Synthesis and biological evaluation of N-cyclopropylbenzamide-benzophenone hybrids as novel and selective p38 mitogen activated protein kinase (MAPK) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2015.06.036

A series of hybrid molecules consisting of benzophenones and N-cyclopropyl-3-methylbenzamides were synthesized and biologically evaluated as novel p38 mitogen activated protein kinase (MAPK) inhibitors. In particular, we found that compound 10g displayed

Full text of DOI:10.1016/j.bmcl.2015.06.036

Bioorganic & Medicinal Chemistry Letters 25 (2015) 3694–3698
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of N-cyclopropylbenzamide-
benzophenone hybrids as novel and selective p38 mitogen activated
protein kinase (MAPK) inhibitors
a,
Jinyuk Heo a, , Hanbo Shin b, , Jun Lee a, Taelim Kim a, Kyung-Soo Inn b, , Nam-Jung Kim
⇑
⇑
a Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea
b Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of hybrid molecules consisting of benzophenones and N-cyclopropyl-3-methylbenzamides were
Received 12 February 2015
Revised 19 May 2015
Accepted 10 June 2015
Available online 16 June 2015
synthesized and biologically evaluated as novel p38 mitogen activated protein kinase (MAPK) inhibitors.
In particular, we found that compound 10g displayed potent p38
a
MAPK inhibitory activity
(IC50 = 0.027
cells.
lM), high kinase selectivity, and significant anti-inflammatory activity in THP-1 monocyte
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
N-Cyclopropylbenzamide
P38 mitogen activated protein kinase
inhibitor
Benzophenone
Hybrid
Kinase selectivity
As a class of mitogen-activated protein kinases (MAPKs) that
can be activated by various stress stimuli, p38 MAPK plays a crucial
role in the production of pro-inflammatory cytokines such as
In 2003, a series of 4-aminobenzophenone derivatives such as
compound 1 were identified as potent p38
a MAPK inhibitors with
high anti-inflammatory activities.4 Further investigation into the
tumor necrosis factor alpha (TNF-
a
), interleukin-1b (IL-1b), and
binding mode of 4-aminobenzophenones within p38a MAPK active
interleukin-6 (IL-6) which are primarily involved in the progres-
sion of chronic inflammatory diseases such as inflammatory bowel
disease (IBD), rheumatoid arthritis (RA), multiple sclerosis, psoria-
sis and neuropathic pain.1 Driven by the huge success of mono-
site by Laufer and his co-workers5 disclosed that oxygen of carbonyl
moiety in these derivatives makes a tight interaction with a hinge
region of the kinase by forming strong double hydrogen bondings
with the NH-group of Met109 and another NH-group of Gly110
instead of amide oxygen via glycine flip (PDB ID: 3QUD).2a,6 This
clonal antibodies which can directly neutralize TNF-a or IL-1b for
the treatment of chronic inflammation, several small molecule
inhibitors of p38 MAPK have been developed over the past several
decades.2 However, until now, none has been put on the clinical
market for therapeutic purpose because safety issues related to
liver toxicity, neurological side effects and low efficacy in preclin-
ical/clinical test have been reported. These issues are partly due to
the lack of kinase selectivity, which leads to off-target effects.2a,d,3
Consequently, the discovery of a potent and selective p38 MAPK
inhibitor based on novel scaffolds, which might be safe and
efficacious in further development stages, remains necessary.
interaction provides high selectivity to the inhibitor toward p38a
MAPK because it is only possible when the kinase has a hinge
region composed of glycine and adjacent linker residue such as
methionine, which exists in 9.2% of all kinases.2a Thus, it is
assumed that the benzophenone scaffold can be
backbone for tight and selective binding to p38 MAPK.
Recently, several biphenyl amides with good anti-inflammatory
activities were developed as novel p38 MAPK inhibitors by GSK
researchers.7 Among them, N-cyclopropyl linked biphenyl amide
2 is one of the most promising p38 MAPK inhibitors. X-ray crys-
tallography of 2 complexed with p38 revealed that the carbonyl
a suitable
a
a
a
a
group of N-cyclopropylmethyl amide forms a hydrogen bonding
with Met109 in the hinge region, with no glycine flip, which is
distinct from benzophenone 1 (PDB ID: 3D7Z). In particular,
N-cyclopropyl amide, which is the opposite fragment of N-cyclo-
propylmethyl amide in compound 2, makes hydrogen bondings
⇑
Corresponding authors. Tel.: +82 2 961 0368; fax: +82 2 966 3885 (K.-S.I.); tel.:
+82 2 961 0580; fax: +82 2 966 3885 (N.-J.K.).
E-mail addresses: innks@khu.ac.kr (K.-S. Inn), kimnj@khu.ac.kr (N.-J. Kim).
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.bmcl.2015.06.036
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

J. Heo et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3694–3698
3695
O
H
N
p38 MAPK
α
Glu71
Lipophilic interaction
Leu74
O
O
& Hydrogen bonding
O
S
NH2
Met109
S
H
N
NH
Met109
NH
NH
NH
NH
O
O
O
Hinge
Ph
O
region
HN
Gly110
O
O
H
N
NH
O
1
2
O
Gly110
H
N
Phe169
O
N
H
Glycine flip
O2C
Asp168
Hybridization
H
N
O
O
R1
Figure 1. Design strategy for novel N-cyclopropylbenzamide-benzophenone hybrids.
O
6d: R1
6e: R1
7d: R2
7e: R2
=
6a: R1
6b: R1
6c: R1
=
=
=
OH
O
O
O
O
OMe
O
c, d or e
c, d or e
O
O
OH
O
=
O
MeO
MeO
Br
Br
R1O
R2O
Br
Br
4
O
a, b
Cl
7a: R2
7b: R2
7c: R2
=
=
=
OH
=
=
OMe
O
Br
O
O
3
O
OH
5
4, 5, 6a-e, 7a-e
or
H
N
H
H
N
Commercially
N
O
f
B
O
available
4-bromo
+
Or
O
O
O
O
O
8
benzophenones
11a: R4
=
OH
O
10a: R3
10b: R3 =
10c: R3
10d: R3 =
=
OH
O
R4O
f
OR3
11b: R4 =
OH
OH
11c: R4
11d: R4
=
O
=
O
O
O
O
O
=
H
N
OMe
OH
O
OMe
OH
g
h
g
h
9a: X = 4-H
9b: X = 4-F
9c: X = 4-Cl
9d: X = 4-MeO
10e: R3
10f: R3
=
11e: R3
11f: R4
=
=
O
X
O
O
O
=
O
OH
9e: X = 3-MeO
OH
10g: R3 =
OH
OH
11g: R4
=
Scheme 1. Synthesis of compound 9a–e, 10a–c, 10e, 10g, 11a–c, 11e, and 11g. Reagents and conditions: (a) N,O-dimethylhydroxylamine hydrochloride, Et3N, CH2Cl2, rt, 97%;
(b) 3-or 4-methoxyphenylmagnesiumbromide, DMF, rt, 96–98%; (c) pyridinium hydrochloride, 130 °C, 70–90%; (d) alkyl halides or 2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-
toluenesulfonate, K2CO3, KI, acetone, 60–85 °C, 80–100%; (e) 2-bromoethylmethylether, NaH, THF, rt, 90%; (f) Pd(PPh3)4, K2CO3, DMF, 120 °C, 25–74%; (g) LiOH, THF/MeOH/
H2O, 71-82%; (h) p-TsOH, H2O/MeOH, 50 °C, 47–53%.
with Asp168 and Glu71 and tightly fits in a lipophilic pocket whose
bases are Leu74, and Phe169, which leads to good and selective
induce glycine flip and N-cyclopropylbenzamide group to tightly
and selectively fit in the enzyme7d could be the way to provide
the novel scaffold for a potent and selective p38 MAPK inhibitor
(Fig. 1). Herein, we report the synthesis and biological evaluation
of N-cyclopropylbenzamide-benzophenone hybrids as novel p38
MAPK inhibitors.
A variety of hybrids equipped with benzophenones and N-cy-
clopropylbenzamides were efficiently synthesized using a concise
synthetic strategy, as outlined in Scheme 1. First, 4-alkoxy-40-bro-
mobenzophenones were prepared from the commercially available
4-bromobenzoyl chloride 3, which was transformed into meta- or
binding with p38
cantly decreases the production of inflammatory cytokines such
as TNF-
a
MAPK.7c,7d In addition, compound 2 signifi-
a.
In an effort to identify a novel p38 MAPK inhibitor with high
kinase selectivity and significant anti-inflammatory activity, we
considered it worthwhile to exploit the pharmacological core moi-
eties of compound 1 and 2 which are potent and selective kinase
inhibitors. Based on the insights gained from those reports, we
envisaged that the combination of the benzophenone group to

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J. Heo et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3694–3698
Acetophenone 13, where the benzene group was not incorpo-
Br
H
N
H
N
a
rated was prepared via Suzuki–Miyaura coupling of the commer-
cially available 12 and the known intermediate 8 (Scheme 2).
The in vitro activities of the synthesized compounds were eval-
uated through SelectScreen™ Kinase Profiling Services (Life
technologies).The assay result of the synthesized compounds is
summarized in Table 1.
O
+
B
O
O
O
O
O
12
13
8
Scheme 2. Synthesis of compound 13. Reagents and conditions: (a) Pd(PPh3)4,
K2CO3, DMF, 120 °C, 67%.
As shown in Table 1, most of the compounds showed potent
p38a MAPK inhibitory activities, with IC50 values in the sub-micro-
molar range. Interestingly, compound 9a, an initially designed
hybrid of the benzophenone and N-cyclopropylamide, was active
para-methoxybenzophenones by Weinreb amide formation and
Grignard addition using methoxybenzene MgBrs in turn.8 The
sequential demethylation of the intermediates 4 and 5 in the pres-
ence of pyridine HCl, followed by alkylation afforded 6a–e and 7a–
e.9 Using the synthesized 4-alkoxy-40-bromo benzophenones and
commercially available other 4-bromobenzophenones, we synthe-
sized most of the desired derivatives such as 9a–e, 10a–d, 10f,
11a–d and 11f via a unified Suzuki–Miyaura coupling of them with
the known compound 8, which has N-cyclopropyl amide.7 The
hydrolysis of 10d and 11d provided 10e and 11e, respectively.
Compounds such as 10g and 11g were prepared through an addi-
tional acetal deprotection of 10f and 11f.
(IC50 = 0.109
methyl group was introduced at A position, showed less activity
than 9a (IC50 = 0.350 M). Thus, the lipophilic moiety such as ben-
lM). However, compound 13, where the simple
l
zene is beneficial for the desired activity. Compounds such as 9b
and 9c that have electron-withdrawing halogens at the para posi-
tion of the benzophenone moiety were also less potent than 9a
(IC50 = 0.287 and 0.271 lM, respectively), whereas 9d which have
a methoxy group at the para position of the benzophenone moiety,
was more potent than 9b and 9c. The meta-methoxy substituted
compound also displayed good potency, similar to 9d.
With the results, we moved our attention to fine-tuning of the
hybrid compounds. Inspired by our result, and previous reports
that incorporation of the hydrophilic substituents on R group,
directing toward the solvent exposable region, might increase
p38 MAPK inhibitory activities of the compounds, due to enhance-
ment of their water solubility and possibilities for additional inter-
actions3a,5,6,10, we focused on the synthesis of analogs with various
ether moieties and investigated their biological activities. In the
case of incorporating hydrophilic moieties at the para position,
compounds such as 10a and 10c, which contain ethers linked with
Table 1
P38a
MAPK inhibitory activities of synthesized compounds
H
N
O
O
A
a
terminal hydroxyl group, exhibited more potent activity
(IC50 = 0.053 and 0.056 M, respectively) than compound 10b with
no terminal hydroxyl group (IC50 = 0.076 M). The carboxylalkoxy
l
R
l
substituent which is more hydrophilic than the hydroxyalkyl ether
group makes the inhibitors less active. It is noteworthy that com-
pound 10g with dihydroxypropoxy residue showed the greatest
a
Compound
R
A
IC50 (lM)
9a
H
0.109
activity with an IC50 of 0.027
icantly more potent than SB203580, the representative p38
inhibitor (IC50 = 0.062 M). Thus, compounds 10a, 10c and 10g
lM, which indicates that it is signif-
a
MAPK
9b
9c
9d
F
Cl
MeO
0.287
0.271
0.135
l
with ethylene glycol or its repeated moiety showed more potent
activities than more hydrophilic carboxylate (10e) and less hydro-
philic methoxy ether (10b), but similar in size to them. These
9e
MeO
0.129
0.053
HO
O
10a
Table 2
Selectivity profiling of compound 10g against a panel of kinasesa
O
10b
10c
0.076
0.056
O
O
Kinase
% Activity
Kinase
% Activity
remainingb
remainingb
HO
HO
O
O
ABL1
BTK
BRAF
CDK1
EGFR (ErbB1)
ERBB2 (HER2)
FLT3
101
105
89
100
94
MAPK8 (JNK1)
MAPK9 (JNK2)
MAPK10 (JNK3)
MAPK11 (p38b)
105
112
96
3
103
93
1
10e
10g
11a
0.085
0.027
0.069
O
HO
HO
O
OH
O
MAPK12 (p38
MAPK13 (p38d)
MAPK14 (p38a)
c
)
94
94
GSK3b
IKK b
JAK1
JAK2
JAK2
LCK
MAPK1 (ERK2)
MAPK3 (ERK1)
102
98
111
96
99
84
MAPK15 (ERK7)
MAPKAPK2
MEK1
SRC
TYK2
cRAF
ROCK2
VEGFR1
98
98
97
92
105
94
93
88
O
O
11b
11c
0.056
0.046
O
HO
O
O
11e
0.098
O
HO
HO
107
108
OH
11g
0.044
O
a
Kinase selectivities of synthesized compounds (1
SelectScreen™ Kinase Profiling Services (Life technologies).
lM) were profiled through
13
SB203580
CH3
0.350
0.062
b
Data are given in percent remaining activity (i.e., 100% indicates no observed
a
inhibition).
IC50s of the compounds were determined in 10 point titration.

J. Heo et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3694–3698
3697
Figure 2. X-ray structures of 1 (Cyan, PDB Code: 3QUD) and 2 (green, PDB Code: 3D7Z), and molecular docking model of 9a (yellow, PDB Code: 3ZYA), and 10g (pink, PDB
Code: 3ZYA) with p38
MAPK, which were visualized using Chimera 1.10 (UCSF Chimera).13
a
results implied that hydroxyl group-including ethers as para sub-
stituents might provide better activities with the analogs, partly
due to their moderate hydrophilicity.
Next, we tried to synthesize the compounds with hydrophilic
moieties at the meta position of the benzophenone moieties.
Compound 11a with hydroxyethoxy ether as a substituent also
showed potent activity but it was slightly less than para isomer
Laboratory).12 As illustrated in Figure 2, both compounds fitted
well into the active site, which concurred with their potent activi-
ties. The estimated free binding energy of more potent compound
10g (ꢀ10.06 kcal/mol) was lower compared to that of 9a
(ꢀ9.54 kcal/mol), indicating that 10g might have energetically
more favored conformation. It is plausible that the benzophenone
moieties in 9a and 10g interact with the hinge region of a kinase
through double hydrogen bondings, which is induced by glycine
flip, whereas N-cyclopropylamide, which forms hydrogen bondings
with Glu71 and Asp168, is oriented toward a lipophilic pocket sur-
rounded by Leu74 and Phe169. Thus, the binding mode of our com-
pound was postulated in accordance with our initial design
strategy.
10a (IC50 = 0.069 lM). Unlike the case of para-substituted analogs,
methoxyethyl analog 11b was slightly more potent than 11a. In
addition, the lengthened glycol ether-including analog 11c showed
more potent activity than 11b. Compound 11g with a dihydrox-
ypropoxy group showed similar activity to 11c. The compound
equipped with carboxylalkoxy group was less active than 11a,
which is similar to the case of para-substituted analogs. These
results suggest that the compounds such as 11b, 11c, and 11g with
longer ether chains are marginal better in comparison to the
shorter ether chain. But the diol 11g was the most active com-
pounds among compounds with hydrophilic meta substituents,
which is consistent in the case of the analogs including para sub-
stituents on R group.
To further determine whether the newly identified p38 MAPK
inhibitor 10g can reduce inflammatory cytokines on a cellular
level, THP-1 cells were treated with increasing concentrations of
10g followed by LPS stimulation. Anti-inflammatory effect of 10g
was tested using enzyme-linked immunosorbent assay (ELISA)
Based on the promising activity of the compound at the kinase
assay, we chose compound 10g as a lead compound for further
study and checked its selectivity against a panel of 94 different
kinases which are considered functionally or structurally similar
to p38 MAPK based on the kinome analysis and the cross reactivity
to other p38 MAPK inhibitors such as BIRB-796.2d,7d,11 The
selectivity profiles of the compound are summarized in Table 2
and full profiles using 94 different kinases are described in
Supplementary information Table S1. Interestingly, 10g showed
significant inhibitory activity against p38 MAPKs but no or weak
inhibitory activities against other kinases including JNKs and LCK,
which implies that it has high selectivity against p38 MAPK over
other kinases.
Figure 3. Anti-inflammatory effects of compound 10g on THP-1 cells: (a) cells were
treated with indicated concentrations of SB203580 or 10g followed by LPS
To investigate the binding mode of the N-cyclopropylamide-
benzophenone hybrids that was identified as a novel p38 MAPK
stimulation for 24 h. Production of TNF
a was determined by ELISA. (b) Cells were
treated with indicated concentrations of SB203580 or 10g followed by LPS
stimulation for 10 h. Synthesis of interleukin-6 (IL-6) mRNA was measured by RT-
qPCR
inhibitor, docking analysis of 9a and 10g within p38a MAPK active
site was performed using Autodock 4.2 (Molecular Graphic

3698
J. Heo et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3694–3698
Wong, B. R. J. Pharmacol. Exp. Ther. 2008, 327, 610; (c) Cohen, S. B.; Cheng, T. T.;
Chindalore, V.; Damjanov, N.; Burgos-Vargas, R.; Delora, P.; Zimany, K.; Travers,
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and quantitative polymerase chain reaction (qPCR). As depicted in
Figure 3, LPS-induced production of TNF- and IL-6, which are
known to be representative inflammatory procytokines were
decreased by 10g treatment in dose-dependent manners, further
proving its p38 MAPK inhibitory biological role.
In summary, we identified a series of N-cyclopropylbenzamide-
benzophenone hybrids as novel p38 MAPK inhibitors based on
rational design and convenient synthetic approaches. In particular,
a
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the analog 10g showed potent and selective p38
a MAPK inhibition
activity (IC50 = 0.027 M) as well as significant anti-inflammatory
l
properties in monocyte cells. Based on molecular modeling, it is
postulated that the binding mode of 9a and 10g is demonstrated
as combining the advantageous moieties of benzophenone and
N-cyclopropyl benzamide group for being potent and selective
p38 MAPK inhibitors. Further work for the development of thera-
peutically useful anti-inflammatory drugs based on our current
study is in progress.
Acknowledgments
9. Wood, P. M.; Woo, L. W.; Labrosse, J. R.; Trusselle, M. N.; Abbate, S.; Longhi, G.;
Castiglioni, E.; Lebon, F.; Purohit, A.; Reed, M. J.; Potter, B. V. J. Med. Chem. 2008,
51, 4226.
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF), which
was funded by the Ministry of Science, ICT & Future Planning
(NRF-2013R1A1A1062292).
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.06.
036.
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