Synthesis of new 4-aryloxy-N-arylanilines and their inhibitory activities against succinate-cytochrome c reductase

Article abstract of DOI:10.1016/j.bmcl.2018.03.014

Succinate-cytochrome c reductase (SCR) is composed of a mixture of mitochondrial complex II (succinate-ubiquinone oxidoreductase) and complex III (cytochrome bc₁ complex). Meanwhile, complexes II and III are two promising targets of numerous antibiotics and fungicides. With an aim to identify new lead structures for SCR, complex II or III, a new series of 4-aryloxy-N-arylanilines were synthesized by introducing a 4-aryloxy phenyl group as one of the aryl groups in diaryl amines. With the economic Cu(OAc)₂·H₂O as the optimal copper promoter, a simple and facile protocol was utilized to afford 24 target products in 56–93% yields. Furthermore, extensive screening results suggested variable inhibitory activities of these compounds against SCR. Exceptionally, compounds 7k–7n showed excellent inhibition potency with their IC₅₀ values in the nanomolar range, demonstrating higher potency than the commercial controls (penthiopyrad and azoxystrobin) by over one order of magnitude.

Full text of DOI:10.1016/j.bmcl.2018.03.014

Accepted Manuscript
Synthesis of new 4-aryloxy-N-arylanilines and their inhibitory activities against
succinate-cytochrome reductase
Hua Cheng, Wei Song, Ren Nie, Yu-Xia Wang, Hui-Lian Li, Xiang-Sheng
Jiang, Jun-Jun Wu, Qiong-You Wu, Cheng Chen
PII:
S0960-894X(18)30193-8
https://doi.org/10.1016/j.bmcl.2018.03.014
BMCL 25668
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
12 December 2017
23 January 2018
5 March 2018
Please cite this article as: Cheng, H., Song, W., Nie, R., Wang, Y-X., Li, H-L., Jiang, X-S., Wu, J-J., Wu, Q-Y.,
Chen, C., Synthesis of new 4-aryloxy-N-arylanilines and their inhibitory activities against succinate-cytochrome
reductase, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.03.014
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1
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Synthesis of new 4-aryloxy-N-arylanilines and their inhibitory activities against
succinate-cytochrome reductase
Hua Cheng a, Wei Song a, Ren Nie a, Yu-Xia Wang c, Hui-Lian Li a, Xiang-Sheng Jiang a, Jun-Jun Wu a,
Qiong-You Wu c, * and Cheng Chenb, ∗
a Department of Chemical Engineering and Food Science, Hubei University of Arts and Science, Xiangyang 441053, P. R. China;
bState Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, P. R. China.
c Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Succinate-cytochrome reductase (SCR) is composed of a mixture of mitochondrial complex II
(succinate-ubiquinone oxidoreductase) and complex III (cytochrome bc1 complex). Meanwhile,
complexes II and III are two promising targets of numerous antibiotics and fungicides. With an
aim to identify new lead structures for SCR, complex II or III, a new series of 4-aryloxy-N-
arylanilines were synthesized by introducing a 4-aryloxy phenyl group as one of the aryl groups
in diaryl amines. With the economic Cu(OAc)2•H2O as the optimal copper promoter, a simple
and facile protocol was utilized to afford 24 target products in 56-93% yields. Furthermore,
extensive screening results suggested variable inhibitory activities of these compounds against
SCR. Exceptionally, compounds 7k-7n showed excellent inhibition potency with their IC50
values in the nanomolar range, demonstrating higher potency than the commercial controls
(penthiopyrad and azoxystrobin) by over one order of magnitude.
Received in revised form
Accepted
Available online
Keywords:
4-Aryloxy-N-arylanilines
Synthesis
Inhibitory activities
Succinate-cytochrome reductase (SCR)
Mitochondrial complex II
Mitochondrial complex III
2016 Elsevier Ltd. All rights reserved.
Oxidative phosphorylation and the Krebs cycle constitute the
highly effective mitochondrial respiration. In animals and
bacteria, the oxidative phosphorylation system is composed of
five multiprotein complexes (complexes I, II, III, IV, and V) and
two mobile electron carriers (ubiquinone and cytochrome c).1
Among them, complex II (succinate-ubiquinone oxidoreductase)
and complex III (cytochrome bc1 complex) are two essential
components of the cellular respiratory chain, while succinate-
cytochrome reductase (SCR) contains a mixture of these two
complexes. The function of complex II is to catalyze the
oxidation of succinate to fumarate with concomitant reduction of
ubiquinone to ubiquinol.2-6 On the other hand, complex III
catalyzes the electron transfer from ubiquinol to a water-soluble
cytochrome c (cyt c) and couples this electron transfer to the
translocation of protons across the membrane, which generates a
proton gradient and membrane potential for ATP synthesis.7-10
Due to their pivotal roles in the life cycle, complexes II and III
have been identified as the promising targets for the development
of numerous pharmaceuticals and agrochemicals. Recently, novel
———
and potent inhibitors of complex II1, 11-16 and complex III1, 17-28
have been successfully discovered. However, due to their long-
term use and high application rates, many pathogens have
developed serious resistance toward the existing inhibitors.15, 29-32
Therefore, discovery of highly active lead compounds bearing
novel structures is highly desirable.
Diaryl ether scaffolds have attracted our great interest because
of their wide availability in a number of bioactive compounds.33-
37
Among this class of compounds, 4-aryloxyphenyl derivatives
are particularly interesting since they exhibit promising activities,
especially against complexes II and III.1,
26, 38-40
For instance,
compound 1, modified from the natural product Antimycin A,
was recognized as a potent inhibitor of complex III (Fig. 1a).38
Further structural modification by incorporating an azole-fused
salicylamide with a 4-(4-chlorophenoxy) phenyl group produced
2a and 2b, which also showed excellent inhibitory activities
against complex III (Fig. 1b).39 Moreover, compound 3 displayed
not only superb inhibition potency against complex III, but also
40
excellent antimalarial drug properties (Fig. 1c).26, Recently,
∗ Corresponding authors. Tel.: +86-27-87651837; fax: +86-27-67867141; e-mail: chengchen@whut.edu.cn (C. Chen);
qywu@mail.ccnu.edu.cn (Q. –Y. Wu).

2
1,2,4-triazole-1,3-disulfonamide 4, which contains a 4-aryloxy
aryl moiety, was identified as a dual inhibitor of complexes II
and III by us (Fig. 1d).1 Therefore, it is highly desirable to
prepare new series of 4-aryloxyphenyl derivatives with versatile
and simplified chemical structures.
Next, optimization of reaction conditions was performed for
the synthesis of the target molecules, and reaction of 5a with 6a
was chosen as the model reaction (as shown in Table 1). Initially,
screening of different copper salts were performed. Cu(OAc)2, a
frequently used promoter for Chan-Lam coupling between
anilines and arylboronic acids, was first attempted. To our
delight, in the presence of 1 equiv. of Cu(OAc)2, 2.00 equiv. of
K2CO3 and DMF as the solvent, compound 7a was obtained in a
60% isolated yield after 48 h at room temperature (entry 1).
When the anhydrous copper salt was changed to the
corresponding monohydrate, a slightly reduced yield was given
(entry 2). However, only trace product was observed when other
copper sources were involved (entries 3-8). Although anhydrous
Cu(OAc)2 was found to be optimal, its monohydrate was selected
as the copper salt for further optimization from the economic
point of view. Secondly, we explored the effect of different bases
on the product yield. The reaction didn’t proceed with Cs2CO3 or
pyridine (entries 9-10). Interestingly, compared with K2CO3, a
slightly improved yield (73% in entry 11 vs. 60% in entry 1) and
shorter reaction time (36 h in entry 11 vs. 48 h in entry 1) were
observed for Et3N. After setting up the best base, we next
optimized the influence of solvents on this reaction. Among the
solvents investigated, acetonitrile was demonstrated to be the
best one and provided a yield of 90% within the same reaction
time (entries 11-13). Furthermore, catalytic amounts of
Cu(OAc)2·H2O resulted in much lower yields even after longer
reaction time (entries 14-16). Therefore, the optimized reaction
conditions, identified as 5 (1.00 mmol), 6 (2.00 mmol),
Cu(OAc)2·H2O (1.0 mmol), Et3N (2.00 mmol) and acetonitrile (5
mL), were used for further study unless otherwise noted.
As a continuous interest of our research work on the
development of potent inhibitors with novel scaffolds, we believe
that new skeletons bearing 4-aryloxyphenyl moieties might be
useful for discovering novel inhibitors of SCR, complex II or
complex III. Indeed, diarylamines draw considerable attention
due to their wide applications in natural products,41 polymers,42
and bioactive molecules.43-45 Since 4-aryloxyphenyl moieties are
also aromatic groups, we envisioned that introducing a 4-aryloxy
phenyl group as one aryl group of diarylamines should provide a
library of potentially valuable and structurally simple 4-aryloxy-
N-arylanilines (as shown in Fig. 2). Herein, we would like to
report the synthesis and characterization of these novel 4-
aryloxy-N-arylanilines as well as an assessment of their
inhibitory activities against SCR, complexes II and III.
Fig. 1. Representative bioactive molecules 1-4 containing 4-aryloxy phenyl
moieties.
Table 1
Optimization of reaction conditionsa.
Fig. 2. The design strategy of our target molecules (TM).
Time
Entry
[Cu]
x
base
y
Solvent
Yieldb
(h)
48
48
48
48
48
48
48
48
48
48
36
36
36
60
60
60
1
2
Cu(OAc)2 1.00
Cu(OAc)2·H2O 1.00
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DCM
60%
55%
trace
trace
trace
trace
trace
trace
trace
trace
73%
86%
90%
72%
68%
27%
Considering the synthetic route of our designed molecules, one
traditional method could be illustrated via efficient amination of
aryl halides with 4-phenoxyaniline catalyzed by a palladium
catalyst.46-48 Later, other synthetic strategies were also utilized for
their synthesis.49-51 Herein, in order to construct a series of highly
functionalized 4-aryloxy-N-arylanilines in a mild and economic
manner, we poured our attention to the Chan-Lam coupling
strategy in which inexpensive copper (II) and copper (I)
complexes are mostly used under aerobic conditions for affording
diaryl amines.52-60 Expectedly, the copper-mediated synthesis of
various 4-aryloxy-N-arylanilines 7 could be realized from 4-
aryloxy anilines 5 and aryl boronic acids 6 (as depicted in
Scheme 1). For clarity, the three phenyl rings of these compounds
were marked as A, B and C, respectively.
3
4
CuCl2
CuCl2·2H2O
CuBr2
1.00
1.00
1.00
1.00
1.00
1.00
5
6
7
CuCl
CuBr
CuI
8
9
Cu(OAc)2·H2O 1.00 Cs2CO3
Cu(OAc)2·H2O 1.00 Pyridine 2.00
10
11
12
13
14
15
16
Cu(OAc)2·H2O 1.00
Cu(OAc)2·H2O 1.00
Cu(OAc)2·H2O 1.00
Cu(OAc)2·H2O 0.50
Cu(OAc)2·H2O 0.25
Cu(OAc)2·H2O 0.10
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
2.00
2.00
2.00 MeCN
2.00 MeCN
2.00 MeCN
2.00 MeCN
a 5a (1.0 mmol), 6a (2.0 mmol), a copper salt (x mmol), a base (y mmol) and
solvent (5.0 mL) were used. b Isolated yields.
Scheme 1. The synthetic route of our designed molecules 7.

3
With the optimized reaction conditions in hand, the reactions
of 6a with various 4-aryloxy anilines were firstly conducted to
afford a variety of target products (as shown in Fig. 3).
Introduction of a substituent at either the ortho or para position
of the phenoxyl group on ring A did not significantly affect the
yields, leading to the formation of compounds 7b-7f in yields
chosen as the control agents. The first and foremost, the
inhibitory activity of 4-phenoxy-N-phenylaniline (1a) was tested
against SCR. Unfortunately, no obvious activity was observed at
the concentration of 10 µM (entry 1). Meanwhile, if a substituent
at either the ortho or para position was introduced as R1, the
corresponding compounds 7b-7f also produced poor levels of
inhibition (entries 2-6). To our delight, employment of a di-
substituted phenyl as ring A resulted in significant improvement
of the inhibitory activities in most cases (entries 7-9). Besides,
compound 7j, where R2 is Br, exhibited outstanding inhibition
potency with an IC50 value of 0.323 µM (entry 10). Notably, a
few nanomolar inhibitors, compounds 7k-7n with various
substituents on both ring A and ring B, were identified as being
much more active than the two commercial controls (entries 11-
14 vs. entries 25-26). Afterwards, effects of different substituents
on R4 were investigated. Various groups including F, Cl, CF3,
Me, tBu were incorporated into ring C at the para position, and it
appears that Cl and CF3 are beneficial for the inhibition potency
(entries 15-19). Moreover, substituents at either the ortho or meta
position displayed variable activities (entries 20-24). Among
them, compounds 7t and 7v, with 3-F and 3-CF3 as the respective
R4 group, manifested excellent inhibition performance (entries 20
and 22).
ranging
difluorophenoxy)aniline
from
80%
to
87%.
(5g),
Besides, 4-(2,3-
4-(5-bromo-2-
fluorophenoxy)aniline (5h) and 4-(2,4-dichlorophenoxy)aniline
(5i), where a di-substituted phenyl group was employed as ring
A, could be successfully transformed into the corresponding
products 7g-7i in good yields. Moreover, effect of substituents on
ring B was also studied, and 3-bromo-4-phenoxyaniline (5j) can
tolerate this reaction and produced compound 7j in 93% yield.
Furthermore, compounds 5k-5n, starting materials with
substituents on both ring A and ring B, reacted also smoothly
with 6a to give the respective compounds 7k-7n in 80-82%
yields.
In order to further confirm whether these compounds are
inhibitors of complex II or III, the inhibitory activities of the
representative inhibitors 7k and 7n against SCR, complex II and
complex III were evaluated and shown in Table 4. Penthiopyrad
and azoxystrobin demonstrated excellent selectivity against
complex II and complex III, respectively (entries 3-4, Table 4).
Unlike the two control agents, compounds 7k and 7n
demonstrated much greater activities against SCR than against
either complex II or III (entries 1-2, Table 4). Indeed, only
moderate inhibition rates against complex II (42% for 7k and
37% for 7n) and low inhibition rates against complex III (15%
for 7k and 13% for 7n) were obtained, which is significantly
lower than those against SCR (78% for 7k and 89% for 7n).
Similar phenomenon was observed in one of our previous
publications in which the synthesized inhibitors also showed
much greater inhibition against SCR than against complex III.19
However, the detailed reason is unclear and further
comprehensive investigations are still required.
Table 2
Reaction of 5a with various boronic acidsa.
Fig. 3. Reaction of 6a with various 4-aryloxy anilines.
Yieldb
90%
80%
75%
60%
88%
81%
78%
72%
57%
75%
56%
Afterwards, compounds 7o-7x were synthesized by reaction of
5a with various boronic acids (as listed in Table 2). Initially,
numerous groups were assembled at the para position. The
results indicated that electron-donating groups (entries 5-6)
provided higher yields than the electron-withdrawing
counterparts (entries 2-4). In addition, a methyl group gave
slightly better yield that the bulkier tert-butyl group (88% in
entry 5 vs 81% in entry 6). Next, the position of the substituents
was found to significantly affect the reaction. It seems that a
substitute at the ortho position showed the worst activity even at
an elaborated temperature probably due to the steric effect.
Furthermore, inhibitory activities of the above newly prepared
compounds were tested against SCR at a concentration of 10 µM,
and the IC50 values of the compounds with inhibitory activities
higher than 50% were further determined (Table 3). In addition,
penthiopyrad (a commercial complex II-inhibiting fungicide) and
azoxystrobin (a commercialized inhibitor of complex III) were
Entry
Compound No.
R
Time (h)
36
72
1
2
7a
7o
7p
7q
7r
7s
H
4-F
3
4
4-Cl
4-CF3
4-Me
4-tBu
3-F
72
72
5
72
72
72
72
6
7
7t
8
7u
7v
7w
7x
3-Cl
3-CF3
3-Me
2-Me
9
72
72
120
10
11
a 5a (1.0 mmol), 6 (2.0 mmol), Cu(OAc)2·H2O (1.0 mmol ), Et3N (2.0 mmol)
and CH3CN (5.0 mL) were used. b Isolated yield.

4
Table 3
Inhibitory activities of the synthesized compounds against porcine SCR.
Entry
1
Comp. No.
7a
R1
R2
R3
H
H
H
H
H
H
H
H
H
H
Cl
H
Cl
Cl
H
H
H
H
H
H
H
H
H
H
R4
H
IC50 (µM)
>10
H
H
2
7b
7c
2-F
H
H
>10
3
2-Br
H
H
>10
4
7d
7e
2-CN
H
H
>10
5
4-OMe
H
H
>10
6
7f
4-OBn
H
H
>10
7
7g
2, 3-F2
H
H
1.451 0.102
>10
8
7h
7i
2-F-5-Br
H
H
9
2, 4-Cl2
H
H
0.172 0.011
0.323 0.012
0.030 0.010
0.043 0.001
0.041 0.002
0.021 0.001
>10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
7j
H
Br
H
7k
7l
2-naphthyla
Cl
H
2, 4-Cl2
Cl
H
7m
7n
7o
2, 4-Cl2
Cl
H
2, 4, 6-Cl3
Cl
H
H
H
H
H
H
H
H
H
H
H
H
4-F
4-Cl
4-CF3
4-Me
4-tBu
3-F
3-Cl
3-CF3
3-Me
2-Me
7p
7q
7r
H
0.464 0.102
0.201 0.014
>10
H
H
7s
H
>10
7t
H
0.723 0.104
>10
7u
7v
H
H
0.362 0.104
>10
7w
7x
H
H
>10
Penthiopyrad
Azoxystrobin
1.321 0.110
0.287 0.011
a The whole ring A was substituted with a 2-naphthyl group.
Table 4
The inhibition effect of the selected inhibitors against SCR, complex II and complex III.
Entry
Compound No.
7k
IC50 (µM), SCR
0.030 0.010
0.021 0.001
1.321 0.110
0.287 0.011
I% (10 µM), SCR
I% (10 µM), complex II
I% (10 µM), complex III
1
2
3
4
78%
89%
82%
99%
42%
37%
90%
23%
15%
13%
7n
Penthiopyrad
Azoxystrobin
<10%
92%

5
derivatives as succinate dehydrogenase inhibitors. J Agric Food
Chem. 2014;62:4063-4071.
In summary, a new series of 4-aryloxy-N-arylanilines were
designed and synthesized via a copper-mediated synthetic
strategy in a simple, mild and economic method. Screening of the
reaction conditions implied that the economic Cu(OAc)2•H2O
was the optimal copper promoter. Under the optimized reaction
conditions, a variety of 4-aryloxy-N-arylanilines were efficiently
synthesized in moderate to excellent yields. Moreover, the
bioassay results indicated that these newly prepared compounds
exhibited varied inhibition against SCR. Excitingly, compounds
7k-7n showed inhibition potency at the nanomolar level, which
demonstrated dramatically higher activity than the commercial
control agents.
12.
Zhu XL, Xiong L, Li H, Song XY, Liu JJ, Yang GF.
Computational and experimental insight into the molecular
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GF. Discovery of N-benzoxazol-5-yl-pyrazole-4-carboxamides as
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Acknowledgements
This research was supported by the National Natural Science
Foundation of China (Nos. 21502062, 21272091 and 21472063),
the Ministry of Education for the 50th Scientific Research
Foundation for the Returned Overseas Chinese Scholars, 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.
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Synthesis of new 4-aryloxy-N-arylanilines
and their inhibitory activities against
succinate-cytochrome reductase
Hua Cheng a, Wei Song a, Ren Nie a, Yu-Xia Wang c, Hui-Lian Li a, Xiang-Sheng Jiang a, Jun-Jun Wu a,
Qiong-You Wu*c and Cheng Chen*b
a Department of Chemical Engineering and Food Science, Hubei University of Arts and Science, Xiangyang
441053, P. R. China;
b State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of
Technology, Wuhan 430070, P. R. China;
c Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan 430079, P. R. China.