell cancer, colon cancer, CNS
cancer, melanoma, ovarian cancer, renal cancer, prostate
cancer, and breast cancer) of nearly 59 cancer cell lines as
per the standard NCI US protocol (http://dtp.nci.nih.gov;
Boyd and Paull 1995; Monks et al. 1991; Shoemaker 2006).
The antiproliferative activity in the form of growth percents
(GPs) and percent growth inhibitions (%GIs) against the six
most sensitive cell lines is given in Table 2. The compounds
4a, 4d, 4f, 4g, 4h, 4j, 4k, 4l, 4m and 4n showed com-
paratively less antiproliferative activity, however the com-
pound, 4g showed moderate antiproliferative activity
against SNB-75, KM12, SF-539, and UO-31 with %GIs
between 50.61 and 40.58. The compound 4e showed sig-
nificant %GIs on 8 cancer cell lines including U251,
OVCAR-4, NCI-H460, 786-O, SF295, ACHN, HCT-116,
and OVCAR3 with %GIs between 97.45 and 68.18. The
compound, 4i showed significant %GIs on 6 cancer cell
lines including A498, TK-10, SNB-75, IGROV1, UO-31,
and with %GIs between 93.82 and 79.63. The compound,
4c showed significant %GIs on nine cancer cell lines
including UO-31, MDA-MB-435, KM12, K-562, A498,
SR, MCF7, NCI-H322M, and RPMI-8229 with %GIs
between 84.31 and 68.98. The compound, 4b showed sig-
nificant %GIs on 16 cancer cell lines including HL-60(TB),
MDA-MB-435, OVCAR-3, K-562, MDA-MB-468, HT29,
NCI-H460, NCI-H522, MCF7, RPMI-8226, SR, NCI/
ADR-RES, SW-620, M14, KM12, and MOLT-4 with %GIs
between 109.62 and 70.76. The anticancer activity of
compounds 4b 4c, 4e and 4i on 59 cancer cell lines is given
in Table 3. The compound which showed GIs of ≥ 68% (i.e.
GP of ≤ 32) was considered to be significantly active
towards that particular cell lines and shown as bold figures
in Table 2 and Table 3 (Corona et al. 2009). The anti-
proliferative activity in terms of average percent GIs for the
compounds, 4b, 4c, 4e, 4i, 5-Fluorouracil (5-FU) and
Imatinib was calculated against each panel of cancer cell
lines and is given in Table 4. The compound, 4b showed
1
0–12 h in ethanol-water system (1:2, v/v) solvent using 20
mol% NaHSO to afford the synthesis of N-(substituted
3
phenyl)-5-aryl-1,3,4-oxadiazol-2-amine analogs (4a–j)/ N-
(
substituted
phenyl)[5-aryl-1,3,4-oxadiazol-2-yl]methyl
amine analogs (4k–t) (Sangshetti et al. 2011). The progress
of reaction was examined throughout by TLC using eluent
benzene/acetone (8:2) and n-hexane/ethyl acetate/formic
acid (5:4:1). The yields of the final compounds were ran-
ging between 58 and 89% after recrystallization with
ethanol. The physical constants of oxadiazole analogues
(
4a-t) is given in Table 1. The structure of the final oxa-
diazole analogs (4a–t) was confirmed by IR, NMR, and
mass spectral data. The IR spectra of the oxadiazoles (4a–t)
afforded characteristic oxadiazole stretching (C–O–C) at
−
1
1
1
247–1261 cm , while C=N stretching was observed at
−
1
511–1519 cm . Similarly, the characteristics NH and OH
stretching were observed at band 3212–3219 and
−
1
3
407–3415 cm , respectively. The number of protons,
multiplicity (singlet/doublet/multiplet) and coupling con-
1
stant (J value in Hz) was observed by recording H NMR in
DMSO-d at 400 MHz, using tetramethyl silane (TMS) as
6
1
an internal standard. The H NMR showed a singlet at δ
2
.12–2.14 ppm for the corresponding methyl group (–CH3);
a singlet at δ 3.67–3.86 ppm for the corresponding methoxy
group (OCH ), a singlet at δ 4.11–4.19 ppm corresponding
3
to methylene (–CH –) linkage for the compounds (4k–t); a
2

Med Chem Res
Table 1 The physical constants of oxadiazole analogs (4a–t)
1
2
*
f
S. no.
Compounds
R
R
R
% Yield
Mp (°C)
a
a
a
a
a
a
a
a
a
a
b
b
b
b
b
b
b
b
b
b
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
2-Methoxy-
2-Methoxy-
2-Methoxy-
2-Methoxy-
2,5-Dimethoxy-
2,5-Dimethoxy-
2,5-Dimethoxy-
2,5-Dimethoxy-
2,5-Dimethoxy-
2,5-Dimethoxy-
2-Methoxy-
2-Methoxy-
2,5-Dimethoxy-
4-Methyl-
4-Fluoro-
0.77
0.71
0.78
0.88
0.72
0.86
0.89
0.80
0.86
0.82
0.76
0.85
0.83
0.84
0.78
0.80
0.74
0.81
0.82
0.77
62
88
74
72
82
77
58
69
72
72
76
72
77
89
76
72
67
62
78
67
160–162
210–212
196–198
166–168
216–218
168–170
160–162
178–180
180–182
208–210
118–120
126–128
112–114
140–142
112–114
158–160
70–72
4-Chloro-
4-Hydroxy-
4-Methoxy-
4-Chloro-
4-Methoxy-
4g
4h
4i
4-Hydroxy-
3,4-Dimethoxy-
4-Hydroxy-3-methoxy-
3,4,5-Trimethoxy-
4-Chloro-
10
11
12
13
14
15
16
17
18
19
20
4j
4k
4l
4-Methoxy-
4m
4n
4o
4p
4q
4r
4s
4t
3,4-Dimethoxy-
4-Chloro-
4-Methyl-
4-Hydroxy-
4-Methyl-
4-Methoxy-
4-Methyl-
3,4-Dimethoxy-
4-Hydroxy-3-methoxy-
2,3,4-Trimethoxy-
2-Furyl-
4-Methyl-
120–122
110–112
108–110
4-Methyl-
4-Methyl-
*
Mobile phase
a
Benzene:acetone (8:2)
b
n-Hexane:ethyl acetate:formic acid (5:4:1)
Table 2 The antiproliferative activity of oxadiazole analogs (4a-t)
Compound/NSC Code Cancer cell lines assay in single dose assay 10 µM concentration
Mean GP
96.50
Range of GP
The most sensitive cell lines
GP
% GI
4
a NSC 791191
75.73 to 108.84
MCF7 (breast cancer)
75.73
24.27
22.70
15.08
14.27
14.26
13.63
109.62
105.90
91.94
88.30
86.02
NCI-H522 (non-small cell lung cancer)
EKVX (non-small cell lung cancer)
UO-31 (renal cancer)
77.30
84.92
85.73
85.74
86.37
−9.62
−5.90
8.06
SR (leukemia)
A549/ATCC (non-small cell lung cancer)
HL-60(TB) (leukemia)
4
b NSC 791192
45.20
−9.62 to 91.06
MDA-MB-435 (melanoma)
OVCAR-3 (ovarian cancer)
K-562 (leukemia)
11.70
13.98
MDA-MB-468 (breast cancer)

Med Chem Res
Table 2 continued
Compound/NSC Code
Cancer cell lines assay in single dose assay 10 µM concentration
Mean GP
Range of GP
The most sensitive cell lines
GP
% GI
HT29 (colon cancer)
16.05
15.69
83.95
84.31
80.52
78.65
77.06
73.26
72.30
19.99
15.67
14.57
13.44
11.69
9.98
4c NSC 791194
4d NSC 793124
4eNSC 790149
4fNSC 790150
4g NSC 790152
4h NSC 790151
4i NSC 790153
4j NSC 790159
56.73
15.69 to 104.42
UO-31 (renal cancer)
MDA-MB-435 (melanoma)
KM12 (colon cancer)
19.48
21.35
22.94
26.74
27.70
80.01
84.33
85.43
86.56
88.31
90.02
2.55
K-562 (leukemia)
A498 (renal cancer)
SR (leukemia)
98.56
71.78
104.27
95.10
101.75
65.37
98.20
80.01 to 112.66
2.55 to 108.04
82.37 to 122.94
49.39 to 119.70
87.93 to 120.77
6.18 to 117.08
76.60 to 121.35
UO-31 (renal cancer)
A549/ATCC (non-small cell lung cancer)
NCI-H522 (non-small cell lung cancer)
RXF 393 (renal cancer)
T-47D (breast cancer)
UACC-62 (melanoma)
U251 (CNS cancer)
97.45
89.54
81.19
73.56
70.8
OVCAR-4 (ovarian cancer)
NCI-H460 (non-small cell lung cancer)
10.46
18.81
26.44
29.20
30.78
82.37
82.78
85.06
88.75
89.26
92.64
49.39
57.72
59.19
59.42
68.69
74.69
87.93
89.77
91.68
92.11
92.62
92.72
6.18
7
86-O (renal cancer)
SF295 (CNS cancer)
ACHN (renal cancer)
69.22
17.63
17.22
14.94
11.25
10.74
7.36
TK-10 (renal cancer)
NCI-H522 (non-small cell lung cancer)
7
86-O (renal cancer)
HT29 (colon cancer)
T-47D (breast cancer)
MOLT-4 (leukemia)
SNB-75 (CNS cancer)
KM12 (colon cancer)
SF-539 (CNS cancer)
UO-31 (renal cancer)
SN12C (renal cancer)
ACHN (renal cancer)
HT29 (colon cancer)
K-562 (leukemia)
50.61
42.28
40.81
40.58
31.31
25.31
12.07
10.23
8.32
HL-60(TB) (leukemia)
NCI-H23 (non-small cell lung cancer)
T-47D (breast cancer)
TK-10 (renal cancer)
A498 (renal cancer)
7.89
7.38
7.28
93.82
85.21
84.77
80.05
79.72
79.63
23.40
17.79
15.89
13.24
TK-10 (renal cancer)
SNB-75 (CNS cancer)
IGROV1 (ovarian cancer)
UO-31 (renal cancer)
KM12 (colon cancer)
NCI-H522 (non-small cell lung cancer)
T-47D (breast cancer)
MOLT-4 (leukemia)
14.79
15.23
19.95
20.28
20.37
76.60
82.21
84.11
86.76
HT-29 (colon cancer)

Med Chem Res
Table 2 continued
Compound/NSC Code
Cancer cell lines assay in single dose assay 10 µM concentration
Mean GP
Range of GP
The most sensitive cell lines
GP
88.80
% GI
11.20
MALME-3M (melanoma)
SR (leukemia)
89.62
72.89
87.28
87.57
88.64
89.23
89.31
66.12
74.69
84.89
86.06
86.41
87.74
75.99
80.94
85.04
85.05
85.48
86.21
73.34
79.54
87.70
88.84
89.51
100.72
55.5
10.38
27.11
12.72
12.43
11.36
10.77
10.69
33.88
25.31
15.11
13.96
13.59
12.26
24.01
19.06
14.96
14.95
15.52
13.79
26.66
20.46
12.30
11.16
10.49
−0.72
44.5
4
4
4
4
k NSC 791196
l NSC 793123
m NSC 791285
n (NSC 790154)
97.87
72.89 to 117.98
UO-31 (renal cancer)
HOP-62 (non-small cell lung cancer)
PC-3 (prostate cancer)
LOX IMVI (melanoma)
NCI-H522 (non-small cell lung cancer)
SNB-75 (CNS cancer)
96.28
95.03
102.16
66.12 to 115.74
75.99 to 112.04
73.34 to 120.65
UO-31 (renal cancer)
NCI-H522 (non-small cell lung cancer)
SR (leukemia)
MOLT-4 (leukemia)
UACC-62 (melanoma)
MDA-MB-231/ATCC (breast cancer)
UO-31 (renal cancer)
A549/ATCC (non-small cell lung cancer)
SNB-75 (CNS cancer)
MCF7 (breast cancer)
HS 578T (breast cancer)
HOP-62 (non-small cell lung cancer)
UO-31 (renal cancer)
SNB-75 (CNS cancer)
NCI/ADR-RES (ovarian cancer)
MCF-7 (breast cancer)
NCI-H226 (non-small cell lung cancer)
MDA-MB-231/ATCC (breast cancer)
MCF-7 (breast cancer)
4
4
4
4
4
4
o
76.0
55.5 to 96.5
41.2 to 74.2
46 to 107.7
MDA-MB-231 (breast cancer)
MCF-7 (breast cancer)
96.5
3.5
p
57.7
41.2
58.8
MDA-MB-231 (breast cancer)
MCF-7 (breast cancer)
74.2
25.8
q
99.85
85.35
84.65
98.46
46.0
54.0
MDA-MB-231 (breast cancer)
MCF-7 (breast cancer)
107.7
51.3
−7.7
48.7
r
51.3 to 119.4
45.1 to 124.2
68.32 to 127.33
MDA-MB-231 (breast cancer)
MCF-7 (breast cancer)
119.4
45.1
−19.4
54.9
s
MDA-MB-231 (breast cancer)
UO-31 (renal cancer)
124.2
68.32
79.56
80.24
82.41
82.93
86.57
52.9
−24.2
31.68
20.44
19.76
17.59
17.07
13.43
47.1
t (NSC 790155)
SNB-75 (CNS cancer)
HOP-92 (non-small cell lung cancer)
KM12 (colon cancer)
T-47D (breast cancer)
IGROV1 (ovarian cancer)
HT29 (colon cancer)
Imatinib NSC 759854
94.56
42.21
52.9 to 122.8
HOP-92 (non-small cell lung cancer)
MDA-MB-468 (breast cancer)
SF-539 (CNS cancer)
56.3
43.7
70.9
29.1
75.5
24.5
5
-Fluorouracil
−19.6 to 95.5
SF-539 (CNS cancer)
−19.6
119.6

Med Chem Res
Table 2 continued
Compound/NSC Code
Cancer cell lines assay in single dose assay 10 µM concentration
Mean GP
Range of GP
The most sensitive cell lines
GP
% GI
HCC-2998 (colon cancer)
A498 (renal cancer)
−17.8
−16.3
−10.8
11.5
117.8
116.3
110.8
88.5
HS 578T (breast cancer)
MCF7 (breast cancer)
NCI-H460 (non-small cell lung cancer)
13.0
87.0
The compound showed percent growth inhibition ≥ 68%, is active for that particular cell line (bold figure). The compounds 4a–n and 4t were
evaluated on NCI 60 cancer cell line while compounds 4o–s was evaluated on two breast cancer cell lines. The data of one dose assay for Imatinib
and 5-FU was taken from the NCI database compound ID NSC 759854 and NSC 19893 (https://dtp.cancer.gov/dtpstandard/servlet/MeanGra
phSummary)
GP growth percent, %GI percent growth inhibition
Table 3 NCI: DTP, The percent growth inhibition (% GI) of testing
Table 3 continued
compounds (4b, 4c, 4e, and 4i) over the full panel of tumor cell lines at
a single dose (10 µM)
Panel
Cell lines
4b
4c
4e
4i
Panel
Cell lines
4b
4c
4e
4i
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
786-O
65.63 18.57 3.13
3.73
35.95 23.18 −1.58 −8.31
62.37 34.88 −4.17 28.37
34.18 7.85 −3.96 −15.27
Leukemia
CCRF-CEM
HL-60(TB)
K-562
62.03 55.88 −8.04 11.43
109.62 36.97 5.25 12.67
88.30 77.06 16.5
67.67
48.21 28.84 2.47
3.3
RPMI-8226
MOLT-4
SR
80.50 68.98 9.58 24.97
70.76 57.54 11.53 39.22
80.27 72.30 20.35 47.65
65.61 36.90 55.26 24.47
Ovarian cancer
47.25 43.12 18.92 80.05
91.94 34.52 68.18 29.45
31.74 39.79 89.54 36.86
13.47 19.04 17.57 29.97
39.85 29.40 14.53 16.43
79.22 49.08 28.15 31.26
52.29 50.35 9.28 46.65
24.24 39.74 73.56 63.31
54.71 73.26 4.02 93.82
27.82 54.98 69.22 62.05
25.43 59.26 9.57 47.34
40.45 49.07 9.87 66.04
31.07 36.44 64.01 85.21
30.5 84.31 48.16 79.72
Non-small cell lung A549/ATCC
cancer
EKVX
49.22 53.77 17.5
17.52
HOP-62
52.59 37.33 53.28 22.37
8.94 25.73 0.03 14.88
26.36 30.52 6.17 22.89
HOP-92
Renal cancer
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
A498
36.12 63.88 25
29.25
ACHN
29.54 70.46 43.06 13.08
83.90 16.1 81.19 17.24
83.35 16.65 10.08 38.92
64.69 −4.42 0.88 −17.08
RXF 393
SN12C
TK-10
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
UO-31
18
14.78 −4.08
9.44
Prostate cancer
Breast cancer
PC-3
43.31 38.7 11.6
25.15
65.91 31.38 68.88 36.18
DU-145
27.71 36.86 30.03 48.58
66.94 50.47 4.04 53.49
MCF7
82.88 71.32 8.36 22.26
83.95 0.05 51.06
76.06 78.65 33.6
0.99
MDA-MB-231/
ATCC
36.5 44.17 14.4
30.56
KM12
79.63
SW-620
SF-268
79.14 40.99 13.76 21.41
39.49 40.30 44.65 31.19
59.71 39.65 70.80 −0.15
42.94 63.59 49.27 50.09
53.55 27.3 41.64 30.05
44.94 61.23 40.62 84.77
65.58 43.81 97.45 34.93
48.29 45.02 26.19 56.68
53.72 24.86 33.15 20.09
HS 578T
BT-549
T-47D
35.49 60.87 48.65 60.43
43.08 26.15 18.07 20.63
67.58 61.07 40.14 56.06
86.02 51.00 25.75 28.32
54.80 43.27 28.22 34.63
CNS cancer
SF-295
SF-539
MDA-MB-468
–
SNB-19
SNB-75
U251
Mean
The compound showed percent growth inhibition ≥ 68%, is active for
that particular cell line (bold figure)
Melanoma
LOX IMVI
MALME-3M
M14
78.25 46.1
6.87 25.36
better antiproliferative activity than the standard drugs 5-FU
and Imatinib on leukemia, melanoma and ovarian cancer.
Similarly the compound 4e and 4i showed better anti-
proliferative activity the standard drugs 5-FU and Imatinib
MDA-MB-435
105.9 80.52 15.37 15

Med Chem Res
Fig. 3 The calculated average %
GI of 4b, 4c, 4e, 4i, 5-
Fluorouracil and Imatinib at 10
80
70
µM drug concentration
60
%
%
GI of 4b
GI of 4c
50
40
30
20
10
0
% GI of 4e
%
%
%
GI of 4i
GI of 5-FU
GI of Imatinib
Leukemia Non-Small Colon
Cell Lung Cancer
Cancer
CNS
Cancer
Melanoma Ovarian
Cancer
Renal
Cancer
Prostate
Cancer
Breast
Cancer
-
10
20
-
Table 4 The average percent
growth inhibitions (GIs) of 4b,
Panel
% GI of 4b % GI of 4c % GI of 4e % GI of 4i % GI of 5-FU % GI of Imatinib
4
c, 4e, 4i, 5-Fluorouracil and
Leukemia
71.01
61.12
37.47
30.27
45.98
34.37
39.32
56.73
37.78
52.52
7.73
27.19
21.04
12.01
38.48
3.15
57.23
51.23
73.63
51.57
55.2
9
Imatinib
Non-small cell lung cancer 48.41
30.86
24.02
57.41
9.29
15.68
5.34
Colon cancer
CNS cancer
64.96
51.04
59.76
52.66
33.46
35.51
53.11
5.80
Melanoma
2.02
Ovarian cancer
Renal Cancer
Prostate cancer
Breast cancer
35.17
39.77
20.82
25.89
38.67
71.64
36.87
36.38
45.44
61.69
53.15
65.34
−7.15
3.86
12.50
12.15
Bold figure shows higher activity
GP growth percent, %GI percent growth inhibition
Table 5 The percent growth
control of oxadiazole analogs
Compound
MCF-7
MDA-MB-231
10−7 10−6
10−
7
M
10−6
M
10−5
55.5
M
10−4
−8.5
M
M
M
10−5
96.5
M
10−4
30.5
M
(4o-s) at different molar
concentrations
4
4
4
4
4
o
p
q
r
82.5
69.9
73.9
63.0
62.9
10.9
92.8
61.2
80.4
80.7
80.5
33.6
124.9
122.9
121.6
120.7
123.7
40.0
112.6
101.9
116.5
121.6
122.1
37.3
41.2
46.0
−23.1
36.8
74.2
107.7
124.2
119.4
−21.9
15.1
150.2
74.0
51.3
19.4
s
45.1
16.9
65.0
ADR
−50.7
−56.4
−29.4
ADR adriamycin
on CNS cancer and renal cancer, respectively. The percent
GIs of the compounds 4b, 4c, 4e, 4i and the standard drugs
Imatinib and 5-FU was compared and the results are shown
in Fig. 2. The compounds 4b, 4c, 4e and 4i showed better
percent GIs than the standard drug imatinib on nearly 49,
GP = 45.20) was found to be comparable to that of the
standard drug 5-FU (mean GP = 42.21). The compound, 4b
showed better percent GIs than 5-FU, on 24 cancer cell
lines. The antiproliferative activity of 4b, 4c, 4e, 4i, Ima-
tinib and 5-FU in terms of percents GIs is shown in Fig. 3.
The data of one dose assay for Imatinib and 5-FU was taken
from the NCI database compound ID NSC 759854 and
NSC 19893, respectively for comparison study (https://dtp.
cancer.gov/dtpstandard/servlet/MeanGraphSummary). Rest
of the compounds (4o-s) were evaluated for antiproliferative
activity on the breast cancer cell lines (MCF-7 and MDA-
4
7, 40 and 44 cancer cell lines among the common 50
cancer cells. The antiproliferative activity of the com-
pounds, 4e and 4i was found to be less, while the anti-
proliferative activity of the compound, 4c was found to be
moderate when compared with the standard drug 5-FU.
The antiproliferative activity of the compound, 4b (mean

Med Chem Res
1
1
1
40
20
00
4
4
4
4
b
c
e
i
8
6
4
2
0
0
0
0
0
%
GI Imatinib
5
-FU
-
-
20
40
Leukemia
Non-Small Cell Lung Cancer
Colon Cancer
CNS Cancer
1
1
1
40
20
00
8
6
4
2
0
0
0
0
0
4
4
4
b
c
e
4i
%
GI Imatinib
5
-FU
-
-
20
40
Melanoma
Ovarian Cancer
Renal Cancer
Prostate
Cancer
Breast Cancer
Fig. 4 The comparison of % GI shown by compounds, 4b, 4c, 4e, 4i, 5-FU and Imatinib against the NCI human cancer cell lines in common at 10
µM
Table 6 LC50, TGI, and GI50 of
quinoline analogs (4o–s) against
Compound
Drug concentrations calculated from graph (µM)
two breast cancer cell lines
MCF-7
LC50
MDA-MB-231
TGI
GI50
LC50
TGI
GI50
4
4
4
4
4
o
p
q
r
>100
>100
>100
>100
>100
82.9
89.0
71.6
>100
>100
>100
2.7
33.9
12.9
55.3
35.2
30.5
<0.1
>100
>100
NE
>100
>100
NE
76.0
59.3
>100
>100
>100
<0.1
>100
>100
>100
>100
>100
39.6
s
ADR
ADR adriamycin, GI50 is the concentration of drug that results in reduction of 50% protein increase, LC50 is
the concentration of drug that results in reduction of 50% of cells, TGI is the concentration of drug that
results in total growth inhibition

Med Chem Res
a
MB-231) as per the sulforhodamine B assay (SRB assay)
Vichai and Kirtikara 2006). The compounds, 4o-s were
Growth curve: Breast cancer cell line MCF-7
1
1
50
00
(
4
4
4
4
4
h
i
−7
−6
tested at four different drug concentrations (10 , 10
,
−
5
−4
10 , and 10 ) and percent growth control was recorded
5
0
0
j
for each compounds is given in Table 5 while the growth
control curves on breast cancer cell line at molar drug
concentrations are given in Fig. 4a (MCF-7) and 4b (MDA-
MB-231). Three dose related parameters, LC , TGI and
k
m
0
.1 µM
1 µM
10 µM
100 µM
-
50
Molar Drug Concentrations
ADR
-
100
5
0
GI50 were also calculated for each compound (4o-s)
(Table 6). The GI50 was found to be 12.9 to 55.3 µM on
MCF-7 cancer cell line while GI50 was found to be 59.3 to
> 100 µM on MDA-MB-231. The compound 4p demon-
strated significant antiproliferative activity with GI50 of 12.9
and 59.3 µM on MCF-7 and MDA-MB-231 cancer cell
lines, respectively. The LC50 was observed to be > 100 µM
for both the cancer cell lines and the TGI values were
ranging from 71.6 to > 100 µM for MCF-7 and > 100 µM
for MDA-MB-231 cancer cell lines (Fig. 5). The images of
growth control on breast cancer cell lines (MCF-7 and
MDA-MB-231) for some the compounds (4o-s) are given in
Fig. 6. The introduction of methylene group can alter the
b
Growth curve: Breast cancer cell line MDA-MB-231
2
1
1
00
50
00
4
h
i
4
4
4
4
j
k
m
5
0
0
ADR
0
.1 µM
1 µM
10 µM
100 µM
-
50
Molar Drug Concentrations
Fig. 5 a Growth curve of oxadiazole analogs on MCF-7 at molar drug
concentrations. b Growth curve of oxadiazole analogs on MDA-MB-
31 at molar drug concentrations
2
Fig. 6 The images of growth
control on MCF-7 and MDA-
MB-231 for some of the
compounds
MCF-7 (Control)
MCF-7; Compound 4o (GI50 = 33.9 MCF-7; Compound 4p (GI50
µM) 12.9 µM)
=
MCF-7; Compound 4r (GI50 = 35.2 MCF-7; Compound 4s (GI50 = 30.5 MCF-7; Adriamycin (GI50 = <0.1
µM)
µM)
µM)
MDA-MB-231 (Control)
MDA-MB-231; Compound 4p
MDA-MB-231; Adriamycin (GI50
= <0.1 µM)
(
GI50 = 59.3 µM)

Med Chem Res
Table 7 In vitro free radical scavenging activities of oxadiazole
analogs (4a–s)
biological activity but not always promising as shown in the
present investigation, however further investigations are in
progress in our laboratory to establish this fact.
S. no.
Compounds
Free radical scavenging
activity IC50 (μM)
The antiproliferative data was taken into consideration to
establish the structure activity relationship (SAR). The
oxadiazole linked aryl nucleus with 4-chloro substitution
showed maximum anticancer activity and followed by 4-
hydroxy, 3-methoxy-4-hydroxy, 3,4-dimethoxy, 2,3,4-
trimethoxy, 4-hydroxy and 4-methoxy substitutions on
phenyl ring. The order of pharmacological activity followed
as 4-Cl > 3-OCH -4-OH, > 3,4-(OCH ) > 2,3,4-(OCH ) >
1
2
3
4
5
6
7
8
9
4a
35.67 ± 2.38
21.07 ± 1.30
15.58 ± 0.91
28.25 ± 1.46
47.27 ± 1.14
55.46 ± 2.00
18.65 ± 0.65
31.47 ± 1.53
23.23 ± 1.90
49.85 ± 1.92
26.30 ± 1.14
42.24 ± 1.16
22.48 ± 1.49
37.58 ± 1.68
20.32 ± 1.60
57.14 ± 1.90
32.06 ± 1.71
26.54 ± 1.44
35.92 ± 0.69
44.61 ± 1.77
12.91 ± 0.66
4b
4c
4d
4e
4f
3
3 2
3 3
4g
4
-OH > 4-OCH . Also 2-methoxy substitution showed
3
4h
comparatively higher activity than 2,5-dimethoxy substitu-
tion and 4-methyl substitution on the amino phenyl ring.
4i
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
4j
4k
In vitro free radical scavenging activities
4l
4m
Since cancer and imbalance of oxidative stress share aspects
of their underlying pathophysiology therefore, some anti-
oxidants are equally effective antiproliferative agents (Rahal
et al. 2014; Milkovic et al. 2014). Therefore, the antioxidant
potential of the all the synthesized compounds was also
evaluated by the DPPH assay and compared with the stan-
dard ascorbic acid (Koleva et al. 2002). Among the twenty
compounds tested, three compounds 4c (R = 2-OCH , R =
4n
4o
4p
4q
18
19
20
21
4r
4s
4t
1
3
2
4
-OH), 4g (R = 2,5-(OCH ) , R = 4-OH) and 4o (R = 4-
Ascorbic acid
1
3 2
2
1
CH , R = 4-OH) showed promising free radical scavenging
3
2
activities having IC50 values of 15.58 ± 0.91, 18.65 ± 0.65,
and 20.32 ± 1.60 µM, respectively compared to standard
ascorbic acid (12.91 ± 0.66 µM). These results clearly
demonstrate that the substitutions on the distal phenyl rings
greatly influenced the antioxidant potential of oxadiazole
analogs. The increased free radical-scavenging activity of
aforesaid compounds might be due to the hydrogen-donating
ability of phenolic compounds and the stability of phenoxyl
radicals formed after the dehydrogenation. In vitro free
radical scavenging activities of oxadiazole analogues (4a-
s) is given in Table 7 and shown in Fig. 7.
Free radical scavenging activity
70
60
50
40
30
20
10
0
Compounds
Fig. 7 In vitro free radical scavenging activities in micro molar con-
centrations (µM) of oxadiazole analogs (4a–t)
Molecular docking studies
Tubulin is one of the important and attractive targets of
anticancer drugs. Many of the anticancer drugs like col-
chicine, combretastatins, vincristine, vinblastine etc. are
inhibitors of tubulin polymerization. The oxadiazole ana-
logs reported in the present investigation were designed
based on the structure of tubulin inhibitor IMC-038525
hence tubulin was chosen as putative target and molecular
docking against tubulin was carried out for these oxadia-
zoles. In our previous investigation some of the oxadiazoles
moderately inhibited the tubulin (Ahsan et al. 2017). Other
investigation also reported tubulin as a potential target for
oxadiazole analogs (Abdel-Aziz et al. 2016; Kamal et al.
2016; Ouyang et al. 2006). The most active compound (4b)
showed good interaction with the residues Lys254, Ala250,
Cys241, Val318, Ala316, Asn258, and Lys352 present in
the hydrophobic cavity of tubulin. Similarly the compound,
4c showed good interaction with the residues Ala250,
Cys241, Val318, Ala316, Asn258, Leu265, and Lys352, the
compound, 4e showed good interaction with the residues
Ala250, Cys241, Leu255, Lys254, Val318, Ala316,
Asn258, Thr353, Ala317, and Lys352, and compound, 4i
showed good interaction with the residues Cys241, Val318,
Ala316, Asn258, Leu255, Thy353, Lys254, and Lys352.

Med Chem Res
Fig. 8 An overview of compounds 4b and 4c, with the tubulin at colchicine binding site (a) and the binding mode of the compounds 4b (b), 4c (c),
4
e (d), and 4i (e)

Med Chem Res
Table 8 The molecular
properties prediction and
molecular docking scores of
oxadiazole analogs (4a–t)
S. no. Compound
MW
HBA HBD Log P NROTB Lipinski’s violation Docking score
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
4a
285.28
301.73
283.29
297.31
331.76
327.12
313.11
357.13
343.12
387.14
315.76
311.34
371.39
299.08
281.12
295.13
325.14
311.13
355.15
331.13
–
5
5
6
6
5
6
6
7
7
8
5
6
8
3
4
4
5
5
6
4
–
1
1
2
1
1
1
2
1
2
1
1
1
1
1
2
1
1
2
1
1
–
4.09
4.61
3.45
3.99
3.83
3.27
2.86
3.18
2.83
3.15
3.30
2.68
2.31
3.98
3.00
3.35
3.32
2.97
3.29
4.30
–
4
4
4
5
5
6
5
7
6
8
5
6
8
4
4
5
5
5
7
5
–
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
–
−6.241
−5.254
−6.332
−6.512
−5.500
−7.006
−6.571
−7.010
−6.524
−5.813
−6.224
−5.897
−6.964
−6.502
−6.245
−6.517
−5.630
−6.435
−5.450
−5.536
−6.302
4b
4c
4d
4e
4f
4g
4h
4i
0
1
2
3
4
5
6
7
8
9
0
1
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
IMC-038525
MW molecular weight, HBA hydrogen bond acceptors, HBD hydrogen bond donors, Log P logarithm of
partition coefficient between n-butanol and water, NROTB number of rotatable bonds
An overview and the binding mode of the compounds 4b,
c, 4e, and 4i are shown in Fig. 8. The SP docking scores of
the compounds 4b, 4c, and IMC-038525 were found to be
5.254, −6.332, and −6.302, respectively. The docking
score of the compound, 4b was found to be higher than the
remaining compounds and IMC-038525. The docking
scores of all the ligands are given in Table 8.
which states that a good bioavailability can be achieved for
molecules having the Log P value ≤ 5, molecular weight ≤
500, number of hydrogen bond acceptor ≤ 10, number of
hydrogen bond donor ≤ 5 (Lipinski et al. 2001). In the
present investigations the molecular weights of the oxa-
diazoles were ranging between 281.12 and 387.14 (MW <
500), the Log P values ranging between 2.31 and 4.61 (Log
P ≤ 5), the hydrogen bond acceptors ranging between 5 and
8 (≤10), and hydrogen bond donors ranging between 1 and
4
−
Molecular properties prediction
2
(≤5). The numbers of rotatable bonds were ranging
Many of the drugs failed to reach the market due to their
low bioavailability, lipophilicity, solubility and pharmaco-
kinetic properties. The bioavailability can be improved by
increasing lipophilicity, reduced molecular flexibility, low
polar surface area etc. The membrane permeability and
bioavailability are more often associated with some of the
basic molecular descriptors including partition co-efficient
between 4 and 8 (≤10). Hence none of the compounds (4a–
t) showed any violations of Lipinski’s rule of five making
them potentially promising agents. The calculated mole-
cular properties predictions are given in Table 8.
Conclusion
(
Log P ≤ 5), molecular weight (MW ≤ 500), and hydrogen
bond donors (≤5)/acceptors (≤10) etc (Refsgaard et al.
005; Ertl et al. 2000; Ahsan et al. 2011). The numbers of
Two new series of oxadiazole analogs were synthesized in
satisfactory yield. Fifteen oxadiazole analogs (4a–n and 4t)
were evaluated for their antiproliferative activity as per the
NCI US standard protocol, while the remaining five com-
pounds, (4o–s) were evaluated for antiproliferative activity
on two breast cancer cell lines as per Sulforhodamine B
assay. Some of the oxadiazoles (compounds 4b, 4c, 4e, and
2
rotatable bonds are important for conformational changes in
the molecule and should not be more than ten. All the
oxadiazoles (4a–t) were subjected to computational studies
for the predication of ADME properties. The Lipinski’s rule
of five was also calculated for each of the compounds,

Med Chem Res
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4
i) showed significant antiproliferative activity in one dose
assay at 10 µM. The compounds 4b, 4c, 4e, and 4i showed
better antiproliferative activity that of the standard drug
Imatinib, however only the antiproliferative activity of
compound 4b was found to be nearly similar than the
standard drug 5-Fluorouracil. The compound 4p showed
significant antiproliferative activity with GI50 of 12.9 µM
(
MCF-7) and 59.3 µM (MDA-MB-231). The antioxidant
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these analogs could be modified to increase the biological
profile. Further investigation in this area is going on our
research laboratory. All these information could be of great
help in the anticancer drug discovery.
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5:2817–2826
J Med Chem
4
The experimental section containing synthetic procedures
and characterization data for all compounds synthesized in
this work, as well as the NMR and mass spectra. The pro-
cedure to evaluate the antiproliferative activity as well as
the antiproliferative activity screening data is provided as
Supporting information.
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Acknowledgements Antiproliferative data were provided by
National Cancer Institute (NCI US), Bethesda, MD, USA. We are
grateful for all help provided by Prof. Doug Smallwood and Mr.
Mohammed Nayel NCI US, Bethesda, MD, USA. The people holding
the management of Maharishi Arvind College of Pharmacy, Jaipur,
Rajasthan, India is acknowledged for providing research facilities. We
are also grateful to DRILS, Hyderabad, and SAIF, Punjab University,
Chandigarh, India for providing spectral data of synthesized
compounds.
Compliance with ethical standards
Finger GC, Dickerson DR, Starr LD, Orlopp DE (1965) Aromatic
fluorine compounds. XIII. Substituted N-phenylglycine ethyl
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Conflict of interest The authors declare that they have no competing
interests.
Imatinib NSC 759854 and 5-Fluorouracil NSC 19893. https://dtp.ca
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