Synthesis, biochemical evaluation and computational simulations of new cytochrome bc1 complex inhibitors based on N-(4-aryloxyphenyl) phthalimides

Article abstract of DOI:10.1016/j.cclet.2018.10.008

The cytochrome bc₁ complex (the bc₁ complex or complex III) is an attractive target for the discovery of numerous pharmaceuticals and pesticides. In order to identify new lead structures for this target, a new series of molecules, N-(4-aryloxyphenyl)phthalimides, were designed and synthesized in a straightforward manner. Our design strategy was to introduce a 4-aryloxyphenyl group, a fragment which exhibited promising bc₁ complex-inhibiting properties, into the aryl group of the valuable N-arylphthalimide backbone. Afterward, the biochemical evaluation of the newly synthesized compounds was carried out, and the results implied that several compounds demonstrated good activities against succinate-cytochrome reductase (SCR, a mixture of mitochondrial complex II and the bc₁ complex). Further studies confirmed that 3e′ a representative compound in this paper, was identified as an inhibitor of the bc₁ complex. Furthermore, computational simulations were also performed to better understand binding of 3e′ to the enzyme complex, which indicated that 3e′ should bind to the Q_o site of the bc₁ complex. Consequently, we harbor the idea that this paper can provide a solid platform for synthesis and discovery of other bc₁ complex inhibitors.

Full text of DOI:10.1016/j.cclet.2018.10.008

Accepted Manuscript
Title: Synthesis, biochemical evaluation and computational
simulations of new cytochrome bc complex inhibitors based
1
on N-(4-aryloxyphenyl) phthalimides
Authors: Hua Cheng, Yan Fu, Qing Chang, Ni Zhang,
Mengwei Bu, Yan Niu, Qiongyou Wu, Chen Cheng, Francis
Verpoort
PII:
DOI:
Reference:
S1001-8417(18)30394-2
https://doi.org/10.1016/j.cclet.2018.10.008
CCLET 4672
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
26-8-2018
30-9-2018
9-10-2018
Please cite this article as: Cheng H, Fu Y, Chang Q, Zhang N, Bu M, Niu Y, Wu Q,
Cheng C, Verpoort F, Synthesis, biochemical evaluation and computational simulations
of new cytochrome bc complex inhibitors based on N-(4-aryloxyphenyl) phthalimides,
1
Chinese Chemical Letters (2018), https://doi.org/10.1016/j.cclet.2018.10.008
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Communication
Synthesis, biochemical evaluation and computational simulations of new cytochrome
bc complex inhibitors based on N-(4-aryloxyphenyl)phthalimides
1
a
a
a
e
a
c
c
b,*
Hua Cheng , Yan Fu , Qing Chang , Ni Zhang , Mengwei Bu , Yan Niu , Qiongyou Wu , Cheng Chen ,
b,d,*
Francis Verpoort
a
Department of Chemical Engineering and Food Science, Hubei University of Arts and Science, Xiangyang 441053, China
State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, China
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, China
National Research Tomsk Polytechnic University, Tomsk 634050, Russian Federation
b
c
d
e
Hubei University of Technology Engineering and Technology College, Wuhan 430068, China
*
Corresponding authors.
E-mail addresses: chengchen@whut.edu.cn (C. Chen), Francis.Verpoort@ghent.ac.kr (F. Verpoort).
Graphical abstract
1
A series of N-(4-aryloxyphenyl)phthalimides were synthesized and identified as new inhibitors of the cytochrome bc complex. Furthermore, results obtained
from computational simulations indicated that 3e′ should bind to the Q site of the bc complex.
o
1
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
1 1
The cytochrome bc complex (the bc complex or complex III) is an attractive target for the
discovery of numerous pharmaceuticals and pesticides. In order to identify new lead structures
for this target, a new series of molecules, N-(4-aryloxyphenyl)phthalimides, were designed and
synthesized in a straightforward manner. Our design strategy was to introduce a 4-
Available online
1
aryloxyphenyl group, a fragment which exhibited promising bc complex-inhibiting properties,
into the aryl group of the valuable N-arylphthalimide backbone. Afterward, the biochemical
evaluation of the newly synthesized compounds was carried out, and the results implied that
several compounds demonstrated good activities against succinate-cytochrome reductase
Keywords:
Cytochrome bc complex
1
Inhibitor
N-(4-Aryloxyphenyl)phthalimide
Synthesis
(
SCR, a mixture of mitochondrial complex II and the bc
that 3e′, a representative compound in this paper, was identified as an inhibitor of the bc
complex. Furthermore, computational simulations were also performed to better understand
binding of 3e′ to the enzyme complex, which indicated that 3e′ should bind to the Q site of the
bc complex. Consequently, we harbor the idea that this paper can provide a solid platform for
synthesis and discovery of other bc complex inhibitors.
1
complex). Further studies confirmed
1
o
Biochemical evaluation
Computational simulation
1
1
Cytochrome bc
1
complex (complex III, EC 1.10.2.2, bc
1
), one of the five multiprotein complexes (complexes I-V), are essential
components of the respiratory chain [1]. Generally, the bc
1
complex is proposed to operate via a Q-cycle mechanism. Based on this
mechanism, it can catalyze the electron transfer from ubiquinol to cytochrome c. At the same time, it couples this electron transfer and
the translocation of protons across the membrane. Accordingly, a proton gradient and membrane potential are generated to drive ATP
synthesis [2-5]. Since the bc
targets for numerous pharmaceuticals and agrochemicals. Over the recent years, great attention has been paid to the development of
various bc complex inhibitors [6-20]. Although numerous inhibitors have been disclosed, discovering active inhibitors with new
scaffolds is still highly desirable [21-24].
1
complex plays a pivotal role in the life process, it has been demonstrated as one of the most attractive
1

4
-Aryloxyphenyl scaffolds draw our considerable attention since they exhibit promising biological activities, especially inhibitory
activities against the bc complex [6,15,25-27]. For instance, compound A, obtained by structural modifications from the natural
product antimycin A, was recognized as a potent inhibitor of the bc complex (Fig. 1a) [6,25]. Moreover, compound B was identified
as an excellent bc complex inhibitor, and it also displayed superb antimalarial activities (Fig. 1a) [15,26]. As the continuation of
developing new and active bc complex inhibitors, we assumed that new structures containing a 4-aryloxyphenyl moiety could be
1
1
1
1
beneficial for discovering new inhibitors of this target. Besides, N-arylphthalimides have attracted our great interest due to their
biological and pharmacological activities [28-44]. In addition, the N-arylphthalimide scaffold features chemical diversity which can be
achieved from easily accessible building blocks. Therefore, employing a 4-aryloxyphenyl group as the aryl motif of N-arylphthalimides
could provide N-(4-aryloxylphenyl)phthalimides, which could be potentially active bc
Herein, we planed to synthesize a series of target compounds and evaluate their inhibitory activities against the bc
1
complex inhibitors (as shown in Fig. 1b).
complex. To our
1
delight, a few active inhibitors were found after extensive screening. Furthermore, computational simulations were performed to
investigate the interaction between a representative inhibitor and the target enzyme. Based on these experimental and theoretical
studies, we envisioned that the newly synthesized compounds were presumably inhibitors binding to the Q site of the bc complex.
o 1
Fig. 1. (a) Representative bc
inhibitors of the bc complex.
1
complex inhibitors A and B containing 4-aryloxyphenyl moieties; (b) N-(4-aryloxylphenyl)phthalimides as potential
1
Scheme 1. The synthetic route of our designed molecules 3.
The conventional method for the synthesis of these compounds was illustrated by reacting 4-aryloxy anilines with phthalic
anhydrides [45-53]. Very recently, Jiang and co-workers reported a carbonylation access to phthalimides using self-sufficient directing
group and nucleophile [54]. Herein, in order to construct a broad range of N-(4-aryloxyphenyl)phthalimides in a facile and efficient
manner, we focused our attention to the easily-accessible standard method. Expectedly, plenty of N-(4-aryloxyphenyl)phthalimides 3
could be afforded by treatment of 4-aryloxy anilines 1 with phthalic anhydrides 2 (as depicted in Scheme 1). It was worth mentioning
that the three phenyl rings of 3 were assigned as A, B and C, respectively so as to facilitate our further explanations. Based on the
reported procedures [45-47], we identified the optimized reaction conditions as 1 (1.0 mmol) and 2 (1.0 mmol) in refluxing acetic acid
(5.0 mL), and were used for further study unless otherwise noted (as illustrated in Table S1 and related description in Supporting
information). With the optimized reaction conditions in hand, target products 3a−r were prepared by the reactions of 2a with various 4-
aryloxy anilines (Fig. S1 in Supporting information). In addition, the reactions of 1a with various phthalic anhydrides were also
explored to yield products 3s−a′ (Table S2 in Supporting information).
Succinate-cytochrome c reductase (SCR), a mixture of mitochondrial complex II (succinate-ubiquinone oxidoreductase) and the bc
1
complex, was selected as the target enzyme for initial biochemical evaluation of the above compounds. Several compounds exhibited
modest levels of inhibition against SCR at a concentration of 10 μmol/L even though low activities were observed for most
compounds, which encouraged us to conduct further structural modifications (Table 1, entries 1-27). We would like to emphasize that
the IC50 values of those compounds with inhibitory rates of above 50% at the concentration of 10 μmol/L were further measured (Table
1
). It was found that a methyl group at R
2 2
was beneficial for the inhibition potency (entry 27). Thus, R was fixed as methyl, and
different substituents on R -R were employed to afford compounds 3b′−d′ in excellent yields (entries 28-30). To our delight, 3b′
3
5
manifested better inhibitory activities than 3a′ in terms of IC50 values (2.08 μmol/L for entry 28 vs. 6.91 μmol/L for entry 27). It was
worth noting that the low levels of inhibition for our target molecules were attributed to the poor aqueous solubility in most cases, so a
hydrophilic carboxylic group was introduced into the molecular structures to give compounds 3e′−g′ (entries 31-33). Notably,
compound 3e′ exhibited good inhibition potency with an IC50 value of 1.74 μmol/L (entry 31). In order to further confirm whether
these compounds were inhibitors of the bc
and the bc complex were evaluated and shown in Table 2. Expectedly, penthiopyrad and azoxystrobin, the selected two commercial
agents, demonstrated excellent activities against complex II and the bc complex, respectively. Similar with azoxystrobin, 3e′ showed a
low inhibition rate against complex II, but selective inhibition against the bc complex. Therefore, 3e′ has been validated as an inhibitor
of the bc complex.
1
complex, the inhibitory activities of representative inhibitor 3e′ against SCR, complex II
1
1
1
1

It has been well-documented that the bc
membrane [55-57]. Therefore, with an aim to further ascertain the binding site of these inhibitors, representative inhibitor 3e′ was
docked into both Q and Q sites to obtain the respective 3e′-Q and 3e′-Q complexes. When 3e′ was docked into the Q site, the
calculated binding free energy was −8.80 kcal/mol for the best binding conformation by using the semi-empirical score function in
AutoDock 4.0. Nevertheless, the binding free energy was calculated as −6.57 kcal/mol if it bound to the Q site (Table S3 in Supporting
1 o i
complex has two quinol/quinone binding sites (Q and Q sites) on opposite sides of the
o
i
o
i
o
i
information). Moreover, 10 ns molecular dynamics (MD) simulations were obtained for both complexes, and the 100 snapshots
achieved from the last 1 ns of each complex were used to calculate the binding free energy. As shown in Table S3, the binding free
energy of 3e′-Q
Boltzmann surface area (MM/PBSA) method in Amber16 program, respectively. Therefore, these results suggested that 3e′ might bind
to the Q site of the bc complex.
Except for the above calculations, plot of root-mean-square deviation (RMSD) of the protein backbone and inhibitor atoms
throughout the whole process of MD simulation were examined from the MD trajectories to evaluate the stability of the 3e′-Q and 3e′-
complexes (Fig. 2). Besides, molecular docking experiments for both binding sites were also done and depicted in Fig. 3. The results
implied that the 3e′-Q complex was very stable within the applied simulation time (Fig. 2A). For the docking of 3e′ into the Q site, it
formed an H-bond with key residue E272, and hydrophobic interactions with F275, F129, F151, I147, L195 and P271 (Fig. 3A)
However, obvious fluctuation was clearly spotted in the MD trajectory of the 3e′-Q complex (Fig. 2B), which was probably due to its
instablity. Moreover, 3e′ formed weak π-π hydrophobic interactions with F18 and F220 of the Q site in Fig. 3B. In order to evaluate
the reliability of our docking results, azoxystrobin (the commercial Q -site inhibitor used as a control agent for bioassays) and
famoxadone (a commercial Q -site inhibitor which bears a 4-aryloxyphenyl group) were docked into the the Q site (as shown in Fig.
C and 3E, respectively). In addition, an overlay of 3e′ and azoxystrobin or famoxadone in the Q site was also demonstrated in Fig.
D or Fig. 3F. These results indicated that 3e′, azoxystrobin and famoxadone formed H-bonds with the key residue E272. However,
o i
and 3e′-Q complexes were calculated as −9.48 and −1.03 kcal/mol using the molecular mechanics/Poisson-
o
1
o
Q
i
o
o
i
i
o
o
o
3
3
o
these two commercial agents could form more hydrophobic interactions with active site residues than 3e′. On the basis of all the above
results, it was proposed that 3e′ should be a Q -site inhibitor.
o
Table 1
Inhibitory activities of the synthesized compounds against porcine SCR.
a
b
c
Entry
Compd.
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
R
1
R
2
R
3
R
4
R
H
2-F
2-Cl
2-Br
2-CN
4-OMe
4-OBn
4-CN
2,3-F
2,4-Cl
2-F-5-Br
5
Yield (%)
90
85
89
81
82
83
82
76
80
87
75
88
81
84
75
84
I (%) , IC50 (μmol/L)
b
c
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
F
5 , >10
15 , >10
10 , >10
3 , >10
15 , >10
18 , >10
16 , >10
1 , >10
26 , >10
22 , >10
3 , >10
6 , >10
24 , >10
21 , >10
16 , >10
43 , >10
b
c
c
b
b
c
b
c
c
c
b
b
b
c
b
c
2
b
c
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
2
b
c
b
c
2-F-5-CF
H
H
3
b
c
c
c
b
b
c
b
Br
H
Cl
Cl
Cl
d
b
1-Naphthyl
b
Cl
Cl
H
2,4-Cl
2,4,6-Cl
3-Chloro-5-
trifluoromethyl)pyridin-
2
b
3
83
72
38 , >10
15 , >10
b
(
d
2
-yl
b
c
c
c
c
c
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
3s
3t
3u
3v
3w
3x
3y
3z
3a′
3b′
3c′
3d′
3e′
3f′
3g′
F
Cl
H
H
H
H
H
F
Cl
NO
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
H
Cl
Cl
H
H
H
H
H
H
H
H
H
H
Cl
Cl
H
Cl
Cl
H
H
H
H
H
H
H
H
82
84
81
83
84
72
75
76
85
85
82
84
70
65
60
39 , >10
21 , >10
46 , >10
10 , >10
19 , >10
7 , >10
47 , >10
23 , >10
55 , 6.91 ± 0.12
70 , 2.08 ± 0.15
47 , >10
5 , >10
85 , 1.74 ± 0.08
81 , 4.38 ± 0.29
56 , 7.39 ± 0.57
95 , 0.29 ± 0.01
b
b
NO
Me
2
b
t
b
Bu
b
c
H
H
H
H
H
H
H
COOH
COOH
COOH
b
c
c
b
2
b
b
b
H
2,4-Cl
2,4-Cl
2,4,6-Cl
2,4-Cl
2,4-Cl
b
2
b
b
2
b
b
3
b
b
b
b
b
2
b
H
H
2
b
2,4,6-Cl
3
b
Azoxystrobin
a
Isolated yields.

b
c
d
Inhibition rates at a concentration of 10 μmol/L.
IC50 values against SCR.
The whole ring A was substituted with this group.
Table 2
The inhibition effects of the selected inhibitors against SCR, complex II and the bc
1
complex.
Complex II
IC50 (μmol/L)
SCR
Entry
Compound
1
The bc complex
a
1
3
4
3e′
1.74 ± 0.08
1.32 ± 0.11
0.29 ± 0.01
29%
3.55 ± 0.13
a
Penthiopyrad
Azoxystrobin
1.19 ± 0.12
< 10%
a
23%
0.53 ± 0.02
a
Inhibition rates at a concentration of 10 μmol/L.
Fig. 2. Time dependence of the RMSD of the whole protein atoms (color in black), protein backbone atoms (color in red) and inhibitors (color in green) (A) 3e′-
and (B) 3e′-Q complexes.
Q
o
i
Fig. 3. (A) The binding mode of 3e′ in the Q
3
o
site. (B) The binding mode of 3e′ in the Q
L71). (D) The overlay of 3e′ and azoxystrobin in the Q site. (E) The binding mode of famoxadone in the Q
site. The red dashed lines in (A), (B), (C) and (E) represent the H-bond distances between an inhibitor and a residue. In addition, the H-bond distances
i
site. (C) The binding mode of azoxystrobin in the Q
o
site (PDB ID:
o
o
site. (F) The overlay of 3e′ and famoxadone in the
Q
o
between 3e′ or azoxystrobin and the residue were depicted in red and blue dashed lines of (D), respectively; the H-bond distances between 3e′ or famoxadone
and the residue were depicted in red and blue dashed lines of (F), respectively.
In summary, a new series of N-(4-aryloxyphenyl)phthalimides with various substituents were synthesized via a simple and efficient
method. With these newly prepared compounds in hand, their inhibitory activities against SCR were evaluated. To our delight, a few
compounds exhibited good inhibition potency against SCR. Especially, compound 3e′ was found to be the most potent inhibitor, and it
was further confirmed to inhibit exclusively the activity of the cytochrome bc
bc complex contains two binding sites, so computational simulations were utilized to clarify the binding site of our compounds. The
results indicated that representative inhibitor 3e′ probably bound to the Q site of the bc complex. Hopefully, this work could be of
1
complex. Furthermore, it has been well-known that the
1
o
1
1
great value for the development of other bc complex inhibitors.
Acknowledgments
This research was supported by the National Natural Science Foundation of China (Nos. 21502062, 21272091 and 21472063),
Hubei Provincial Department of Education (No. Q20102606), Xiangyang Science and Technology Bureau (No. 2010GG1B33), and
Structural Biomedicine and Pharmacochemistry of Hubei University of Arts and Science. Francis Verpoort acknowledges the support
from the Russian Foundation for Basic Research (No. 18-29-04047) and the Tomsk Polytechnic University Competitiveness
Enhancement Program grant (No. VIU-195/2018).
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