New pyrimidine-benzoxazole/benzimidazole hybrids: Synthesis, antioxidant, cytotoxic activity, in vitro cyclooxygenase and phospholipase A2-V inhibition

Article abstract of DOI:10.1016/j.bioorg.2019.103218

To enhance the cytotoxicity of benzimidazole and/or benzoxazole core, the benzimidazole/benzoxazole azo-pyrimidine were synthesized through diazo-coupling of 3-aminophenybenzimidazole (6a) or 3-aminophenylbenzoxazole (6b) with diethyl malonate. The new az

Full text of DOI:10.1016/j.bioorg.2019.103218

Bioorganic Chemistry 92 (2019) 103218
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
New pyrimidine-benzoxazole/benzimidazole hybrids: Synthesis,
antioxidant, cytotoxic activity, in vitro cyclooxygenase and phospholipase
A2-V inhibition
Mohamed A. Abdelgawada,b,⁎, Rania B. Bakra,b, Waqas Ahmad , Mohammad M. Al-Sanea ,
c
a
b
Heba A.H. Elshemy
a
b
Pharmaceutical Chemistry Department, College of Pharmacy, Jouf University, Aljouf 2014, Saudi Arabia
Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
c
School of Pharmaceutical Sciences, University Sains Malaysia, 11800 Pulau Pinang, Malaysia
A R T I C L E I N F O
A B S T R A C T
Keywords:
To enhance the cytotoxicity of benzimidazole and/or benzoxazole core, the benzimidazole/benzoxazole azo-
pyrimidine were synthesized through diazo-coupling of 3-aminophenybenzimidazole (6a) or 3-aminophe-
nylbenzoxazole (6b) with diethyl malonate. The new azo-molanates 6a&b mixed with urea in sodium ethoxide
to afford the benzimidazolo/benzoxazolopyrimidine 7a&b. The structure elucidation of new synthesized targets
was proved using spectroscopic techniques NMR, IR and elemental analysis. The cytoxicity screening had been
carried out against five cancer cell lines: prostate cancer (PC-3), lung cancer (A-549), breast cancer (MCF-7),
pancreas cancer (PaCa-2) and colon cancer (HT-29). Furthermore, the antioxidant activity, phospholipase A2-V
and cyclooxygenases inhibitory activities of the target compounds 7a&b were evaluated and the new compounds
showed potent activity (cytotoxicity IC50 range from 4.3 to 9.2 µm, antioxidant activity from 40% to 80%, COXs
or LOX inhibitory activity from 1.92 µM to 8.21 µM). The docking of 7a&b was made to confirm the mechanism
of action.
Benzoxazole
Benzimidazole
Cytotoxicity
COXs
Antioxidant
1
. Introduction
Cancer disease is the most dangerous disease coming after cardio-
respectively [15]. In addition, benzimidazole derivative 2 (Fig. 1) was
recorded to demonstrate cancer inhibitory effect against both HepG-2
and HCT-116 with IC50 = 2.10 and 1.25 µM [16]. Also, hybridizing
benzoxazole ring with piperazine moiety produced compound 3 (Fig. 1)
which showed anticancer activity towards MCF-7 cell lines with
IC50 = 12 nM [17]. On the other hand, pyrimidine ring drawn much
attention due to its biological importance as anti-inflammatory [18,19],
antioxidant [20,21] and anticancer [22,23]. For example, the pyrimido-
triazine-9-carbonitrile had been prepared by Fathalla et al. [24a] and
was evaluated for its anticancer activity towards liver cancer cell line
(HEPG-2). The result of evaluation detected that compound 4 (Fig. 1)
had better anticancer activity (IC50 = 3.74 µg/ml) than the standard
drug 5-fluorouracil (IC50 = 5 µg/ml).
vascular disease, and in 2018, it produced death of about 9.6 million
deaths [1]. Although there is a great advance in treating cancer through
targeting therapy, there is a need for process of anticancer drug dis-
covery and development. So, efforts have been made for synthesis of
potential anticancer drugs. As a result from that millions of variants
organic or natural compounds have been synthesized and shown cy-
totoxic activity against different types of cancer cell [2]. Moreover, COX
enzymes and phospholipase A2 had been reported to be highly found in
solid tumors such as bladder and breast cancer [3–5].
Benzoxazole and benzimidazole scaffolds constitute many bioactive
compounds possessing significant pharmacological activities for ex-
ample antihistaminic [6], and antimicrobial [7,8], anti-inflammatory
COX-2 inhibitors could use it to prompt apoptosis is TRAIL receptor
(cytokine that is normally secreted by all of our cells and could induce
apoptosis in tumor cells). Another target for COX-2 inhibitors is PI3
Kinase; PI3 Kinase is a provocateur for Bad protein, the protein that has
a major role in cancer development. COX-2 inhibitors stop the activity
of Bcl-xL and induce the activity of Bcl-2 and by this, they restrain
[
9–11], antioxidant [12] and anticancer [7,13,14].
In 2017, the benzimidazol-2-yl-phenyl-hydrazono-pyrazol-3-one (1)
(
Fig. 1) had been prepared and was found to exhibit anticancer activity
against A549 and MCF-7 and cell lines with IC50 = 8.46 and 6.42 µM,
⁎
Corresponding author at: Pharmaceutical Chemistry Department, College of Pharmacy, Jouf University, Aljouf 2014, Saudi Arabia.
E-mail address: mhmdgwd@ju.edu.sa (M.A. Abdelgawad).
https://doi.org/10.1016/j.bioorg.2019.103218
Received 4 February 2019; Received in revised form 12 July 2019; Accepted 24 August 2019
Available online 26 August 2019
0045-2068/ © 2019 Elsevier Inc. All rights reserved.

M.A. Abdelgawad, et al.
Bioorganic Chemistry 92 (2019) 103218
Fig.1. Chemical structures of some reported benzimidazole derivatives (1, 2), and benzoxazole derivative (3) and pyrimidine derivative (4) as anticancer agents.
apoptosis. Bcl-xL is a promoter for cell proliferation. COX-2 inhibitors
activate procaspase-8 and convert it in to its active form (Caspase 8).
This is a major step in the process of cell apoptosis [24b–24d].
Based on these studies and our research for preparing bioactive
candidates with anticancer activity [25–27], we decided to synthesize
novel benzimidazole and/or benzoxazole derivatives mixed with pyr-
imidine ring hoping that the new hybrids might exhibit anticancer ac-
tivity with less side effects.
demonstrated better scavenging activity against the DPPH radical than
benzimidazole derivative 7a at all the used concentrations.
2
.2.2. In vitro sPLA2-V and COXs inhibitory activity assay
The potency of the newly prepared target compounds 7a and 7b as
cyclooxygenase (COX) and phospholipase A2-V (sPLA2-V) inhibitors
was determined as the concentration causing 50% inhibition (IC50) for
COX and sPLA2-V enzymes using an enzyme immunoassay (EIA) kit.
The results showed that the target compounds (7a and 7b) potent in-
hibitory activity against COX-1 (IC50 = 2.76, 1.92 µM), and moderate
activity towards COX-2 (IC50 = 7.47, 8.21 µM), but both compounds
have moderate inhibitory against secretory Phospholipase A2-V
2
. Results and discussion
2.1. Chemistry
(
sPLA2-V) (Table 1).
The steps of compounds 6a&b and 7a&b preparations are displayed
in Scheme 1. First, compounds 5a&b were prepared as the reported
procedures [4].
2.2.3. Cytotoxic activity
The cytotoxic activity of the newly target compounds was recorded
using MTT assay against breast carcinoma (MCF-7), lung cancer
(A549), human prostate cancer (PC-3), human pancreatic cancer (PaCa-
2) and colorectal adenocarcinoma (HT-29) cell lines. From the obtained
data, both the target compounds 7a and 7b showed moderate activity
against all the tested cell lines (Table 2) with IC range = 4.3–8.8 µM.
The new compounds were prepared following reported methods for
diazocoupling of diazonium salts with active methylene in presence of
sodium acetate [27]. The structure of azo-diethylmalonate 6a and 6b
was elucidated from NMR spectra which showed aliphatic peaks at δ
(
m) 1.22 to 1.56 and (m) 4.20–4.46 indicating diethyl groups of ester.
5
0
The azo-pyrimidinone derivatives 7a and 7b prepared as result of re-
action of azo-compound 6a and 6b with urea or/and thiourea in basic
solution of sodium ethoxide. The absence of aliphatic NMR peaks and
presence of new NH peaks of azo-diethyl malonate 6a and 6b prove the
cyclization and formation of new pyrimidinones 7a and 7b. The target
compound structure was recognized by elemental and spectroscopic
analyses.
In addition, the benzimidazole derivative 7a showed higher cytotoxic
activity than the benzoxazole derivative 7b against all the cell lines
except non-small cell lung cancer (A549). Moreover, the target 7a de-
monstrated comparable anticancer activity against colorectal adeno-
carcinoma (HT-29) cell lines (IC = 5.9 µM) to that showed by the
5
0
standard drug doxorubicin (IC50 = 5.36 µM) (see Table 2).
2.3. Molecular docking study
2.2. Pharmacological screening
The target compounds 7a&b were exposed to molecular modeling
2
.2.1. Screening of antioxidant activity using DPPH
study to explore modes of binding interactions with COX-2 enzyme by
the use of MOE.2010 software (Molecular Operating Environment). The
3D crystal structure of COX-2 enzyme combined with the cocrystallized
ligand (PDB code: 1CX2) was used for this study. Bromocelecoxib, S-58
binded with COX-2 isoform forming two hydrogen bonding interactions
with His90 and Arg513 with binding affinity = −11.93 kcal/mol.
Docking of compound 7a within COX-2 binding site displayed that 7a
was good fitted with the receptor with three hydrogen bonding inter-
actions with energy score = −11.50 kcal/mol (Table 3, Fig. 3).
Free radical scavenging effect of novel benzoxazole 7a and benzi-
midazole 7b had been evaluated using colorimetric test: DPPH (2,2-
diphenyl-1-picrylhydrazyl) radical scavenging test using trolox as a
standard. The results of inhibitory effects at different concentrations of
the compounds 7a and 7b are explained in Fig. 2 this graph was plotted
with the candidate concentration (μg/mL) on the x-axis and percentage
scavenging effects on the y-axis. From this graph, both candidates ex-
hibited good scavenger effect and the benzoxazole derivative 7b
2

M.A. Abdelgawad, et al.
Bioorganic Chemistry 92 (2019) 103218
COOH
NH2
X
N
X
a
+
NH2
NH2
5
a,b
b
O
O
N
N
O
N
H
O
X
6
a,b
c
O
N
N
O
N
H
NH
X
N
H
O
7
a,b
Scheme 1. Reagent and reaction conditions; (a) PPA, reflux for 5h neutralization with Na2CO3, (b), HCl, sodium nitrite, DEM, sodium acetate, stirring for 2 h, (c)
Sodium ethoxide, urea, ethanol, reflux for 4 h, water, HCl, cooling for 2 h.
Fig. 2. DPPH radical scavenging effect of the target compounds 7a, 7b and torlox at different concentrations (10, 50 and 100 μM). SD = 0.23.
3

M.A. Abdelgawad, et al.
Bioorganic Chemistry 92 (2019) 103218
Table 1
Table 3
Inhibition of secretory Phospholipase A2-V (sPLA2-V), COX-1, and COX-2 by
Molecular modeling data for compounds 7a, 7b and 5-SC during docking in the
tested compounds 7a and 7b.
active site of COX-2 enzyme (PDB: 1CX2).
Compound No.
&
&
Compound
sPLA
2
-V
COX-1
COX-2
Affinity
No.of
hydrogen
bonds
Distance (Å) from
main residue
Functional
group
IC50 (µM)
IC50 (µM)
IC50 (µM)
Kcal/mol
7
a
b
7.51 ± 1.84
5.72 ± 2.15
0.69 ± 0.01
ND*
2.76 ± 0.5
1.92 ± 0.9
ND*
7.47 ± 1.3
8.21 ± 1.6
ND*
7
7a
−11.50
3
2.88
2.48
2.78
2.79
2.51
2.30
Arg513
Tyr355
Val523
Gln192
Arg513
Arg513
His90
eC]O
C]N
Dexamethasone
Indomethacin*
0.29 ± 0.07
3.82 ± 0.08
Pyrazole NH
eC]O
7
b
−11.95
−11.93
2
2
ND* not done.
eC]O
5
-SC
eSO
2
2
2
.41
eSO
Moreover, docking of compound 7b within COX-2 enzyme recorded
that this compound showed docking score (S) = −11.50 kcal/mol.
Furthermore, this compound 7b showed two hydrogen bonding inter-
actions; (i) C]O with Arg513 (2.51 Å), ii) C]O with Gln192 (2.79 Å)
−1
1
(
2C]O) cm
;
H NMR (DMSO‑d
CH ), 7.25–7.33 (m, 3H, aminophenyl H-2,4,6),
.41–7.58 (m, 1H, phenyl H-3),7.69–7.78(m, 2H, benzoxazole H-5, 6),
6
) δ 1.18–1.43 (m, 6H, CH
2
CH
3
),
4
7
8
.21–4.49 (m, 4H, CH
2
3
(
Table 3, Fig. 4).
. Material and methods
1
3
.22–8.36 (m,2H, benzoxazole H-4,7), 11.98 (s, 1H, NHeN]);
C
3
NMR (DMSO‑d
6
) δ 14.32, 14.58, 61.47, 61.97, 111.23, 115.99, 119.99,
21.45, 124.48, 125.28, 125.65, 129.29, 142.15, 145.94, 150.62,
62.00, 162.67; Anal. Calcd for C20 : C, 62.99; H, 5.02; N,
1.02. Found: C, 62.90; H, 5.10; N, 11.10
1
1
1
3.1. Chemistry
H
19
N
O
3 5
Thomas-Hoover apparatus was used for determination of melting
points (uncorrected). The chemical structure of the prepared com-
1
3
pounds was proved by NMR (using a BrukerAvance III 100 MHz for
C
3.1.4. General procedure for synthesis of compound 7a&b
1
and 400 MHz for H, Bruker AG, Switzerland). IR (by Nicolet 550 Series
II Magna FT-IR), Mass (by Hewlett Packard 5988) spectroscopy and
elemental analysis (.by Perkin-Elmer 2400 analyzer, Perkin-Elmer,
Norwalk, CT, USA). Compounds 5a&b were synthesized according to
the literature procedure [4].
A mixture of 6a&b (0.01 mol), urea (0.01 mol) in sodium ethoxide
solution (0.03 mol sodium, 20 mL absolute ethanol) was heated under
reflux for 4 h. (20 mL) Hot water was added to the mixture, and then
sufficient quantity of hydrochloric acid was added till the mixture be-
came acidic and then kept in the refrigerator for 5 h. The products 7A&b
were filtered, and dried then crystallized from ethanol.
3
.1.1. General methods for synthesis of 6a&b
To a cooled diazonium solution prepared from stirring compound
3
.1.5. 5-{[3-(1H-Benzimidazol-2-yl)-phenyl]-hydrazono}-pyrimidinone-
,4,6-trione (7a)
5
a or 5b (0.01 mol) in (10%, 10 mL) hydrochloric acid and solution of
2
sodium nitrite (0.01 mol, 5 mL water), a mixture of (0.01 mol) diethyl
malonate and (0.01 mol) sodium acetate in (50%, 20 mL) aqueous
ethanol was added and stirred for 4 h in ice bath. The product was
filtered and crystallized from (95%) ethanol.
Dark reddish crystals in 90% yield. mp 300 °C; IR: 3460, 3300,
250, 3169 (4NH), 3043 (CH, Aromatic), 1720, 1687, 1681 (3C]O)
3
−
1 1
cm
;
H NMR (DMSO‑d ) δ 7.20–7.37 (m, 2H, aminophenyl H-2,4),
6
7
7
.5 (s, 1H, aminophenyl H-6), 7.65–7.67(m, 1H, aminophenyl H-3),
.75–7.76(m, 2H, benzimidazole H-5, 6), 8.41–8.48 (m,2H, benzimi-
3
.1.2. 2-{[3-(1H-Benzimidazol-2-yl)-phenyl]-hydrazono}-malonic
acid
dazole H-4,7), 11.39 (s, 1H, NHeN]),13.16 (s,1H, imidazole NH),
diethyl ester (6a)
13
1
1
1
4.15 (s, 2H, NH, pyrimidinone); C NMR (DMSO‑d
6
) δ 111.75,
Yellowish white crystals in 90% yield; mp 145–147 °C; IR: 3445.6
2NH), 3088.5 (CH, Aromatic), 2985.8 (CH, Aliphatic), 1701.4, 1666.3
17.46, 119.00, 119.24, 122.22, 123.05, 127.86, 128.29, 135.51,
42.93, 144.33, 150.29, 151.10; Anal. Calcd for C17 : C, 58.62;
(
(
H
12
N
O
6 3
−
1
1
2C]O) cm
;
H NMR (DMSO‑d
CH
.38–7.64 (m, 4H, phenyl H-3, benzimidazole H-5, 6), 8.01–8.18
6
) δ 1.22–1.56 (m, 6H, CH
2
CH ),
3
H, 3.47; N, 24.13. Found: C, 58.60; H, 3.50; N, 24.10.
4
7
.20–4.40 (m, 4H, CH
2
3
)7.04–7.20 (m, 3H, aminophenyl H-2,4,6),
(
m,2H, benzimidazole H-4,7), 12 (s, 1H, NHeN]); 13.80 (s,1H, imi-
3.1.6. 5-{[3-(1H-Benzoxazol-2-yl)-phenyl]-hydrazono}-pyrimidinone-
2,4,6-trione (7b). pale
1
3
dazole NH), C NMR (DMSO‑d
6
) δ 14.34, 14.59, 61.37, 61.84, 111.62,
15.87, 119.10, 122.06, 122.80, 123.16, 125.88, 128.19, 135.46,
43.92, 144.35, 151.48, 162.12, 162.80; Anal. Calcd for C20 O4:
1
1
Reddish crystals in 80% yield. mp 300 °C; IR: 3450, 3400, 3280
−
1 1
H
20
N
4
(3NH), 3040 (CH Aromatic), 1730, 1690, 1675 (3C]O) cm ; HNMR
C, 63.15; H, 5.30; N, 14.73. Found: C, 63.20; H, 5.20; N, 14.70.
(DMSO‑d ) δ 7.28–7.44 (m, 2H, aminophenyl H-2,4), 7.74–7.92 (m, 1H,
6
aminophenyl H-3,6, benzimidazole-2-yl H-5, 6), 8.28–8.44 (m, 2H,
3
.1.3. 2-{[3-(1H-Benzoxazol-2-yl)-phenyl]-hydrazono}-malonic
acid
benzimidazole-2-yl H-4,7), 11.30 (s, 1H, NHeN]), 11.61 (s, 1H, NH,
diethyl ester (6b)
pyrimidinone), 14.23 (s, 2H, NH, pyrimidinone); Anal. Calcd for
Yellowish white crystals in 85% yield; mp 158–160 °C; IR: 3200.5
NH), 3000.3 (CH, Aromatic), 2900.4 (CH, Aliphatic), 1720.7, 1680.4
C
17
20.10.
H
11
N
3
O : C, 58.62; H, 3.17; N, 20.05. Found: C, 58.70; H, 3.10; N,
4
(
Table 2
Cytotoxicity activity of the target compounds 7a and 7b.
Comp.
Cell viability %
Cytotoxicity activity IC50
PC-3
±
SEM (µM)
MCF-7
A-549
PaCa-2
HT-29
7
a
b
84
87
–
5.4 ± 1.2
7.2 ± 2.3
9.2 ± 1.5
8.4 ± 1.2
4.3 ± 0.8
7.9 ± 1.6
4.5 ± 1.3
8.8 ± 1.2
5.9 ± 1.4
8.8 ± 2.2
7
Doxorubicin
2.01 ± 0.87
1.17 ± 0.35
0.91 ± 0.12
1.57 ± 0.02
5.36 ± 1.98
4

M.A. Abdelgawad, et al.
Bioorganic Chemistry 92 (2019) 103218
Fig. 3. Binding of the compound 7a inside COX-2 active site. (A) The interactions of 7awith COX-2 (using MOE site finder program), (B) 3D interactions of 7a with
Arg513, Val523 and Tyr355amino acids.
Fig. 4. Binding of the compound 7b inside COX-2 active site. (A) The interactions of 7b with COX-2 (using MOE site finder program), (B) 3D interactions of 7b with
Arg513 and Gln192 amino acids.
3
.2. Pharmacological screening
3.2.3. Cytotoxic activity
Cytotoxic activity of the newly prepared targets was measured by
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetra-
zolium reduction assay as reported [31].
3.2.1. DPPH radical scavenging activity
Scavenging DPPH assay was determined using of 1,1-diphenyl-2-
picrylhydrazyl (DPPH) as reported [28]. 0.08 mL solution of the new
compounds was mixed with a 1.92 mL 6 × 10–5 M solution of 1,1-di-
phenyl-2-picrylhydrazyl (DPPH) in ethanol and then absorbance re-
duction was calculated at λ = 515 nm over 3 min against a blank
sample (containing methanol only). The ability of the tested samples to
quench DPPH free radicals was determined according to the equation:
scavenging % = [(AC − AA)/AC] × 100 where: AC—absorbance of the
control at 0 min, AA—absorbance of the sample after 3 min. The anti-
oxidant activity was expressed as µmol of Trolox per 100 g of fresh
weight (FW) (TE—Trolox equivalent).
3
.3. Molecular docking study
The crystal structures of COX-2 isoform was obtained from protein
data bank at research collaboration for structural Bioinformatics
(
RSCB) (PDB:ID 1CX2) [32]. Docking of the co-crystallized ligand had
been performed to estimate amino acid binding and root mean standard
deviation (rmsd) which is equal to 0.87 Å. 3D structure of the tested
compounds was designed by Molecular Operating Environment (MOE,
Version 2005.06, Montreal, Canada). The 3D structures were proto-
nated, energy minimized and docked within COX-2 active site.
3
.2.2. In vitro COX and sPLA2-V inhibition assay
4
. Conclusion
The in vitro inhibition of ovine COX-1/COX-2 was calculated by
enzyme immunoassay (EIA) kit as the reported procedure [29] and
sPLA2-V inhibition was measured using Ellman’s method [30].
Novel hybrid structures of benzoxazole and/or benzimidazole with
pyrimidine scaffold 7a and 7b had been designed and synthesized.
5

M.A. Abdelgawad, et al.
Bioorganic Chemistry 92 (2019) 103218
These new compounds had been evaluated for their antioxidant and
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Supplementary data to this article can be found online at https://
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