Design and Synthesis of Novel 1a,3,4-Oxadiazole Derivatives as Cytotoxic Agents: A Combined Experimental and Docking Study

Article abstract of DOI:10.1134/S1070428020050280

Abstract: A novel series of 3,5-disubstituted-1a,3,4-oxadiazole derivatives was synthesized and screened for in vitro anticancer activity. The newly synthesized compounds were characterized by ¹H, ¹³C NMR, IR spectroscopy and mass sp

Full text of DOI:10.1134/S1070428020050280

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 5, pp. 924–934. © Pleiades Publishing, Ltd., 2020.
Design and Synthesis of Novel 1a,3,4-Oxadiazole Derivatives
as Cytotoxic Agents: A Combined Experimental
and Docking Study
P. Perlaa,b, N. Seelama,*, and R. Berab
a Department of Chemistry, Koneru Lakshmaiah Education Foundation, Green Fields, Vaddeswaram, 522502 India
b United States Pharmacopeia India Pvt. Ltd., IKP Knowledge Park, Genome Valley,
Turkapally Village, Hyderabad, 500101 India
*e-mail: pullaraoperla.klu@gmail.com
Received August 19, 2019; revised October 11, 2019; accepted December 20, 2019
Abstract—A novel series of 3,5-disubstituted-1a,3,4-oxadiazole derivatives was synthesized and screened for in
1
vitro anticancer activity. The newly synthesized compounds were characterized by H, 13C NMR, IR spectros-
copy and mass spectrometry. Among all the synthesized compounds, Oxaprozin derivatives containing 1,3,4-oxa-
diazole ring with 4-fluorobenzyl, 4-methoxybenzyl, methyl, and butyl substituents showed promising anticancer
activity against HTB-57 cancer cell line, and derivatives with 4-fluorobenzyl, 4-methoxybenzyl, and propyl sub-
stituents exhibited a higher anticancer activity against a PPC-1 cell line. The possible binding mode interactions
of the synthesized compounds with the key active site of the proline rich tyrosine kinase 2 Pyk2 receptor (PDB
ID: 5TO8) were investigated using theAutoDock 4.2 docking protocol to find that the 1,3,4-oxadiazole Oxaprozin
derivatives with methyl, ethyl, and propyl substituents had the highest binding energies (ΔG = –7.8, –7.6, and
–6.8 kcal/mol, respectively) with Glu441, Leu431, Ala455, Val487, Met502, Leu556, Lys457, and Glu509.
Keywords: oxaprozin, 1,3,4-oxadiazole, anticancer activity, molecular docking, 5TO8
DOI: 10.1134/S1070428020050280
INTRODUCTION
spectrum biological activity profiles [4] owing to the
presence of an NCO oxophoric linkage. Several methods
for facile construction of the oxadiazole scaffold have
been developed [5]. Symmetrically and unsymmetrically
2,5-disubstituted oxadiazole derivatives have been
encompassed with promising pharmacological profiles,
such as antitubercular [6], antimicrobial [7], anticancer
[8], antiepileptic [9], antifungal [10], analgesic [11],
antitumor [12], etc. Compounds comprising oxadiazole
as a core nucleus are in late stages of clinical trials,
for example, Zibotentan, Ataluren and Raltegravir,
or are already used as important non-steroidal anti-
inflammatory drugs (NSAIDs), for example Naproxen,
Meloxicam,andIndometacin.Someoxadiazolesarevery
good bioisosteres of esters and amides, which ensures
stronger hydrogen bonding with different receptors
and, as a result, much enhancing biological responses.
On the other hand, the therapeutic use of Oxaprozin
[3-(4,5-diphenyl-1,3-oxazol-2-yl)propanoic acid], one
of the leading NSAIDs in the global clinical market,
Cancerremainsthesecondmajorchallengingmedical
disorder among the causes of morbidity and mortality
worldwide. However, the existing chemotherapy
regimens are unsuccessful to meet the expectations and
lead to unsatisfactory results [1]. According to the WHO
estimates, about 17.1 million new cases and 9.6 million
death cases related to cancer were registered in 2018 [2].
Hence, there is a clinical urgency for addressing these
issues and generating suitable candidates with newer
modes of action and fewer or no side effects for cancer
therapy. In view of the wide prevalence of multidrug-
resistant Gram-positive and Gram-negative pathogenic
bacteria that cause life-threatening infections in living
organisms, thereby forming acquired resistance to many
existing drugs, the desperate need in miracle agents [3]
to treat such infections becomes even more obvious.
The 1,3,4-oxadiazole pharmacophore has gained
much attention over the past years due to its broad-
924

DESIGN AND SYNTHESIS OF NOVEL 1a,3,4-OXADIAZOLE DERIVATIVES AS CYTOTOXIC AGENTS
925
Scheme 1.
Cl
O
S
O
OH
OH
N
N
H
O
O
N
OH
O
S
O
O
O
Naproxen, NSAIDs
H3C O
NH
Meloxicam, NSAIDs
Indometacin, NSAIDs
O
F
O
N
O
N
N
O
CH3
N
H
N
O
H
N
S
N
N
O
N
N
OH
O
F
O
H3C
OH
H3C
O
N
N
N
Zibotentan
(anticancer agent)
Ataluren
(cystic fibrosis agent)
Raltegravir
(antiretroviral agent)
is restricted by its side effects, such as gastrointestinal
injury(GI),pepticulceration,andperforation,developing
due to the presence of the corrosive carboxylic group, as
well as considerable damage to the renal system [13]
(Scheme 1).
of H2SO4 as a catalyst. The subsequent hydrazinolysis
of compound 2 with 100% hydrazine hydrate in
methanol under reflux provided hydrazide 3 [15]. The
intermolecular cyclization of the latter with CS2 in
boiling ethanol under strongly basic conditions gave
the key 1,3,4-oxadiazole intermediate 4 in a good yield.
Finally, compound 4 was reacted with electrophilic
halides 5a–5m in K2CO3 at ambient temperature for
7–9h to obtain the corresponding target products 6a–6m
in excellent yields.
As part of our work on the identification of
dormant heterocyclic scaffolds, we have designed the
synthesis of hybrid template 6, starting from Oxaprozin
(Scheme 2). To mask the potential side effects of
the carboxylic motif of Oxaprozin, we obtained its
1,3,4-oxadiazole bio- isostere for safer profiles. Different
substituents were introduced in the other vacant position
of the oxadiazole ring via C–N bond formation, which
was expected to enhance the lipophilicity of the
resulting derivatives and improve their pharmacokinetic
properties by facilitating penetration into the cell wall.
The compositions and structures of the synthesized
compounds were confirmed by elemental analysis,
IR, 1H and 13C NMR spectroscopy, and mass
1
spectrometry. The H NMR spectrum of compound
6a displays signals at δ 11.31 ppm (NH) and 7.62–
7.27 ppm (aromatic protons). The 13C NMR spectrum
of compound 6a showed signals at δC 162.63 (C2) and
155.84 ppm (C5), providing evidence for the presence
of the 1,3,4-oxadiazole core, as well as at δC 141.02–
121.77 ppm (aromatic carbons). The IR spectrum of 6a
contained stretching absorption bands at 1483 [ν(C=N)],
1581 [ν(C=C)], and 1152 and 1052 cm−1 [ν(C−O−C)].
The latter two bands are assignable to the C−O−C
linkages in the oxadiazole and oxazole rings. The mass
spectrum displayed a molecular ion peak at m/z 440.6
[M + 1]+, which confirmed the molecular weight of
3-benzyl-5-[2-(4,5-diphenyloxazol-2-yl)ethyl]-1,3,4-
oxadiazole-2(3H)-thione.
The aim of this work was to combine the oxaprozin
and 1,3,4-oxadiazole rings in one compact structure
for the purpose of synergism. We also extended our
effort to a molecular docking study of this biologically
interesting, from the viewpoint of anticancer activity,
class of compounds [14].
RESULTS AND DISCUSSION
The hitherto unknown 1,3,4-oxadiazole derivatives
of Oxaprozin were synthesized by conventional
methods (Scheme 2). Ester 2 was prepared by refluxing
its acid precursor with methanol for 8 h in the presence
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 5 2020

926
PERLA et al.
Scheme 2.
i
ii
1
2
3
Oxaprozin
iii
iv
4
6a–6m
i, CH3OH, H2SO4, reflux, 7 h; ii, NH2NH2·H2O, CH3OH, reflux, 8 h;
iii, EtOH, KOH, CS2, reflux, 9 h; iv, RX (5a–5m), K2CO3, DMF, rt, 7–9 h.
5, 6, R = PhCH2 (a), p-FC6H4CH2 (b), p-PhCH2OC6H4CH2 (c), p-MeOC6H4CH2 (d),
p-ClC6H4CH2 (e), Me (f), Et (g), Pr (h), Bu (i), octyl (j), isobutyl (k), allyl (l), propargyl (m); 5, X = F, Cl.
Molecular docking study. The synthesized
oxadiazoles 6a–6m were identified as potent anticancer
agents, and, therefore, we considered it of interest to
employ molecular docking to simulate their interactions
with the catalytic domain of the proline-rich tyrosine
kinase 2Pyk2 and find the best binding conformations
[16]. The results of molecular docking simulation for
all the synthesized compounds are summarized in
Table 2. Three- and two-dimensional representations of
bonds between the protein and ligands are depicted in
Fig. 1.The amino acid residues Gly434, Phe435, Phe436,
Glu441, Lys457, Phe471, Glu508, Leu431, Ala455,
Val487 and Leu556 and Asp567 of the protein 5TO8
are involved in H-bonding and hydrophobic interactions
with almost all the ligand molecules. Ligands 6f, 6d,
and 6h showed the highest percentage inhibitions
(Table 1) and docking score binding energies (Table 2)
as compared to the other ligands.
Anticancer activity testing. In vitro cytotoxicity
of compounds 6 was assessed using MTT colorimetric
assay according to the ATCC protocol at 25 μM against
the PPC-1 prostate adenocarcinoma and HTB-57
lung adenocarcinoma cell lines. Doxorubicin (DXN)
was used as reference. The resulting data are listed in
Table 1. As seen from the table 1, all the test compounds,
except for 6k, demonstrated a higher activity than the
reference compound against both cancer cell lines.
It was found that HTB-57 cells were more sensitive
to the test compounds than PPC-1 cells. Compound
6d displayed promising activity and compounds 6b,
6f, and 6i demonstrated moderate to good activity
against the HTB-57 cell line. Compounds 6d, 6h,
and 6b showed the highest percentage inhibitions of
52.61, 41.65, and 34.76%, respectively. Among the
derivatives with electron-donor groups, the activity
against the lung cancer cell line decreased in the series
6d (4-methoxybenzyl) > 6f (methyl) > 6b (4-fluoroben-
zyl) > 6i (butyl), and the activity against the prostate
cell line decreased in the series 6d (4-methoxybenzyl) >
6h (propyl) > 6b (4-fluorobenzyl). The introduction of
unsaturation, specifically compounds 6l (allyl) and 6m
(propargyl), decreased activity against both the test cell
lines.
The docking results indicate that compounds 6a–
6m are held in the active pocket by a combination of
hydrophobic and van der Waals interactions with the
catalytic site of the 5TO8 protein. Compounds 6f, 6g,
6h, and 6m displayed the highest binding energies
(ΔG = –7.8, –7.6, –6.8, and –6.5 kcal/mol, respectively),
whereas 6e, 6i and 6j exhibited mediocre scores. Figu-
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DESIGN AND SYNTHESIS OF NOVEL 1a,3,4-OXADIAZOLE DERIVATIVES AS CYTOTOXIC AGENTS
927
Table 1. In vitro cytotoxicity and physicochemical properties (log p/Clog p) of compounds 6a–6m by the MTT colorimetric
assay
Percentage inhibition (%) at 25 μM
Compound no.
log p/Clogp
PPC-1
23.63
34.76
31.70
52.61
22.06
20.31
9.32
HTB-57
17.23
44.32
33.32
64.24
24.28
45.72
21.20
32.65
43.68
21.20
9.28
6a
6.3/5.95
6.45/6.09
7.9/7.64
6b
6c
6d
6.17/5.87
6.85/6.66
4.56/4.18
4.9/4.71
6e
6f
6g
6h
41.65
30.58
17.45
6.70
5.39/5.24
5.81/5.77
7.47/7.89
5.79/5.64
5.26/4.96
4.78/4.28
Not determined
6i
6j
6k
6l
6m
14.46
22.46
60.12
23.17
18.64
49.08
Doxorubicin
Table 2. Molecular docking results for the synthesized molecules docked into the chemokine receptor 5TO8
Ligand no. Docking score binding energies ΔG (kcal/mol) H-bonding π–π interactions
Trp94, His113
6a
–4.9
–5.4
–5.5
–6.3
–5.1
–7.8
–7.6
–6.8
–6.3
–6.0
–4.6
–5.8
–6.5
–6.6
–
6b
Gln200
His113
6c
Tyr190
Trp94, His113, Tyr116
His113
6d
Gln200
6e
Tyr190, Leu556
Leu431, Leu556
Leu431, Phe435, Val439
Gln200
Trp94, His113, Tyr116
Ala455, Val487
Leu431, Glu509, Val439
Trp94, Tyr116, His203
His113, His203
Trp94, His203
6f
6g
6h
6i
Trp591, Glu509
Gln200, Tyr255
Leu504, Asp567
–
6j
6k
His113, His203
Tyr116, His203
Lys457, Asp567, Phe568
Trp94
6l
6m
Gly434, Phe568
Tyr121, Gln200
Doxorubicin
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 5 2020

928
PERLA et al.
(a)
(b)
6f
6g
Fig. 1. (a) Autodock 3D representation of the docking interactions in the catalytic site of the 5TO8 protein: superimposition of the
(thick tubes) co-crystallized native ligands and (balls and sticks) best docked poses of compounds 6f and 6g. Hydrogen bonds are
shown by violet (6f) and light green dashed lines (6g) and π–π-stacking interactions are shown by light ash-colored (6f) and light
yellow dashed lines (6g). (b) Autodock 2D representation of the hypothetical binding modes of compounds 6f and 6g in the active site
of Pyk2.
re 1 demonstrates the predicted binding modes and
detailed protein–inhibitor interactions of compounds 6f
and 6g with the receptor. For compound 6f, H-bonding
with Leu431 (2.37 Å) and Leu556 (2.52 Å) and
π–π stacking with Ala455 and Val487 were found.
Compound 6m showed a high docking score with the
target receptor. The oxadiazole nitrogen interacts with
the side chain of Gly434 (3.82 Å), and the oxadiazole
ring shows π–π stacking with a hydrophobic residue
Tyr116 and a polar residue His203. For ligand 6g,
interactions with the largest number of amino acids
(Leu431, Phe435, Val439, Ala455, Lys457, Val487,
Glu509, Phe568, and Leu556) with ΔG = –7.6 kcal/mol
were predicted. It was also found that the oxadiazole
ring plays a key role in H-bonding with the catalytic
site residues. The molecular docking results suggest that
compounds 6f, 6g, 6h, and 6m have a potential to inhibit
the proline-rich tyrosine kinase 2Pyk2 receptor 5TO8.
excretion (ADME) properties using the Molinspiration
online property calculation toolkit [17, 18]. The resulting
data are listed in Table 3. Compounds 6a, 6b, 6c, 6g, and
6h obeyed the Rule-of-Five, which implies their drug
likeness. Compounds 6d–6f, 6i, 6j, 6l, and 6m showed
one violation and 6k, two violations of the Rule-of-Five
and, therefore, can be considered as moderately and
poorly orally bioavailable, respectively. The result of this
in silico ADME prediction analysis advocates that most
of the synthesized compounds follow the computational
assessment and thus represent a pharmacologically
active frame for further potential hits.
EXPERIMENTAL
Materials and Instrumentation. All the chemicals
were purchased from local suppliers and used without
further purification. All reactions were carried in dry
solvents under an inert atmosphere. The reaction
progress was monitored by TLC on Merck Kieselgel
60 F254 plates. Purification was performed by column
chromatography on a Merck silica gel (100–200 mesh).
The melting points were determined in open capillary
Molinspiration calculations. Further we performed
a computational investigation of compounds 6a–6m to
predict their absorption, distribution, metabolism, and
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DESIGN AND SYNTHESIS OF NOVEL 1a,3,4-OXADIAZOLE DERIVATIVES AS CYTOTOXIC AGENTS
929
Table 3. Molinspiration molecular descriptorsa for structures 6a–6m
Compound no. miLog P TPSA % Abs N atoms
MW
nON
5
nOHNH
n violations
N
6
Volume, Å3
317.23
334.03
350.83
367.63
434.84
367.42
345.20
339.73
388.88
393.81
486.07
414.42
402.41
264.88
6a
4.27
4.64
5.00
5.70
7.72
5.39
4.91
4.42
5.86
6.02
7.51
5.92
6.54
3.75
64.96
64.96
64.96
64.96
64.96
64.96
64.96
64.96
64.96
64.96
74.19
74.19
64.96
63.33
86.26
86.26
86.26
86.26
86.26
86.26
86.26
86.26
86.26
86.26
83.03
83.03
86.58
86.83
26
27
28
29
33
29
28
28
32
33
40
34
33
22
363.44
377.47
391.5
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
1
1
1
1
0
0
1
1
2
1
1
0
6b
5
7
6c
5
8
6d
405.52
461.63
405.52
389.48
387.46
439.54
457.53
545.66
469.57
473.99
293.32
5
9
6e
5
13
8
6f
5
6g
5
8
6h
5
7
6i
5
8
6j
6k
5
8
6
11
9
6l
6
6m
5
8
Oxaprozin
4
5
a miLog P—Logarithm of n-octanol/water partition coefficient; %Abs—percentage absorption; TPSA—topological polar surface area; MW—
molecular weight; nON—number of H-bond acceptors; nOHNH—number of H-bond donors; N—number of rotatable bonds.
tubes on a Cintex melting point apparatus and are
uncorrected. The IR spectra were recorded in KBr on a
Perkin–Elmer 400 FTIR spectrometer or a Varian 670-
IR FTIR spectrometer (ATR) in the frequency range
and 1% antibiotic mixture (10,000 U penicillin and
10 mg streptomycin per mL). The prostate cancer
cell line PPC-1 was maintained in an RPMI-1640
medium containing 10% NBCS, 100 IU/mL penicillin,
100 mg/mL streptomycin, and 2 mM-glutamine. Cell
lines were maintained at 37°C in a humidified 5%
CO2 incubator (Thermo Scientific) and processed
by initial trypsinization to detach the adhered cells
followed by centrifugation to obtain cell pellets. Fresh
media were added to the pellets for cell counting on a
haemocytometer, and 100 μL of the media with cells
ranging from 5,000–6,000 per well were dispensed in a
96-well plate. The plate was incubated overnight in CO2
incubator for the cells to adhere and regain its shape.
After 24 h cells were treated with 25 μM solutions of the
test compounds in the media. The cells were incubated
for 48 h to assay the effect of the test compounds on the
cell lines. A zero-hour reading with untreated cells and
control with 1% DMSO were taken to subtract further
from the 48 h reading. After 48 h incubation, the cells
were treated with the MTT [(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide] dissolved in PBS
(5 mg/mL) and incubated for 3–4 h at 37°C. The
formazan crystals thus formed were dissolved in 100 μL
1
of 600–4000 cm–1. The H and 13C NMR spectra were
recorded in CDCl3 and DMSO-d6 on a Bruker DRX-
300 (300 MHz FT NMR) or a Varian Mercury 500 MHz
spectrometer. The ESI mass spectra were measured
on a Jeol SX-102 spectrometer and high-resolution
mass spectra (HRMS) were recorded on an Agilent
Technologies 6510 Q-TOF spectrometer.
Cytotoxicity testing. The in vitro anticancer activity
of the test compounds was tested using the MTT
colorimetric assay [19, 20] as per the ATCC protocol.
The cell lines used for testing included human prostate
carcinoma–derived PPC-1 cells (ATCC no. CVCL-
4778) and human lung adenocarcinoma–derived HBT-
57 cells (ATCC no. SKLU1), which were procured from
the American Type Culture Collection, Manassas, VA,
USA. The lung cancer cell line HBT-57 was maintained
in a DMEM medium containing 10% newborn calf
serum (NBCS) along with 1% non-essential amino
acids, 0.2% sodium bicarbonate, 1% sodium pyruvate
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PERLA et al.
3-(4,5-Diphenyloxazol-2-yl)propanehydrazide
(3). To a solution of compound 2 (4.70 g, 15 mmol) in
ethanol (50 mL), hydrazine hydrate (1.6 mL, 30 mmol)
was added, and the mixture was refluxed for about 8 hr.
Excess ethanol was distilled off, the residue was poured
into water, and the resulting solution was extracted with
ethyl acetate (2 × 30 mL). The combined organic extracts
were dried over Na2SO4 and evaporated under a vacuum.
The crude product was purified by recrystallization from
ethanol to obtain 88% of compound 3 as white solid,
mp 109°C, Rf 0.50 (ethyl acetate–hexane, 70 : 30). IR
spectrum, ν, cm–1: 3324, 3285 [ν(NH, NH2)], 3034
[ν(=CH)], 2921 [ν(CH)], 1659 [ν(C=O)], 1513 [ν(C=C)],
of DMSO, and the viability was measured at 540 nm on
a Spectra Max multimode reader.
Molecular modeling. The ligands were sketched
in Sybyl 6.7 and saved it in.the format of mol2 [21].
All the sketched molecules were converted to energy
minimized 3D structures by using Gasteiger-Huckel
charges for in silico protein–ligand docking using
autodock Tools [22]. Each molecule was docked
separately using Autodock 4.2 software. Initially the
molecule was loaded, torsions were set and saved it in
PDBQT format. All the heteroatoms were removed from
the 5TO8.PDB (crystal structure of macrocyclization of
FAK inhibitors improves Pyk2 potency). After adding
hydrogens, the model was saved in the PDBQT format,
later ligands were prepared by optimizing the torsion
angles and saved them in PDBQT format [23]. The PDB
was also saved in PDBQT format. All calculations for
protein-ligand flexible docking were performed using
the Lamarckian Genetic Algorithm (LGA) method.
A grid box with the dimensions of X: 15.137, Y:
17.850 and Z: –3.573 Å, with a default grid spacing of
0.375 Å was used. The best conformation was chosen
with the lowest docked energy, after the docking
search was completed. The interactions of pantothenate
synthetase protein and ligand conformations, including
hydrogen bonds and the bond lengths were analyzed.
1
1437 [ν(C=N)], 1060 [ν(COC)]. H NMR spectrum
(500 MHz, CDCl3), δ, ppm: 2.72 t (2H, CH2, J 7.4 Hz),
3.20 t (2H, CH2, J 7.4 Hz), 4.77 br.s (2H, NH2),
4.72 br.s (1H, NH), 7.31–7.38 m (6Harom), 7.55 d.d
(2Harom, J 8.2 Hz), 7.60 d.d (2Harom, J 8.2 Hz). 13C NMR
spectrum (100 MHz, CDCl3), δ, ppm: 23.03, 29.90,
128.64, 128.97, 129.53, 130.07, 132.49, 135.05, 138.69,
145.05, 162.22, 175.36. Mass-spectrum, m/z: 308.0
[M + 1]+.
5-[2-(4,5-Diphenyloxazol-2-yl)ethyl]-1,3,4-oxa-
diazole-2(3H)-thione (4). A mixture of compound 3
(4 g, 14 mmol), KOH (0.95 g, 16 mmol), and CS2
(1.75 mL, 27 mmol) in ethanol (45 mL) was stirred under
reflux for 9 h until H2S no longer evolved. The progress
of the reaction was monitored by TLC. The solvent
was then distilled off, and the residue was poured over
crushed ice, and the solution was acidified with 10% HCl
until pH 5. The precipitated crude product was filtered
off, washed with water, dried, and recrystallized from
ethanol to obtain 85% of compound 4 as a white solid,
mp 156°C, Rf 0.42 (ethyl acetate–hexane, 40 : 60). IR
spectrum, ν, cm–1: 3372 [ν(NH)], 3079 [ν(=CH)], 2914,
2766 [ν(CH)], 1621 [ν(C=S)], 1555, 1511 [ν(C=C)],
Synthesis and Characterization. Methyl 3-(4,5-
diphenyloxazol-2-yl)propanoate (2). To a solution
of oxaprozin (2 g, 17 mmol) in methanol (15 mL), a
few drops of conc. H2SO4 was added, and the resulting
mixture was refluxed for 7 h. After completion of
the reaction as indicated by TLC, excess methanol
was distilled off. The residue was diluted with a 10%
NaHCO3 solution, the resulting solution was extracted
with ethyl acetate, dried over Na2SO4, and evaporated
under a vacuum. The crude product was purified
by recrystallization from ethanol to obtain 90% of
compound 2 as a white solid, mp 57°C, Rf 0.48 (ethyl
acetate–hexane, 20 : 80). IR spectrum, ν, cm–1: 3049
[ν(=CH)], 2946, 3049 [ν(CH)], 1734, 3049 [ν(C=O)],
1590, 3049 [ν(C=C)], 1496 [ν(C=N)], 1060 [ν(COC)].
1H NMR spectrum (500 MHz, CDCl3), δ, ppm: 2.92 t
(2H, CH2, J 7.4 Hz), 3.20 t (2H, CH2, J 7.4 Hz), 3.74 s
(3H, OCH3), 7.26–7.38 m (6Harom), 7.56 d.d (2Harom, J
8.2 Hz), 7.64 d.d (2Harom, J 8.2 Hz). 13C NMR spectrum
(75 MHz, CDCl3), δ, ppm: 23.03, 29.90, 60.87, 128.64,
128.97, 129.05, 132.07, 133.49, 136.05, 138.54, 145.07,
162.17, 173.02. Mass-spectrum, m/z: 308.0 [M + 1]+.
1
1435 [ν(C=N)], 1155 [ν(COC)]. H NMR spectrum
(500 MHz, CDCl3), δ, ppm: 3.27–3.37 m (4H, CH2CH2),
7.26–7.38 m (6Harom), 7.55–7.63 m (4Harom), 11.31 br.s
(1H, SH). 13C NMR spectrum (75 MHz, CDCl3), δ, ppm:
23.29, 24.09, 126.50, 128.05, 128.41, 128.74, 131.65,
135.09, 146.05, 160.51, 162.51. Mass-spectrum (ESI-
MS), m/z: 350.0 [M + 1]+.
Synthesis of compounds 6a–6m (general pro-
cedure). To a solution of compound 4 (1.0 equiv) in
DMF (5 vol), substituted halide 5a–5m (1.2 equiv) and
K2CO3 carbonate (1.5 equiv) were added. The reaction
mixture was stirred at ambient temperature for 7–9 h,
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DESIGN AND SYNTHESIS OF NOVEL 1a,3,4-OXADIAZOLE DERIVATIVES AS CYTOTOXIC AGENTS
931
diluted with water, and extracted with ethyl acetate
(2 × 20 mL). The crude product was purified by column
chromatography. Compounds 6a–6m were obtained
(100 MHz, CDCl3), δ, ppm: 22.94, 24.91, 36.34, 69.96,
115.01, 126.44, 127.38, 127.59, 127.81, 127.95, 128.08,
128.53, 128.60, 128.70, 130.33, 132.20, 135.15, 136.69,
145.68, 158.54, 160.53, 164.26, 166.23.Mass-spectrum,
m/z: 546.0 [M + 1]+. Found, %: C 72.01; H 4.72; N 7.55;
S 5.12. C33H27N3O3S. Calculated, %: C 72.64; H 4.99;
N 7.70; S 5.88.
1
in yields of 63–87% and characterized by H and 13C
NMR spectroscopy, mass spectrometry, and elemental
analysis.
3-Benzyl-5-[2-(4,5-diphenyloxazol-2-yl)ethyl]-
1,3,4-oxadiazole-2(3H)-thione (6a). Light brown solid,
mp 90°C, Rf 0.46 (ethyl acetate–hexane, 30 : 70). IR
spectrum, ν, cm–1: 3057, 3029 [ν(=CH)], 2920, 2848
[ν(CH)], 1614 [ν(C=S)], 1588 [ν(C=C)], 1495 [ν(C=N)],
1440 [ν(CN)], 1221, 1155 [ν(COC)]. 1H NMR spectrum
(500 MHz, CDCl3), δ, ppm: 3.34–3.29 m (4H, CH2),
4.77 s (2H, NCH2), 7.36–7.26 m (6Harom), 7.57 d.d
(2Harom, J 8.8 Hz), 7.62 d.d (2Harom, J 8.8 Hz). 13C NMR
spectrum (125 MHz, CDCl3), δ, ppm: 18.28, 20.23,
32.02, 121.77, 123.15, 123.34, 123.42, 123.86, 123.94,
124.05, 124.37, 127.53, 130.74, 141.02, 155.84, 161.63.
Mass-spectrum, m/z: 440 [M + 1]+. Found, %: C 71.05;
H 4.82; N 9.56; S 7.30. C26H21N3O2S. Calculated, %:
C 71.15; H 4.70; N 9.16; S 7.25.
5-[2-(4,5-Diphenyloxazol-2-yl)ethyl]-3-(4-metho-
xybenzyl)-1,3,4-oxadiazole-2(3H)-thione (6d). Light
yellow solid, mp 88°C, Rf 0.43 (ethyl acetate–hexane,
30 : 70). IR spectrum, ν, cm–1: 3043 [ν(=CH)], 2925,
2849 [ν(CH)], 1575 [ν(C=C)], 1473 [ν(C=N)], 1146,
1060 [ν(COC)]. 1H NMR spectrum (500 MHz,
CDCl3), δ, ppm: 3.45–3.30 m (4H, CH2), 3.90 s (3H,
OCH3), 5.12 s (2H, NCH2), 6.61 d (2Harom, J 8.5 Hz),
7.45–7.31 m (8Harom), 7.56 d.d (2Harom, J 8.2 Hz),
7.62 d.d (2Harom, J 8.2 Hz). 13C NMR spectrum
(125 MHz, CDCl3), δ, ppm: 23.02, 24.99, 36.41, 55.30,
114.17, 126.51, 127.37, 127.90, 128.18, 128.62, 128.69,
128.77, 130.40, 132.27, 135.28, 145.77, 159.41, 160.62,
164.39, 166.32. Mass-spectrum, m/z: 470.15 [M]+,
470.15 [M + 1]+. Found, %: C 68.45; H 5.04; N 9.02;
S 6.72. C27H23N3O3S. Calculated, %: C 69.06; H 4.94;
N 8.95; S 6.83.
5-[2-(4,5-Diphenyloxazol-2-yl)ethyl]-3-(4-fluoro-
benzyl)-1,3,4-oxadiazole-2(3H)-thione (6b). White
solid, mp 76°C, Rf 0.43 (ethyl acetate–hexane, 30 : 70).
IR spectrum, ν, cm–1: 3040 [ν(=CH)], 2914, 2848
[ν(CH)], 1692 [ν(C=S)], 1577, 1500 [ν(C=C)], 1478
[ν(C=N)], 1232 [ν(CN)], 1232 [ν(COC)], 1150
3-(4-Chlorobenzyl)-5-[2-(4,5-diphenyloxazol-2-
yl)ethyl]-1,3,4-oxadiazole-2(3H)-thione (6e). White
solid, mp 86°C, Rf 0.46 (ethyl acetate–hexane, 30 : 70).
IR spectrum, ν, cm–1: 3063 [ν(=CH)], 2928, 2838
[ν(CH)], 1675 [ν(C=C)], 1485 [ν(C=N)], 1163, 1093
[ν(COC)]. 1H NMR spectrum (500 MHz, CDCl3),
δ, ppm: 3.41–3.36 m (4H, CH2), 4.40 s (2H, NCH2),
7.42–7.30 m (10Harom), 7.57 d.d (2Harom, J 8.2 Hz),
7.61 d.d (2Harom, J 8.2 Hz). 13C NMR spectrum
(125 MHz, CDCl3), δ, ppm: 23.07, 24.91, 34.75, 114.54,
126.49, 127.05, 127.07, 128.21, 128.33, 128.55, 129.34,
129.21, 129.56, 130.50, 131.52, 132.55, 135.46, 146.76,
158.55, 160.57, 163.41, 167.25. Mass-spectrum, m/z:
474.0 [M + H]+, 476.0 [M + 1]+2. Found, %: C 65.46;
H 4.22; N 8.79; S 6.12. C26H20ClN3O2S. Calculated, %:
C 65.89; H 4.25; N 8.87; S 6.77.
1
[ν(COC)], 952 [ν(CF)]. H NMR spectrum (500 MHz,
CDCl3), δ, ppm: 2.08–2.19 m (4H, CH2), 3.21 s (2H,
NCH2), 6.03–6.19 m (10Harom), 6.36 d.d (2Harom, J
8.2 Hz), 6.45 d.d (2Harom, J 8.2 Hz). 13C NMR spectrum
(75 MHz, CDCl3), δ, ppm: 23.02, 24.95, 35.94, 115.63,
115.80, 126.51, 127.90, 128.19, 128.61, 128.69, 128.76,
130.83 130.90. Mass-spectrum, m/z: 457.2 [M]+, 456.1
[M – 1]+. Found, %: C 68.38; H 4.25; F 4.34; N 9.20;
S 7.10. C26H20FN3O2S. Calculated, %: C 68.25; H 4.41;
F 4.15; N 9.18; S 7.01.
3-[4-(Benzyloxy)benzyl]-5-[2-(4,5-diphenyl-
oxazol-2-yl)ethyl]-1,3,4-oxadiazole-2(3H)-thione
(6c). White solid, mp 91°C, Rf 0.43 (ethyl acetate–
hexane, 30 : 70). IR spectrum, ν, cm–1: 3047 [ν(=CH)],
2925, 2854 [ν(CH)], 1578 [ν(C=C)], 1484 [ν(C=N)],
5-[2-(4,5-Diphenyloxazol-2-yl)ethyl]-3-methyl-
1,3,4-oxadiazole-2(3H)-thione (6f). White solid,
mp 80°C, Rf 0.35 (ethyl acetate–hexane, 30 : 70). IR
spectrum, ν, cm–1: 3054 [ν(=CH)], 2926, 2863 [ν(CH)],
1670 [ν(C=S)], 1593 [ν(C=C)], 1484 [ν(C=N)], 1166,
1051 [ν(COC)]. 1H NMR spectrum (300 MHz, CDCl3),
δ, ppm: 2.70 s (3H, CH3), 3.50–3.30 m (4H, CH2), 7.42–
1
1247, 1029 [ν(COC)]. H NMR spectrum (400 MHz,
CDCl3), δ, ppm: 3.45–3.30 m (4H, CH2), 4.40 s (2H,
NCH2), 5.03 s (2H, OCH2), 6.91 d (2Harom, J 8.5 Hz),
7.48–7.27 m (13Harom), 7.56 d.d (2Harom, J 8.2 Hz),
7.62 d.d (2Harom, J 8.2 Hz). 13C NMR spectrum
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932
PERLA et al.
7.31 m (6Harom), 7.59 d.d (4Harom, J 8.2 Hz). 13C NMR
spectrum (125 MHz, CDCl3), δ, ppm: 14.55, 23.03,
25.02, 126.51, 127.90, 127.96, 128.18, 128.61, 128.69,
128.77, 128.90, 129.04, 129.93, 132.26, 133.13, 135.21,
145.77, 160.63, 165.41, 166.33. Mass-spectrum, m/z:
364.0 [M + 1]+. Found, %: C 66.94; H 4.92; N 11.86;
O 8.42; S 8.71. C20H17N3O2S. Calculated, %: C 66.10;
H 4.71; N 11.56; O 8.80; S 8.82.
(2H, NCH2, J 7.3 Hz), 7.43–7.29 m (6Harom), 7.56 d.d
(2Harom, J 8.2 Hz),7.62 d.d (2Harom, J 8.2 Hz). 13C NMR
spectrum (125 MHz, CDCl3), δ, ppm: 19.23, 22.03,
26.53, 29.42, 35.98, 44.06, 114.71, 122.41, 123.09,
126.01, 126.84, 129.18, 131.48, 136.99, 137.56, 140.06,
143.92, 148.45, 162.56, 170.04. Mass-spectrum, m/z:
406.15 [M + 1]+. Found, %: C 68.91; H 6.07; N 10.93;
S 8.06. C23H23N3O2S. Calculated, %: C 68.12; H 5.72;
N 10.36; S 7.91.
5-[2-(4,5-Diphenyloxazol-2-yl)ethyl]-3-ethyl-
1,3,4-oxadiazole-2(3H)-thione (6g). White solid,
mp 90°C, Rf 0.40 (ethyl acetate–hexane, 30 : 70). IR
spectrum, ν, cm–1: 3052 [ν(=CH)], 2927, 2863 [ν(CH)],
1576 [ν(C=C)], 1452 [ν(C=N)], 1269, 1111 [ν(COC)].
1H NMR spectrum (400 MHz, CDCl3), δ, ppm: 1.45 t
(3H, CH3, J 7.3 Hz), 3.23 q (2H, NCH2, J 7.3 Hz),
3.45–3.35 m (4H, CH2), 7.40–7.30 m (6Harom), 7.56 d.d
(2Harom, J 8.2 Hz), 7.62 d.d (2Harom, J 8.2 Hz). 13C NMR
spectrum (100 MHz, CDCl3), δ, ppm: 14.68, 22.99,
25.01, 26.89, 126.46, 127.84, 128.11, 128.54, 128.62,
128.73, 132.23, 135.16, 145.70, 160.57, 164.63, 166.14.
Mass-spectrum, m/z: 378.12 [M + 1]+. Found, %:
C 66.51; H 5.82; N 11.44, O 9.08; S 8.23. C21H19N3O2S.
Calculated, %: C 66.82; H 5.07; N 11.13; O 8.48; S 8.49.
5-[2-(4,5-Diphenyloxazol-2-yl)ethyl]-3-octyl-
1,3,4-oxadiazole-2(3H)-thione (6j). White solid,
mp 86°C, Rf 0.53 (ethyl acetate–hexane, 30 : 70). IR
spectrum, ν, cm–1: 3063 [ν(=CH)], 2958, 2926 [ν(CH)],
1605 [ν(C=S)], 1594 [ν(C=C)], 1484 [ν(C=N)], 1156,
1063 [ν(COC)]. 1H NMR spectrum (300 MHz, CDCl3),
δ, ppm: 0.85–0.82 m (8H, CH2), 1.64–1.57 t (3H, CH3,
J 7.0 Hz), 1.81–1.78 t (2H, CH2, J 7.0 Hz), 2.50–2.38 m
(2H, CH2), 3.34 s (2H, CH2), 4.47–4.42 t (2H, NCH2,
J 7.3 Hz), 4.65 s (2H, NCH2), 7.87–7.80 m (2Harom),
7.97–7.93 t (1Harom, J 7.5 Hz), 8.23–8.21 d (1Harom
,
J 8.0 Hz), 8.79 s (1Harom). 13C NMR spectrum
(125 MHz, CDCl3), δ, ppm: 19.26, 22.06, 26.41, 29.44,
36.00, 44.08, 125.03, 125.46, 126.88, 127.53, 128.90,
129.23, 131.19, 134.34, 137.60, 140.12, 143.09, 143.94,
162.54, 170.07. Mass-spectrun (ESI-MS), m/z: 462.0
[M + 1]+. Found, %: C 70.91; H 6.62; N 8.84; S 7.01.
C27H31N3O2S. Calculated, %: C 70.25; H 6.77; N 9.10;
S 6.95.
5-[2-(4,5-Diphenyloxazol-2-yl)ethyl]-3-propyl-
1,3,4-oxadiazole-2(3H)-thione (6h). White solid,
mp 89°C, Rf 0.43 (ethyl acetate–hexane, 30 : 70). IR
spectrum, ν, cm–1: 3058 [ν(=CH)], 2964, 2871 [ν(CH)],
1581 [ν(C=C)], 1482 [ν(C=N)], 1152, 1061 [ν(COC)].
1H NMR spectrum (500 MHz, CDCl3), δ, ppm: 1.03 t
(3H, CH3, J 7.3 Hz), 1.81 m (2H, SCH2CH2), 3.19 t (2H,
NCH2, J 7.3 Hz), 3.44–3.33 m (4H, CH2), 7.40–7.29 m
3-Isobutyl-5-[2-(4,5-diphenyloxazol-2-yl)ethyl]-
1,3,4-oxadiazole-2(3H)-thione (6k). Yellow solid,
mp 81°C, Rf 0.40 (ethyl acetate–hexane, 30 : 70). IR
spectrum, ν, cm–1: 3003 [ν(=CH)], 2924, 2784 [ν(CH)],
1686 [ν(C=S)], 1495 [ν(C=N)], 1225, 1093 [ν(COC)].
1H NMR spectrum (300 MHz, CDCl3), δ, ppm: 1.03 d
(6H, CH3, J 6.7 Hz), 2.13–1.95 m (1H, CH), 3.12 d (2H,
NCH2, J 6.7 Hz), 3.47–3.30 m (4H, CH2), 7.41–7.28 m
(6Harom), 7.56 d.d (2Harom, J 8.2 Hz), 7.62 d.d (2Harom
,
J 8.2 Hz). 13C NMR spectrum (125 MHz, CDCl3),
δ, ppm: 12.94, 22.50, 22.81, 24.81, 34.22, 126.29,
127.67, 127.95, 128.36, 128.46, 128.58, 132.08, 134.99,
145.52, 160.45, 164.65, 165.96. Mass-spectrum, m/z:
392.0 [M + 1]+. Found, %: C 67.76; H 5.60; N 10.92;
S 8.02. C21H19N3O2S. Calculated, %: C 67.50; H 5.41;
N 10.73; S 8.19.
(6Harom), 7.56 d.d (2Harom, J 7.4 Hz), 7.62 d.d (2Harom
,
J 7.4 Hz). 13C NMR spectrum (125 MHz, CDCl3),
δ, ppm: 14.50, 21.71, 23.02, 25.06, 31.22, 32.22, 126.52,
127.90, 128.27, 128.60, 128.58, 128.79, 132.28, 136.22,
146.76, 162.67, 163.95, 166.28. Mass-spectrum, m/z:
406.15 [M + H]+. Found, %: C 69.42; H 6.01; N 10.83;
S 8.05. C23H23N3O2S. Calculated, %: C 68.12; H 5.72;
N 10.36; S 7.91.
3-Butyl-5-[2-(4,5-diphenyloxazol-2-yl)ethyl]-
1,3,4-oxadiazole-2(3H)-thione (6i). Light yellow solid,
mp 76°C, Rf 0.48 (ethyl acetate–hexane, 30 : 70). IR
spectrum, ν, cm–1: 3052 [ν(=CH)], 3002, 2953 [ν(CH)],
1736 [ν(C=S)], 1583, 1495 [ν(C=C)], 1435 [ν(C=N)],
1
1227, 1167 [ν(COC)]. H NMR spectrum (300 MHz,
3-Allyl-5-[2-(4,5-diphenyloxazol-2-yl)ethyl]-
1,3,4-oxadiazole-2(3H)-thione (6l). Yellow solid,
mp 72°C, Rf 0.43 (ethyl acetate–hexane, 30 : 70). IR
CDCl3), δ, ppm: 1.64 t (3H, CH3, J 7.3 Hz), 2.24–
2.12 m (4H, SCH2CH2), 3.50–3.32 m (4H, CH2), 3.98 t
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DESIGN AND SYNTHESIS OF NOVEL 1a,3,4-OXADIAZOLE DERIVATIVES AS CYTOTOXIC AGENTS
933
spectrum, ν, cm–1: 3059 [ν(=CH)], 2926, 2856 [ν(CH)],
1583 [ν(C=C)], 1481 [ν(C=N)], 1161, 1059 [ν(COC)].
1H NMR spectrum (300 MHz, CDCl3), δ, ppm: 3.31–
3.49 m (4H, CH2), 3.84 d (2H, NCH2, J 6.7 Hz), 5.19
d (1H, CH=CH2, J 9.8 Hz), 5.35 d (1H, CH=CH2, J
17.3 Hz), 6.10–5.86 m (1H, CH), 7.44–7.30 m (6Harom),
7.56 d.d (2Harom, J 7.5 Hz), 7.62 d.d (2Harom, J 7.5 Hz).
13C NMR spectrum (125 MHz, CDCl3), δ, ppm: 23.03,
24.98, 35.16, 119.72, 126.53, 127.91, 128.18, 128.61,
128.69, 131.70, 132.27, 135.22, 145.78, 160.61, 164.06,
166.45. Mass-spectrum, m/z: 390.12 [M + 1]+. Found, %:
C 67.44; H 4.12; N 10.43; S 8.36. C22H19N3O2S.
Calculated, %: C 67.84; H 4.92; N 10.79; S 8.23.
ACKNOWLEDGMENTS
The authors are highly grateful to the management of
the United States Pharmacopeial Convention (USP) for
their immense support and motivation for completion of this
work. We also extend our gratitude to the management of the
Department of Chemistry, KLEF (Deemed to be University)
for Ph.D registration.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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