Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1

Article abstract of DOI:10.1016/j.bmcl.2018.02.011

Human mPGES-1 has emerged as a promising target in exploring a next generation of anti-inflammatory drugs, as selective mPGES-1 inhibitors are expected to discriminatively suppress the production of induced PGE₂ without blocking the normal biosynthesis of other prostanoids including homeostatic PGE₂. Therefore, this therapeutic approach is believed to reduce the adverse effects associated with the application of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs). Identified from structure-based virtue screening, the compound with (Z)-5-benzylidene-2-iminothiazolidin-4-one scaffold was used as lead in rational design of novel inhibitors. Besides, we further designed, synthesized, and evaluated 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and structurally related derivatives for their in vitro inhibitory activities. According to in vitro activity assays, a number of these compounds were capable of inhibiting human mPGES-1, with the desirable selectivity for mPGES-1 over COX isozymes.

Full text of DOI:10.1016/j.bmcl.2018.02.011

Accepted Manuscript
Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methyl-
ene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel in-
hibitors of mPGES-1
Kai Ding, Ziyuan Zhou, Shuo Zhou, Yaxia Yuan, Kyungbo Kim, Ting Zhang,
Xirong Zheng, Fang Zheng, Chang-Guo Zhan
PII:
S0960-894X(18)30100-8
https://doi.org/10.1016/j.bmcl.2018.02.011
BMCL 25607
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 December 2017
31 January 2018
7 February 2018
Please cite this article as: Ding, K., Zhou, Z., Zhou, S., Yuan, Y., Kim, K., Zhang, T., Zheng, X., Zheng, F., Zhan,
C-G., Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,
5H)-triones and related derivatives as novel inhibitors of mPGES-1, Bioorganic & Medicinal Chemistry Letters
(2018), doi: https://doi.org/10.1016/j.bmcl.2018.02.011
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Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-
yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel
inhibitors of mPGES-1
Kai Ding,a,b,c,† Ziyuan Zhou,a,b,† Shuo Zhou,a,b,† Yaxia Yuan,a,b,d Kyungbo Kim,a,b Ting Zhang,a,b Xirong
Zheng,a,b Fang Zheng,a,b and Chang-Guo Zhana,b,d,*
aMolecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South
Limestone Street, Lexington, KY 40536
bDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Lime-stone
Street, Lexington, KY 40536
cDepartment of Chemistry, University of Kentucky, 505 Rose Street, Lexington, KY 40506
dCenter for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, 789 South
Limestone Street, Lexington, KY 40536
Keywords: Anti-inflammatory drugs; pyrazole; barbituric acid; mPGES-1 inhibitor
Footnote: †These authors contributed equally to this work.
Correspondence:
Chang-Guo Zhan, Ph.D.
Director, Molecular Modeling and Biopharmaceutical Center (MMBC)
Director, Chemoinformatics and Drug Design Core of CPRI
University Research Professor
Endowed College of Pharmacy Professor in Pharmaceutical Sciences
Professor, Department of Pharmaceutical Sciences
College of Pharmacy
University of Kentucky
789 South Limestone Street
Lexington, KY 40536
Phone: 859-323-3943
FAX: 859-257-7585
E-mail: zhan@uky.edu
ABSTRACT: Human mPGES-1 has emerged as a promising target in exploring a next generation of anti-
inflammatory drugs, as selective mPGES-1 inhibitors are expected to discriminatively suppress the production of
induced PGE2 without blocking the normal biosynthesis of other prostanoids including homeostatic PGE2.
Therefore, this therapeutic approach is believed to reduce the adverse effects associated with the application of
traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs). Identified
from structure-based virtue screening, the compound with (Z)-5-benzylidene-2-iminothiazolidin-4-one scaffold
was used as lead in rational design of novel inhibitors. Besides, we further designed, synthesized, and evaluated
5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and structurally related
derivatives for their in vitro inhibitory activities. According to in vitro activity assays, a number of these
compounds were capable of inhibiting human mPGES-1, with the desirable selectivity for mPGES-1 over COX
isozymes.
In the eicosanoid pathway, arachidonic acid (AA)
is converted to prostaglandin H2 (PGH2) by the action
of cyclooxygenases (COX-1 and COX-2). PGH2
serves as a common precursor for various biologically
active prostanoids, such as thromboxane A2 (TXA2),
PGD2, PGI2, PGF2α, and PGE2, depending on different
1

distal synthases.1, 2 Among these prostanoids, PGE2 is
well recognized as an important inflammatory
mediator. PGE2 is isomerized from PGH2 catalyzed
by three distinct synthases, including microsomal
prostaglandin E2 synthase-1 (mPGES-1), mPGES-2,
and cytosolic prostaglandin E2 synthase.3 Unlike the
other two constitutively expressed enzymes, the
expression of mPGES-1, similar to that of COX-2, is
highly inducible in response to pro-inflammatory
stimuli.4
the treatment of inflammation-related symptoms by
either non-selectively inhibiting COX isozymes,5 or
selectively inhibiting COX-2,6 respectively. However,
both categories shut down the biosynthesis of all
downstream prostanoids and, so, their application is
associated with considerable adverse effects. The
tNSAIDs trigger gastrointestinal (GI) ulceration
because of the interference with COX-1-derived
protective function in GI tract;7 coxibs, as specific
COX-2 inhibitors, on the other hand, break the
internal balance of vasodilative PGI2 and
vasoconstrictive TXA2 and thus result in
cardiovascular risk.8 Since PGE2 is the major
inducible PG in inflammation, inhibiting mPGES-1 is
believed as a promising therapeutic approach in the
development of the next generation of anti-
inflammatory drugs.9
In the previous study, we reported the discovery
of
(Z)-5-benzylidene-2-iminothiazolidin-4-one
derivative 1 (Figure 1A) as a human mPGES-1
inhibitor with moderate potency (IC50 = 3.5 µM)
through structure-based virtual screening.10, 11 Based
on the simulated binding mode of 1 with crystal
structure (PDB ID: 4BPM,12 Figure 1B) of human
mPGES-1, we redesigned the core scaffold and
synthesized benzylidenebarbituric acid derivatives (2,
with IC50 = 622 nM, as an example, Figure 1A) as
mPGES-1 inhibitors. The barbituric acid was
introduced in order to maintain and possibly enhance
the polar interaction with the enzyme at the active site.
Flexible alkoxy side chain was attached to the central
benzene ring so as to fit the size of the hydrophobic
pocket surrounded by I32, G35, L39, Y130, T131,
L135, and A138. As predicted by molecular docking,
the barbituric ring interacts with S127 by forming a
hydrogen bond (HB) between the barbituric carbonyl
group and hydroxyl group of serine, while the central
benzene ring with alkoxy substitution occupies the
hydrophobic groove where the long hydrocarbon “tail”
of PGH2 locates (Figure 1C).
While developing the benzylidenebarbituric acid
derivatives, we carefully analyzed the binding mode
of these compounds with mPGES-1, and noticed that
there is still substantial unoccupied area in the active
site, especially the small hydrophobic pocket around
the central benzene ring of 2 and above the cofactor
glutathione (GSH) of the enzyme. We then decided to
introduce pyrazole into the core scaffold not only
because of its existence in many bioactive molecules,
but also its versatility for multi-functionalization. We
kept the barbituric acid “head” because of the
importance of the hydrogen bond between carbonyl
and hydroxyl group of S127. Substituents on
Figure 1. Molecular structures of the lead 1,
benzylidenebarbiturc acid derivative 2 and the
designed scaffold 3 and their binding with human
mPGES-1. (A) Ligand structures; (B) binding with
the lead 1; (C) binding with 2; (D) binding with 3.
As two generations of anti-inflammatory drugs,
traditional non-steroidal anti-inflammatory drugs
(tNSAIDs) and coxibs represent the mainstream for
2

pyrazole-1 and 3 positions were expected to occupy
the hydrophobic pockets wrapping the hydrocarbon
“tail” of PGH2 and above GSH. Thus, a series of 5-
((1,3-diphenyl-1H-pyrazol-4-
strategies of improving the inhibitory efficacy in light
of the binding complex include the modification on
barbituric acid moiety for maintaining and
strengthening a hydrogen bond with S127, and the
substitution on 1- and/or 3-phenyl in order to enhance
the hydrophobic interaction with the nonpolar groove.
As expected, a number of these compounds were
active against human mPGES-1 and selective for
mPGES-1 over COX isozymes.
yl)methylene)pyrimidine-2,4,6
(1H,3H,5H)-trione
derivatives and other structurally related compounds
were designed and synthesized. The docking study of
the simplest scaffold 3 (Figure 1A) with mPGES-1
revealed that 3 binds in a similar region in the active
site as 2 in the binding complex (Figure 1D). The
Scheme 1. Reagents and conditions: (a) K2CO3 (2.00 equiv.), DMF, 80 oC; (b) 5 % glacial AcOH in EtOH, reflux;
(c) POCl3 (4.00 equiv.), DMF, 0 oC~60 oC; (d) EtOH/H2O (4:1, v/v), reflux.
Scheme 2. Reagents and conditions: (a) 5 % glacial AcOH in EtOH, reflux; (b) POCl3 (4.00 equiv.), DMF, 0
oC~60 oC; (c) EtOH/H2O (4:1, v/v), reflux.
3

Scheme 3. Reagents and conditions: (a) NH4OAc (2.00 equiv.), glacial AcOH, 108 oC.
Table 1. Structural-activity relationship (SAR) on the
shown in Scheme 1. 4-Alkoxyacetophenone (4b~4g),
substitution of central pyrazole ring
obtained from the reaction of 4-hydroxyacetophenone
and alkyl bromide,13 or acetophenone (4a) was
condensed with 4-chlorophenylhydrazine in reflux
ethanol containing 5 % glacial acetic acid.14, 15 The
ethylidene hydrazine (5a~5g) was formed as
precipitate at room temperature and filtered off. The
next step was Vilsmeier-Haack-Arnold ring closing
formylation,13 by treating 5a~5g with POCl3/DMF.
The
produced
1H-pyrazole-4-carbaldehyde
intermediate (6a~6g) was coupled with barbituric acid
or 2-thiobarbituric acid in refluxing EtOH/H2O (4:1,
v/v) to afford the final product (7a~7g or 8a~8g).16
The length and shape of the aliphatic side chain
were investigated in the SAR study. We fixed the
substituent at pyrazole-1-position as 4-chlorophenyl
and variated the side chain on 3-phenyl. From the in
vitro data shown in Table 1, it was observed as
compared to that without a side chain (7a and 8a),
compounds with linear side chains (7b~7f and 8b~8f)
were generally more potent against human mPGES-1,
whereas benzyl substitution (7g and 8g), however, did
not improve the inhibitory potency. Linear side chains
with 4 or 6 carbons yielded compounds with highest
potency, whereas longer side chains, such as octyl or
decyl, did not show a more potent inhibition. Notably,
compounds with 2-thiobarbituric acid “heads” were
generally more potent as compared to those with
barbituric acid ones. We also changed the substituent
in pyrazole-1-position from 4-chlorophenyl to phenyl
group. In this case, 4c was used as starting substituted
acetophenone. Followed the similar protocol as
outlined in Scheme 2, 11 and 12 were prepared. These
compounds (11 and 12) were slightly less potent than
those with 4-chlorophenyl substituent (7c and 8c,
respectively).
IC50 (nM)a for
Comp. R2
X
Y
mPGES-1
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
O
O
O
O
O
O
O
S
S
S
S
S
337±85
265±96
169±41
285±65
361±51
294±83
598±142
561±192
95±16
56±10
52±15
92±19
93±14
7a
7b
7c
7d
7e
7f
7g
8a
8b
8c
8d
8e
8f
C2H5O
nC4H9O
nC6H13O
nC8H17O
nC10H21O
BnO
H
C2H5O
nC4H9O
nC6H13O
nC8H17O
nC10H21O
BnO
S
S
O
S
797±160
212±34
92±20
8g
11
12
nC4H9O
nC4H9O
H
aData are expressed as means ± SD (standard
deviation) of single determinations obtained in
triplicate.
The synthesis of this series of compounds
followed a straightforward multi-step protocol, as
4

Table 2. The SAR on the polar head
2-cyanoacetic acid and 2,4-thiazolidinedione. As
shown in Table 2, compounds with malononitirle and
2-cyanoacetamide “heads” (13b, 13c and 14b, 14c)
were not very active against human mPGES-1,
whereas those with 2-cyanoacetic acid (13a and 14a)
showed submicromolar potency. It was noted that
compounds 13f and 14f, obtained from the coupling
of 6b and 6d with 2,4-thiazolidinedione N-acetic acid,
were capable of inhibiting human mPGES-1 with low
naonomolar potency (IC50 = 41 ± 5 nM and 36 ± 11
nM, respectively).
IC50 (nM)a for
mPGES-1
Comp.
R
C2H5
283±83
13a
C2H5
C2H5
n.d.b (51%±10%)c
n.d. (32%±21%)
13b
13c
C2H5
C2H5
1,590±560
1,040±290
13d
13e
C2H5
41±5
13f
nC6H13
83±34
14a
nC6H13
nC6H13
n.d. (64%±1.4%)
n.d. (14%±14%)
14b
14c
Figure 2. Molecular structures of 7c, 7e and 14f and
their binding with human mPGES-1. (A) Compound
structures; (B) binding with the lead 7c; (C) binding
with 7e; (D) binding with 14f.
nC6H13
nC6H13
1,390±300
1,730±670
14d
14e
To further understand the SAR of these
synthesized compounds, we selected compounds 7c,
7e and 14f and used the AutoDock Vina program17 as
the molecular docking tool to investigate their binding
modes with human mPGES-1. 14f was chosen for
further docking study because it is the most active one
with the scaffold (possessing a carboxylic acid polar
“head”) for the mPGES-1 inhibitors in Table 2. 7c
and 7e were chosen from compounds in Table 1 with
another scaffold (barbituric acid derivatives). Of the
barbituric acid derivatives in Table 1, we are mainly
interested in the compounds with Y = O, because the
compounds with Y = S are less soluble in water.
Within all of the barbituric acid derivatives with Y =
O in Table 1, 7c is the most potent one for human
mPGES-1. 7e was also chosen for comparison with 7c
because they are different only in the length of the
nC6H13
36±11
14f
aData are expressed as means ± SD (standard
deviation) of single determinations obtained in
b
c
triplicate. n.d. = not determined. The value in the
parenthesis refers to the % inhibition of the compound
at a concentration of 10 µM against the mPGES-1
(IC50 values were determined only for the compounds
that showed ≥70% inhibition).
With these (2-thio)barbituric acid derivatives in
hand, as depicted in Scheme 3, we broadened the
structural diversity with pyrazole core by coupling
1H-pyrazole-4-carbaldehyes (6b and 6d) with various
activated methylene compounds such as malononitrile,
5

side chain (R2).
The predicted binding modes are shown in
against COX isozymes was also evaluated for some of
the more promising compounds (with IC50 < 100 nM
against human mPGES-1). As shown in Table 3, at a
concentration as high as 100 µM, compounds 8b~8f,
12, 13f, 14a and 14f inhibited COX-1/2 for less than
20 %. So, these compounds are highly selective for
the mPGES-1 over COX-1/2.
In summary, in light of the binding complex of
both the lead and the benzylidenebarbituric acid
scaffold with human mPGES-1, we designed and
synthesized a novel series of 5-((1,3-diphenyl-1H-
pyrazol-4-yl)methylene)-pyrimidine-2,4,6
(1H,3H,5H)-triones and other structurally related
derivatives.20 These compounds were evaluated in
vitro for their inhibitory potency against human
mPGES-1 and selectivity over COX-1/2, leading to
discovery of various potent and selective inhibitors of
human mPGES-1. The most potent one is 14f (IC50 =
~36 nM against human mPGES-1) without significant
inhibition against COX-1/2.
Figure 2. The substituted phenyl group on pyrazole-
1-position occupies the hydrophobic groove where the
long hydrocarbon side chain of PGH2 locates. The
other substituted phenyl group on pyrazole-3-position
fits into the small hydrophobic pocket above GSH.
Since this pocket is small, a bulky group on pyrazole-
3-position is not favorable as reflected in the
inhibitory data that 7e (with longer octyl side chain) is
an inferior inhibitor as compared with 7c (with a
shorter butyl side chain). The substituents on
pyrazole-4-position attaches on the surface of the
protein. When the barbituric acid is present, the
carbonyl group on the barbituric ring forms a
hydrogen bond with the hydroxyl group of S127. .
While replacing the barbituric acid with 2,4-
thiazolidinedione N-acetic acid, however, the
carboxyl group forms hydrogen bonds with the NH
groups of R52 and H53. So, 14f is a potent inhibitor
against human mPGES-1.
ACKNOWLEDGMENTS
This work was supported in part by the funding
of the Molecular Modeling and Biopharmaceutical
Center at the University of Kentucky College of
Pharmacy, the National Science Foundation (NSF
grant CHE-1111761), and the National Institutes of
Health via the National Center for Advancing
Translational Sciences (UL1TR001998) grant. The
authors also acknowledge the Computer Center at
University of Kentucky for supercomputing time on a
Dell Supercomputer Cluster consisting of 388 nodes
or 4,816 processors.
Table 3. Inhibition against COX-1/2
% Inhibition of
Compound
COX-1/2 at 100 µMa
1.0±4.5
4.4±8.6
0.7±5.4
0±0.2
8b
8c
8d
8e
11±16
8f
16±4.1
6.8±6.4
19±0.1
1.2±29
12
13f
14a
14f
REFERENCES AND NOTES
1.
Norberg, J. K.; Sells, E.; Chang, H. H.; Alla,
S. R.; Zhang, S.; Meuillet, E. J., Pharm Pat
Anal 2013, 2, 265.
aThe % inhibition of the compound at a concentration
of 100 µM against the COX-1/2 (mixed COX-1 and
COX-2). The enzyme mixture contained equal
amounts of COX-1 and COX-2 in terms of their
enzyme activities. In this way, when a compound can
significantly inhibit either COX-1 or COX-2, it will
show the significant inhibitory effects against the
mixed COX-1 and COX-2.
2.
3.
Garavito, R. M.; DeWitt, D. L., Biochim.
Biophys. Acta 1999, 1441, 278.
Murakami, M.; Nakatani, Y.; Tanioka, T.;
Kudo, I., Prostaglandins Other Lipid Mediat.
2002, 68-69, 383.
4.
5.
Funk, C. D., Science 2001, 294, 1871.
Samuelsson, B.; Morgenstern, R.; Jakobsson,
P. J., Pharmacol. Rev. 2007, 59, 207.
Hawkey, C. J., Best Pract. Res. Clin.
Gastroenterol. 2001, 15, 801.
FitzGerald, G. A.; Patrono, C., N. Engl. J.
Med. 2001, 345, 433.
Buttgereit, F.; Burmester, G. R.; Simon, L. S.,
Am. J. Med. 2001, 110 Suppl 3A, 13S.
For the in vitro evaluation of these compounds,
we first conducted the single-concentration screening
at 10 µM against human mPGES-1. Compounds that
showed significant inhibition (≥70%) were tested
further for their IC50 values against human mPGES-1.
The protocol for the protein preparation and in vitro
activity assays were the same as described
previously.10, 11, 18, 19 Further, the inhibitory activity
6.
7.
8.
6

9.
Cheng, Y.; Wang, M.; Yu, Y.; Lawson, J.;
Funk, C. D.; Fitzgerald, G. A., J. Clin. Invest.
2006, 116, 1391.
Hamza, A.; Zhao, X.; Tong, M.; Tai, H. H.;
Zhan, C. G., Bioorg. Med. Chem. 2011, 19,
6077.
Zhou, Z.; Yuan, Y.; Zhou, S.; Ding, K.;
Zheng, F.; Zhan, C. G., Bioorg. Med. Chem.
Lett. 2017, 27, 3739.
Li, D.; Howe, N.; Dukkipati, A.; Shah, S. T.;
Bax, B. D.; Edge, C.; Bridges, A.;
Hardwicke, P.; Singh, O. M.; Giblin, G.;
Pautsch, A.; Pfau, R.; Schnapp, G.; Wang,
M.; Olieric, V.; Caffrey, M., Cryst. Growth
Des. 2014, 14, 2034.
Yamasaki, K.; Hishiki, R.; Kato, E.;
Kawabata, J., ACS Med. Chem. Lett. 2011, 2,
17.
Ragab, F. A.; Abdel Gawad, N. M.; Georgey,
H. H.; Said, M. F., Eur. J. Med. Chem. 2013,
63, 645.
Harikrishna, N.; Isloor, A. M.; Ananda, K.;
Obaid, A.; Fun, H.-K., RSC Advances 2015,
5, 43648.
Baron, R.; Huang, C. H.; Bassani, D. M.;
Onopriyenko, A.; Zayats, M.; Willner, I.,
Angew. Chem. Int. Ed. Engl. 2005, 44, 4010.
Trott, O.; Olson, A. J., J. Comput. Chem.
2010, 31, 455.
19.
20.
Huang, X. Q.; Yan, W. L.; Gao, D. Q.; Tong,
M.; Tai, H.-H.; Zhan, C.-G., Bioorg. Med.
Chem. 2006, 14, 3553.
10.
11.
12.
Analytical data and yields for the most potent
compounds: (13f) 1H NMR (400 MHz,
DMSO) δ 13.47 (s, 1H), 8.76 (s, 1H), 8.05 (d,
J = 8.7 Hz, 2H), 7.68 (s, 1H), 7.57 (dd, J =
26.7, 8.6 Hz, 4H), 7.09 (d, J = 8.6 Hz, 2H),
4.35 (s, 2H), 4.10 (q, J = 6.9 Hz, 2H), 1.36 (t,
J = 6.9 Hz, 3H). 13C NMR (101 MHz,
DMSO) δ 168.00, 166.61, 164.74, 159.29,
153.83, 137.53, 131.57, 130.03, 129.48,
128.35, 124.12, 123.13, 120.93, 119.57,
115.31, 114.84, 63.24, 42.37, 14.63. HRMS
(ESI+) m/z calcd for C23H19ClN3O5S (MH)+:
484.0728, found: 484.0728. Yield: 74 %.
13.
14.
15.
16.
1
(14f) H NMR (400 MHz, DMSO) δ 8.78 (s,
1H), 8.06 (d, J = 8.8 Hz, 2H), 7.69 (s, 1H),
7.63 (s, 1H), 7.61 – 7.47 (m, 3H), 7.09 (d, J =
8.7 Hz, 2H), 4.36 (s, 2H), 4.03 (t, J = 6.5 Hz,
2H), 1.82 – 1.64 (m, 2H), 1.48 – 1.28 (m,
13
6H), 0.88 (t, J = 6.8 Hz, 3H). C NMR (101
MHz, DMSO) δ 168.01, 166.62, 164.75,
159.47, 153.86, 137.55, 131.59, 130.04,
129.50, 128.40, 124.15, 123.13, 120.97,
119.59, 115.32, 114.90, 67.64, 42.34, 31.03,
28.63, 25.21, 22.11, 13.95. HRMS (ESI+) m/z
calcd for C27H27ClN3O5S (MH)+: 540.1354,
found: 540.1352. Yield: 71 %.
17.
18.
Hamza, A.; Tong, M.; AbdulHameed, M. D.;
Liu, J.; Goren, A. C.; Tai, H. H.; Zhan, C. G.,
J Phys Chem B. 2010, 114, 5605.
7

Graphical Abstract
Rational molecular design, followed by synthesis and in vitro activity assays for evaluating both the
potency and selectivity, has led to the discovery of a set of novel, potent and selective mPGES-1
inhibitors.
8