Synthesis, antibacterial activities and molecular docking study of thiouracil derivatives containing oxadiazole moiety

Article abstract of DOI:10.1080/00397911.2021.1904990

A series of novel thiouracil derivatives 9 containing an oxadiazole moiety have been synthesized by structural modification of a lead SecA inhibitor, 2. These compounds have been evaluated for their antibacterial activities against Bacillus amyloliquefaciens, Staphylococcus aureus and Bacillus subtilis. Among them, compounds 9g and 9n exhibited promising antibacterial activities against the tested strains. Compound 9g was also tested for its inhibitory activities against SecA ATPase, and the IC₅₀ value of compound 9g was 19.9 μg/mL, lower than that of compound 2 (20.8 μg/mL). Molecular docking work indicates that compound 9g likely occupies the pocket formed by SecA IRA2 and NBD domain.

Full text of DOI:10.1080/00397911.2021.1904990

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis, antibacterial activities and molecular
docking study of thiouracil derivatives containing
oxadiazole moiety
Peng-Lei Cui, Di Zhang, Xiu-Min Guo, Shu-Jing Ji & Qing-Mei Jiang
To cite this article: Peng-Lei Cui, Di Zhang, Xiu-Min Guo, Shu-Jing Ji & Qing-Mei Jiang
(
2021) Synthesis, antibacterial activities and molecular docking study of thiouracil derivatives
containing oxadiazole moiety, Synthetic Communications, 51:11, 1754-1762, DOI:
0.1080/00397911.2021.1904990
1
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https://doi.org/10.1080/00397911.2021.1904990
Synthesis, antibacterial activities and molecular docking
study of thiouracil derivatives containing
oxadiazole moiety
a
b
a
a
a
Peng-Lei Cui , Di Zhang , Xiu-Min Guo , Shu-Jing Ji , and Qing-Mei Jiang
a
b
College of Science, Hebei Agricultural University, Baoding, China; College of Food Science and
Technology, Hebei Agricultural University, Baoding, China
ABSTRACT
ARTICLE HISTORY
A series of novel thiouracil derivatives 9 containing an oxadiazole
moiety have been synthesized by structural modification of a lead
SecA inhibitor, 2. These compounds have been evaluated for
their antibacterial activities against Bacillus amyloliquefaciens,
Staphylococcus aureus and Bacillus subtilis. Among them, compounds
Received 23 July 2020
KEYWORDS
Antibacterial activities;
thiouracil; molecular
docking; SecA inhibitor
9
g and 9n exhibited promising antibacterial activities against the
tested strains. Compound 9g was also tested for its inhibitory activ-
ities against SecA ATPase, and the IC50 value of compound 9g was
19.9 lg/mL, lower than that of compound 2 (20.8 mg/mL). Molecular
docking work indicates that compound 9g likely occupies the pocket
formed by SecA IRA2 and NBD domain.
GRAPHICAL ABSTRACT
Introduction
With the widespread use of antibiotics, bacterial resistance is increasingly becoming a
[
1–4]
global public health issue.
Therefore, new types of antibacterial drugs are in urgent
need. Traditionally, the search for new antibacterial agents often takes on the following
approaches: (1) modifying the known antibacterial drugs; (2) searching for novel targets
for drug discovery work; (3) developing new methods for the treatment of bacterial
[
5–7]
infection.
Along these lines, we have been interested in inhibiting the bacterial key
protein in secretory pathway (Sec pathway) as a way to achieve antibacterial effects.
The secretory pathway is an important way of transmembrane transport for the pro-
teins in bacteria, and more than 1/3 proteins were transported outside of the cytoplasm
to become functional. SecA is one of the key enzymes in the Sec machinery, which
CONTACT Peng-Lei Cui
plcui@hebau.edu.cn, 936369081@qq.com
College of Science, Hebei Agricultural
University, Baoding, China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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Figure 1. Chemical structures of compounds 1–4.
[
8,9]
provides the energy for the Sec pathway by hydrolysis of the ATP.
In addition, SecA
is conserved and essential for bacterial and does not exist in the human. SecA which is
a peripheral membrane protein should be accessible to the small molecule com-
[
10–14]
pounds.
Therefore, drug developing with SecA as a target has drawn much atten-
tion and it is very promising to find the next generation of antibacterial drugs. Known
small organic molecules that can inhibit the SecA include Rose Bengal 1, bisthiouracil
[
15–17]
2, and bistriazole derivative 3 (Figure 1).
In order to develop novel SecA inhibi-
tors as antibacterial agents, and to better understand the SAR and the biological mech-
anism of SecA, it is worthwhile to explore the chemistry space of known inhibitor to
increase structural diversity.
Recently, with the SecA as target, we adopt the active group splicing method to modify
the structure of SecA inhibitors bisthiouracil 2. There are more N and O heteroatoms in
thiouracil which seems to produce more hydrogen bonding with the target. Thiouracil
derivatives show a wide range of biological activities, such as antibacterial activity and anti-
[
18]
cancer activity.
The acyl thiourea and triazolo-thiadiazole moieties were introduced to
the compound 2 to produce a series of thiouracil derivatives containing the acyl thiourea or
triazolo-thiadiazole moieties. Some of these compounds have high SecA inhibitory activity
[
19]
and antibacterial activity, among which the compound 4 (Figure 1) showed high antibac-
terial and SecA inhibitor activities (its IC50 value against SecA was 9.7 lg/mL which was
obviously lower than that of the lead compound 2).
Oxadiazole is an important nitrogen-containing heterocyclic pharmacophore, and
[
20,21]
their derivatives have many biological activities, such as anti-cancer,
anti-inflam-
According to the method of
combinatorial optimization,” herein, we would like to report the design and synthe-
[
22,23]
[24,25]
matory,
anti-bacterial and anti-fungal effects.
“
sis of a series of compounds 9, containing oxadiazole (Figure 2), modified from the
parent compound 2. We hypothesize that the oxadiazole scaffolds could mimic the
thiouracil to have the capability to form more hydrogen bonding interaction with
the target protein SecA, and would be beneficial to improve the antibacter-
ial activity.

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P.-L. CUI ET AL.
Results and discussion
Chemistry
The synthetic route of the desired thiouracil derivatives containing an oxadiazole moiety
9
are shown in Scheme 1. The synthesis started with aromatic aldehydes reacting with
semicarbazide to give compound 5, which was converted to compound 6 upon reaction
with bromine. And this compound and 4-(chloromethyl)benzoyl chloride were dissolved
in dry tetrahydrofuran and reacted at room temperature to obtain intermediate 7. The
elimination of hydrogen chloride in the reaction process will increase the acidity of the
reaction system, protonation the amino group in compound 6, and reduce the reaction
activity. Therefore, in order to make the reaction smoothly, basic substances (such as
Figure 2. Design strategy for target compounds 9.
Scheme 1. Synthesis of compounds 9. Conditions and reagents: (a) water/ethanol reflux; (b) acetic
acid/sodium acetate, bromine, r. t.; (c) THF, TEA, r.t.; (d) K CO , acetonitrile, reflux.
2
3

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Table 1. In vitro anti-bacterial activity of compounds 9a–o.
MIC (lg/mL)
Compounds
R1
R2
Bacillus amyloliquefaciens
Staphylococcus aureus
Bacillus subtilis
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
2
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
H
H
H
H
H
H
4-CH
4-OCH
4-Ph
2-Cl
4-Cl
2,4-diCl
H
100
>100
>100
100
50
50
25
100
50
100
50
50
50
50
50
12.5
25
100
100
>100
>100
50
50
6.25
50
100
50
25
25
50
50
100
100
50
25
50
6.25
100
100
50
50
25
3
3
H
H
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
4-CH
3
4-OCH
4-Ph
2-Cl
4-Cl
2,4-diCl
3
25
12.5
50
50
12.5
25
25
25
2,6-diCl
Norfloxacin
25
triethylamine) are added as acid binding agent. The aromatic aldehyde reacted with
[
12]
ethyl cyanoacetate and thiourea to give compound 8 with the 50–75% yield.
The sub-
stituents on the benzene ring of aromatic aldehydes have a great influence on the yield.
For example, the yield of aromatic aldehydes with 4-ph in the benzene ring with higher
steric hindrance is lower. The compound 8 further on reaction with thiouracil 7 in
acetonitrile under reflux gave the target 9. The structures of all the new compounds
were characterized by NMR, MS, and elemental analysis.
Taking the structure of compound 9a as an example, in the NMR spectra, the single
peak at the chemical shift d 4.313 is the proton signal peak of CH between the sulfur
2
atom and the benzene ring, and the other are the proton signal peak on the ben-
zene ring.
Biological assay
In vitro antibacterial activity
The in vitro antibacterial activities of the new compounds 9a–o were tested and the
tested strains included Bacillus amyloliquefaciens, Bacillus subtilis and Staphylococcus
aureus. Norfloxacin and the lead compound 2 (Figure 1) were selected as control (the
results are shown in Table 1). The results show that some of the compounds, such as
9
e, 9g, 9k, 9l, 9m and 9n have strong and selective antibacterial activities. Among
them, compound 9g had the strongest inhibitions, and MIC values against the three
tested bacteria were 25, 12.5, 12.5 lg/mL respectively, which were similar with that of
norfloxacin, or even lower. In addition, the MIC of compounds 9e, 9l and 9m against
Bacillus subtilis were 25 lg/mL and that of 9n was 12.5 lg/mL. Their inhibitory activities
against Bacillus subtilis were superior to that of compound 2. The MIC of compounds
9
k, 9l and 9o against Staphylococcus aureus were 25 lg/mL and that of 9n was 12.5 lg/
mL, which showed strong inhibition against Staphylococcus aureus, similar with that of
the compound 2 and norfloxacin. The anti Bacillus amyloliquefaciens activities of other
compounds in compound 9a–o were generally lower than that of compound 2 and

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P.-L. CUI ET AL.
Figure 3. SecA Inhibitory activities of 9g and 2.
norfloxacin, except 9g. When R2 is 2,4-diCl, compounds 9g and 9n have more
higher antibacterial activities than the others, but there are CH or OCH on the phenyl
3
3
near the thiouracil the new compounds have poor activities which indicated that when
there are more Cl in R the newly synthesized have more stronger activities. It seems
2
that the introduction of Cl atoms on the marginal phenyls would be helpful for
the activities.
SecA inhibitory activity test
The most potent compounds 9g were evaluated for their inhibitory activities against
SecA ATPase sourced from BL21.19 [secA(am) supFtstrp (am)zch::Tn10recA::catclp
A::kan]. The results indicated that compound 9g showed significant enzyme inhibitory
activity as shown in Figure 3. For example, the inhibition by 9g was (50.1 ± 1.7)% at
2
0 lg/mL and (59.3 ± 1.6)% at 25 lg/mL respectively, which were slightly higher than
those of compound 2 at the same concentrations. Compound 9 g was studied for its
0% inhibitory concentration (IC ), and the IC value was 19.9 lg/mL, which was
5
5
0
50
lower than that of compound 2 (20.8 lg/mL). It seems that both compounds 9 g and 2
have antibacterial activities as SecA inhibitors.
Computational modeling
To achieve some initial insights into the binding interactions,
[
26–28]
the newly synthe-
sized compound 9g was docked into the SecA crystal structure. Two possible binding
pockets were selected: the ATPase ATP-binding site and the pocket, which is formed by
[
18,19]
IRA2 and NBD domain, as proposed before.
20 outputs were generated and the
docking scores were 3.78–5.61 at the ATP-binding site and 5.00–6.67 at the pocket.
Thus, it is reasonable to suggest that the new inhibitor binds at a similar position as the
lead structure. The interactions are shown in Figure 4: molecule 9g generated hydro-
gen-bond interactions with SER213, ALA507, GLY508, GLY510 and ARG566.

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Figure 4. The proposed docking conformation of the compound 9g (pink sticks). Protein structures
are shown in cyan sticks and ribbons. The molecule ATP is shown in cyan sticks.
Conclusions
A series of thiouracil derivatives containing oxadiazole 9 were designed, synthesized and
evaluated for their antibacterial activities. Some of the compounds 9 have strong anti-
bacterial activities. Additionally, compound 9g expressed stronger inhibitory activity
against the SecA ATPase than the known inhibitor 2, suggesting that both compounds
are antibacterial agents as SecA inhibitors. Molecular simulation showed that compound
9
g likely binds to a pocket formed by SecA IRA2 and NBD domain.
Experimental
Column chromatography was carried out on flash silica gel (300–800 mesh). TLC ana-
lysis was conducted on silica gel plates (Silica G UV254). Melting points were measured
in an open capillary on a SGW X-4 melting point apparatus and are uncorrected.
Element analysis was performed using a Heraeus (CHNO, rapid) elemental analyzer.
1
13
NMR spectra were recorded at 600 MHz for H and 150 MHz for C on a Bruker
instrument. Chemical shifts (d values) and coupling constants (J values) are given in
1
ppm and hertz, respectively, using TMS ( H NMR) as internal standard. ESI-MS spectra
were determined using an Agilent G6300 ion Trap mass spectrometer, and signals were
recorded in m/z. Absorption spectra were recorded on a FLUOstar Omega
Microplate Reader.
General procedures for preparation of compounds 9
To a solution of the aldehyde (RCHO, 10 mmol), ethyl cyanoacetate (1.0 mL, 10 mmol),
and thiourea (0.76 g, 10 mmol) in absolute ethanol (50 mL) was added piperidine
(2.0 mL, 20 mmol); the mixture was refluxed overnight and then cooled to room

1
760
P.-L. CUI ET AL.
temperature. The precipitate was dissolved in 0.5 M NaOH (20 mL) and washed
with ethyl acetate (10 mL ꢀ 3). The aqueous solution was acidified to pH 2 by slow
addition of 1 M HCl. Then the product precipitated (crystallized) out to give
[
18,19]
compound 8.
Semicarbazide (5 mmol) and water (50 mL) were added into a 250 mL flask and
stirred to dissolve. Then aromatic aldehyde (5 mmol) and ethanol (20 mL) were added
and the mixture was stirred under reflux reaction for 3 h to give crude 5. This crude
product was recrystallized from ethanol to give the pure product 5. Compound 5
(3 mmol), anhydrous sodium acetate (6 mmol) and glacial acetic acid (12 mL) were
added into a 100 mL flask and stirred to dissolve, then the mixture of bromine (0.6 mL)
and glacial acetic acid (2 mL) were slowly added to stir at room temperature. After com-
pletion of the reaction, the mixture was poured into ice-water (100 mL) to give white
precipitate, filtered and recrystallized from ethanol to give compound 6.
4-(Chloromethyl)benzoyl chloride (2 mmol), dry tetrahydrofuran (20 mL) and trime-
thylamine (2 mL) were added into a 100 mL flask and stirred to dissolve. Then the com-
pound 6 (2 mmol) was added to stir at room temperature for 12 h. After completion of
the reaction, the mixture was poured into cold water (150 mL). The tetrahydrofuran dis-
solved in water, then the light yellow precipitate was produced, filtered and dried to
give compound 7.
A solution of compound 8 (1.1 mmol), compound 7 (1 mmol) and K CO (3 mmol)
2
3
in acetonitrile (30 mL) were heated under reflux reaction. After the completion of this
reaction monitored by TLC, the solvent was removed to obtain crude 9. Compound 9
was washed with 0.2 mol/L NaOH, then dried and separated by column chromatography
(Vethyl acetate/Vmethanol ¼ 8:1–15:1) to obtain the target products 9.
4
-(((5-Cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl)thio)methyl)-N-(5-phenyl-1,3,4-
oxadiazol-2-yl)benzamide(9a)
Light yellow powder (75%), m.p. 234.2–237.3 C; H NMR (DMSO-d , 600 MHz) d:
ꢁ
1
6
8
.003–8.016(d, J ¼ 7.8 Hz, 1H, ArH), 7.867–7.879 (d, J ¼ 7.2 Hz, 1H, ArH), 7.750–7.760
(
m, 4H, ArH), 7.497–7.510 (d, J ¼ 7.8 Hz, 2H, ArH), 7.456–7.467 (m, 4H, ArH),
13
7
1
1
.348–7.361 (d, J ¼ 7.8 Hz, 2H, ArH), 4.313 (s, 2H, CH ); C NMR (DMSO-d ,
2
6
50 MHz) d: 170.31, 169.30, 167.08, 166.37, 138.68, 137.25, 129.57, 128.99, 128.88,
28.54, 128.45, 128.07, 128.01, 127.82, 126.81, 124.91, 33.75; MS (ESI) m/z: 505.0 ([M-
þ
H] ). Anal. Calcd for C H N O S: C, 64.02; H, 3.58; N, 16.59. Found: C, 64.10; H,
2
7
18 6 3
3.70; N, 16.68.
Experimental procedures and characterization data associated with this article can be
found, in the online version.
Acknowledgments
We gratefully acknowledge Prof. Binghe Wang and the use of Orion that is supported by
Georgia State University’s Research Solutions and the free academic licensing program of
Openeye. We gratefully acknowledge Prof. Liyan Yu in the Chinese Academy of Medical Sciences
for the evaluation of inhibitory activities against SecA ATPase.

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Disclosure statement
The authors declare that they have no known competing financial interests or personal relation-
ships that could have appeared to influence the work reported in this paper.
Funding
This research was supported financially by the Natural Science Foundation of Hebei Province
[
B2019204032] and the Scientific Research Project of Hebei Agricultural University for Self-
trained Talents [PY201812].
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