Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent suppressor of PGE2 production: Synthesis, biological activity, and molecular docking study

Article abstract of DOI:10.1016/j.bmcl.2015.11.024

Preliminary hit-to-lead optimization of a novel series of phenylsulfonyl hydrazide derivatives, which were derived from the high throughput screening hit compound 1 (IC₅₀ = 5700 nM against PGE₂ production), for a potent suppressor of

Full text of DOI:10.1016/j.bmcl.2015.11.024

Accepted Manuscript
Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent suppressor
of PGE2 production: Synthesis, biological activity, and molecular docking study
Minju Kim, Sunhoe Lee, Eun Beul Park, Kwang Jong Kim, Hwi Ho Lee, Ji-Sun
Shin, Katrin Fischer, Andreas Koeberle, Oliver Werz, Kyung-Tae Lee, Jae Yeol
Lee
PII:
S0960-894X(15)30233-X
http://dx.doi.org/10.1016/j.bmcl.2015.11.024
BMCL 23280
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 March 2015
22 October 2015
9 November 2015
Please cite this article as: Kim, M., Lee, S., Park, E.B., Kim, K.J., Lee, H.H., Shin, J-S., Fischer, K., Koeberle, A.,
Werz, O., Lee, K-T., Lee, J.Y., Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent suppressor of
PGE2 production: Synthesis, biological activity, and molecular docking study, Bioorganic & Medicinal Chemistry
Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.2015.11.024
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Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent
suppressor of PGE2 production: Synthesis, biological activity, and
molecular docking study
Minju Kim a, 1, Sunhoe Lee a, 1, Eun Beul Park a, Kwang Jong Kim a, Hwi Ho Lee b, Ji-Sun Shin c,
Katrin Fischer d, Andreas Koeberle d, Oliver Werz d,*, Kyung-Tae Lee b,*, Jae Yeol Lee a,*
a Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung
Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
b Department of Life and Nanopharmaceutical Science, Kyung Hee University, 26 Kyungheedae-ro,
Dongdaemun-gu,, Seoul 02447, Republic of Korea
c Reactive Oxygen Species Medical Research Center, School of Medicine, Kyung Hee University, 26
Kyungheedae-ro, Dongdaemun-gu,, Seoul 02447, Republic of Korea
d Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-
University Jena, Philosophenweg 14, 07743 Jena, Germany
1 The contributions of the authors are equal.
(Corresponding authors: Tel. +82-2-961-0726; Fax +82-2-961-0443; e-mail: oliver.werz@uni-jena.de;
ktlee@khu.ac.kr; ljy@khu.ac.kr)
Keywords: inflammation; prostaglandin E2; phenylsulfonyl hydrazide; mPGES-1; molecular
docking study
Abstract: Preliminary hit-to-lead optimization of a novel series of phenylsulfonyl hydrazide
derivatives, which were derived from the high throughput screening hit compound 1 (IC50 = 5,700
nM against PGE2 production), for a potent suppressor of PGE2 production is described. Subsequent
optimization led to the identification of the potent lead compound 8n with IC50 values of 4.5 and 6.9
nM, respectively, against LPS-induced PGE2 production and NO production in RAW 264.7
macrophage cells. In addition, 8n was about 30- and >150-fold more potent against mPGES-1
enzyme in a cell-free assay (IC50 = 70 nM) than MK-886 and hit compound 1, respectively.
Molecular docking suggests that compound 8n could inhibit PGE2 production by blocking the PGH2
binding site of human mPGES-1 enzyme.

PGE2 (prostaglandin E2) has long been considered the principal prostaglandin of acute
inflammation and of chronic diseases such as rheumatoid arthritis1 and inflammatory bowel disease.2
Macrophages play particularly important roles in inflammation because they produce many pro-
inflammatory molecules such as PGE2. Therefore, the pharmacological interference of PGE2
production has been postulated as a means of alleviating a number of disease states mediated by
excessive and/or protracted macrophage activation. As PGE2 is produced in relative abundance by
COX-2 (cyclooxygenase-2) action, selective COX-2 inhibitors such as celecoxib and rofecoxib
suppress PGE2 levels relative to other prostaglandins. However, coxib drugs such as Bextra® and
Vioxx® were withdrawn from the market in 2004 and 2005, respectively, because they have been
linked with an increased risk of adverse cardiovascular events with high doses and chronic usage.3
Therefore, the exploration of alternative pharmacological approaches leading to safer anti-
inflammatory drugs that do not alter COX-2 activity is of urgent need. One promising approach to
circumvent COX-related side effects while maintaining anti-inflammatory efficacy is the interference
with microsomal prostaglandin E2 synthase (mPGES)-1. This mPGES-1 enzyme, a PG synthase
downstream of COX-2, specifically catalyzes the biosynthesis of COX-2-derived PGE2 from PGH2
(prostaglandin H2)4 and thus, its inhibition would ideally not affect the formation of house-keeping
PGs. Therefore, small molecule inhibitors of mPGES-1 are considered valuable for anti-
inflammatory therapy with reduced side effects.5-15 Several compounds like MF-63, MK-866, and
Triclosan are mPGES-1 inhibitors, which were assayed in in vitro studies, but some of them have
shown poor bioavailability and hepatotoxicity.16-17
In our previous research, we had initiated both virtual screening and real high throughput
screening (HTS) using the master library from Korean Chemical Bank and identified hit compound 1
featuring a phenylsulfonyl hydrazide core (Figure 1).18 Since compound 1 displayed strong
suppression of LPS-induced PGE2 production (IC50 = 5,700 nM against PGE2) in RAW 264.7
macrophage cells, our efforts were focused on the hit-to-lead optimization via structure–activity
relationship (SAR) study on the phenylsulfonyl hydrazide template to identify novel compounds with

improved in vitro potency. After analysis in a cell-free mPGES-1 enzyme assay, a molecular docking
study on the putative active site of mPGES-1 was carried to shed light into the mPGES-1/inhibitor
binding interactions.
Figure 1. Discovery of HTS hit compound 1 and lead compound 8n via SAR study
Scheme 1. Retrosynthetic analysis of phenylsulfonyl hydrazide derivatives 8
In order to improve the potency of hit compound 1, only two areas were addressed with a
fixed phenyl ring at P-3 region as a preliminary research: the effect of both substituents of phenyl
ring and phenoxy ring at P-1 and P-2 region (Figure 1), respectively, on LPS-induced PGE2

production. We designed synthetic route to obtain phenylsulfonyl hydrazide derivatives 8 via a
retrosynthetic analysis (Scheme 1). The target compound 8 could be obtained from the nucleophilic
substitution reaction of phenyl chloroformate 6 with phenylsulfonyl hydrazide 7, which could be
obtained from the reaction of phenylsulfonyl chloride 5 and phenylhydrazine 4. The phenyl
chloroformate 6 could also be obtained from the reaction of phosgene 3 and phenol 2. As illustrated
in Scheme 2, the reaction of appropriately substituted phenols 2d-h with 0.6 equivalent of
triphosgene 3 (instead of toxic phosgene gas) in the presence of N, N-diisopropylethylamine (Hünig’s
base) gave commercially unavailable phenyl chloroformates 6d-h in excellent yields. Next, N-
(phenyl)-phenylsulfonyl hydrazide 7a-g were synthesized in low to moderate yields via the
sulfonation of phenylhydrazine 4 using appropriately substituted phenylsulfonyl chlorides 5a-g in the
presence of triethylamine (TEA). Finally, N-(phenoxycarbonyl)-N’-(phenyl)phenylsulfonyl
hydrazide 1 and 8a-t were obtained in various yields by coupling of N-(phenyl)phenylsulfonyl
hydrazide 7a-g and phenyl chloroformates 6a-h (commercially available 6a-c and synthesized 6d-h)
in the presence of TEA under THF reflux condition.
Scheme 2. Reagents and conditions: (a) DIPEA, THF, 0 °C, 12 h for 6d-h; (b) TEA, CH2Cl2, 0 °C to
rt, 3-6 h; (c) TEA, THF, 60 °C, 4-8 h.

Table 1. Biological activity of N-(phenoxycarbonyl)-N’-(phenyl)phenylsulfonyl hydrazide derivatives
Structure
PGE2
IC50 (nM) c
Yield
(%) a
Viability
Entry
(µM) b
R1
R2 R3
R4
R5
R6
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
H
H
H
H
H
H
Me
MeO
H
82
96
90
81
63
36
48
89
49
15
44
52
81
17
10
82
78
28
17
14
50
> 10
> 10
> 10
> 10
> 10
≥ 10
> 10
> 10
> 10
> 10
> 10
> 10
> 10
≥ 10
> 10
> 1
5,700
1,020
584
1
8a
H
H
H
8b
8c
Me
H
5,720
1,010
32.6
Me
H
Me
BnO
H
8d
8e
Me
H
Me
MeO
H
34.1
8f
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
n-Pr
t-Bu
Ph
H
4,430
490
8g
H
MeO
H
8h
8i
MeO
H
165
Et
28.5
20.5
17.1
50.0
8j
H
EtO
PhO
BnO
8k
8l
H
H
8m
8n
8o
H
CH2CH2CH2
4.5
H
H
H
H
H
H
H
PhO
BnO
PhO
BnO
PhO
BnO
134
H
> 1
56.9
161
8p
8q
8r
H
> 1
Ph
H
> 1
93.0
177
Me Me Me
Me Me Me
H
> 1
8s
H
> 1
81.5
8t
NS398 d
7.0
a Isolated yield of final step for each compound; Cytotoxicity of each compound using
MTT assay; IC50 value is the compound concentration required to produce 50%
b
c
d
inhibition of LPS-induced PGE2 production in RAW 264.7 macrophages; Positive
control as a selective COX-2 inhibitor for assay of PGE2 production inhibition.
In order to check that the suppressive effects of all synthesized compounds on PGE2
production could be attributable to non-specific cytotoxicity, initially, we examined the cytotoxicity
of synthetic compounds in RAW 264.7 cells in the presence of LPS using MTT assays.19 None of the

compounds affected the viabilities of RAW 264.7 cells at 1 or 10 µM concentration over 24 h (Table
1). Therefore, all compounds were screened for their ability to suppress PGE2 production in LPS-
induced RAW 264.7 cells at a concentration of 1 or 10 µM over 24 h using NS398 (@ 3 µM) as a
positive control. PGE2 concentration in the medium was measured using an EIA kit for PGE2
according to the manufacturer’s recommendation. Then, active compounds exhibiting >50%
suppression of PGE2 production at the given concentration were pushed forward for IC50
determinations.20 All experiments were carried out at least twice and they gave similar results. The
biological activities of all compounds are summarized as both cell viabilities and IC50 values of PGE2
production in Table 1 with NS398 utilized as a positive control in PGE2 assays. Our initial efforts
focused on modifications of the P-1 region via the introduction of substituent on R1 position of hit
compound 1 (Table 1). Introduction of a simple methyl group led to a similar activity (8c) compared
to hit compound 1, whereas a slightly improved activity was found when a methoxy group was
introduced (8g), indicating that small substituents were well tolerated at this position. Interestingly,
compounds (8f and 8i) bearing an additional methoxy group at the R4 position in P-2 region
exhibited a dramatically enhanced activity (in particular, IC50 = 34.1 nM for 8f) compared to their
corresponding mono-substituted analogs (8c and 8g). With respect to the R6 position in P-2 region,
the introduction of methyl (8a) or methoxy groups (8b) resulted in an approximately 5- or 10-fold
increase in activity compared to parental compound 1. In addition, compounds (8d and 8h) having
the same methyl or methoxy groups at both R1 and R6 positions were also 5- and 10-fold more active
than those of mono-substituted analogs (8c and 8g), respectively. The introduction of methyl and
benzyloxy groups on R1 and R6 positions, respectively, exhibited potent inhibitory activity (IC50
=
32.6 nM for 8e) comparable to that of compound 8f (IC50 = 34.1 nM). With these overall results in
hand, we further investigated the role of R6 substituents by incorporating ethyl (8j), ethoxy (8k),
phenoxy (8l) or benzyloxy (8m) groups into this R6 position, which led to a dramatically increase of
activity (IC50 = 17.1 to 50 nM), indicating the importance of bulky substituents at this position that
can be accommodated at the binding site of certain enzyme. In particular, the importance of a

benzyloxy substituent at this position was confirmed by comparing 8c and 8d (IC50 = 5,720 and
1,010 nM) with 8e (IC50 = 32.6 nM). Furthermore, benzyloxy derivatives (8p, 8r and 8t) were
generally more active than their corresponding phenoxy analogs (8o, 8q and 8s) with the exception
of compounds 8l (IC50 = 17.1 nM). When a bulky group (phenoxy or benzyloxy) was located as R6
substituent, a small group (methyl or methoxy: 8e, 8l or 8m) displayed better in vitro potency than
bulky substituents (n-Pr, t-Bu or Ph: 8o-8r) at R1 position and a 2,4,6-trimethylphenyl ring (8s-8t) at
P-1 region, indicating that only small groups as R1 substituent were tolerated for stronger activity
again. As observed in this preliminary hit-to-lead study, more potent activity was reached by the
compound 8n bearing a methoxy group at R1 position and trimethylene unit at R5-R6 position.
Compound 8n (IC50 = 4.5 nM) was 1.5-fold more active than NS398 (IC50 = 7.0 nM) as positive
control and also displayed about 1,100-fold better activity than the original hit compound 1.
Additionally, compound 8n was tested for inhibition of NO production in LPS-stimulated RAW
264.7 cells and found to exhibit an IC50 value of 6.9 nM. Figure 2 shows the concentration–response
inhibition of 8n towards the secretion of PGE2 and NO.
Figure 2. Effects of compound 8n on (a) PGE2 and (b) NO production in LPS-stimulated RAW
264.7 cells. The cells were co-incubated with LPS (10 ng/mL) and different concentrations of 8n
ranging from 0.1 to 10 nM. The supernatants were then collected for the measurement of PGE2 and
NO production using EIA kit and a Griess reagent, respectively. 8n significantly inhibited PGE2 and
NO levels in LPS stimulated macrophages. The values are expressed as the means SD of three
#
∗
∗∗
individual samples. p <0.05 versus the control cells; p <0.05, p <0.01, ∗∗∗p <0.001 versus LPS-
stimulated cells; statistical significances were compared using ANOVA and Dunnett’s post hoc test.

Among all the synthetic compounds, 8 selected compounds that potently suppressed PGE2
production (IC50 < 60 µM) were investigated for interference with mPGES-1 activity in a cell-free
assay, using the microsomal fraction of interleukin-1β-stimulated human A549 cells as enzyme
source.21 Compounds with low potency (1 and 8d) were tested as well for comparison, and MK-886
(10 µM) was used as a reference compound. The results summarized in Table 2 show that all
compounds except 8e and 8p significantly inhibited mPGES-1 activity at a concentration of 10 µM.
As compounds 8d, 8l and 8n repressed mPGES-1 activity at 10 µM by more than 50%, we
determined the IC50 values by more detailed concentration response studies. Compound 8n turned
out to be most potent with an IC50 = 70 nM, while 8d and 8l were less efficient (IC50 = 6,100 and
6,600 nM, respectively). The mPGES-1 reference inhibitor MK-886 reduced PGE2 production by 84%
at 10 µM with an IC50 = 2 µM (in line with literature data)21-22 under our assay condition. Therefore,
the most active compound 8n showed about 30- and >150-fold higher potency than MK-886 and hit
compound 1, respectively, against mPGES-1 enzyme in a cell-free assay.
Table 2. Inhibition of human mPGES-1 in a cell-free assay by selected compounds
Remaining activity of
mPGES-1
MolDock
Entry
mPGES-1 at 10 µM (%) a
IC50 (µM) b
Score c
63.6 2.5
41.3 9.2
81.2 5.7
55.7 12.4
63.6 5.8
62.5 2.6
37.1 11.8
62.6 2.7
18.5 6.8
79.9 9.0
16.3 2.4
> 10
6.1 5.7
> 10
-135.2
-150.4
-160.6
-148.9
-151.3
-159.1
-165.0
-167.6
-168.8
-163.7
-182.4
1
8d
8e
> 10
8f
> 10
8j
> 10
8k
8l
6.6 4.8
> 10
8m
0.07 0.03
> 10
8n
8p
MK-886 d
2.0 e
a
The remaining mPGES-1 activity is given as percentage of uninhibited
b
control (= 100%) and presented as means
S.E.; IC50 values are
presented as means S.E. of n = 3 independent experiments; c MolDock
score during docking in the mPGES-1 (PDB code: 4AL0) active site by
d
using MVD2013.6.0.1; MK886 (10 µM) was used as a reference
compound; reported data for MK88621-22
;
NS398 was used as a
e
f
selective COX-2 inhibitor for the reliability of docking data.

As can be seen from Table 1 and 2, inhibition of mPGES-1 by the test compounds was in
line with the suppression of PGE2 formation except for compound 8d. Thus, for 8l and 8n that were
the most efficient mPGES-1 inhibitors, these compounds also efficiently inhibited PGE2 production
with IC50 values of 17.1 and 4.5 nM, respectively, confirming our preliminary results regarding the
phenylsulfonyl hydrazide derivatives as putative mPGES-1 inhibitors.18
Figure 3. Predicted binding poses retrieved from flexible docking of compounds 8n [(a) and (b)] and
1 [(c) and (d)] in human mPGES-1 (PDB: 4AL0) putative binding sites. The atom coloring for the
compounds is the following: carbons in grey, oxygens in red, nitrogens in light purple, and sulfur in
yellow. GSH (glutathione) as a cofactor is depicted as green ball and stick model. The key amino
acids of chain 1 and 2 participating in hydrogen bonding are depicted as dark grey stick model.
Hydrogen bonds are shown in blue dotted line. The hydrogens are omitted for the simplicity. In (b)
and (d), the amino acids of chain 1 and 2 participating in hydrogen bonds and hydrophobic
interactions are depicted as grey wireframe models.

Next, molecular docking studies were performed in order to rationalize the different
biological activities of compounds tested against mPGES-1 enzyme by using the recently crystallized
structure of mPGES-1 (PDB code: 4AL0)23 because hit compound 1 was found to suppress PGE2
production via the inhibition of mPGES-1 enzyme.18 Recently, it has been reported that PGH2
covalently binds together with GSH (glutathione) into the active site of mPGES-1 and isomerizes to
PGE2 with the help of several amino acids including key amino acid Ser127 close to GSH.23 In
addition, a hypothetical mPGES-1 inhibitor can act either as a false substrate (PGH2) or as a cofactor
analog (GSH), or it can behave in both ways.24 Recently, we found that the appropriate correlation
between real IC50 values and MolDock scores for known mPGES-1 inhibitors was found only in the
presence of GSH.25 In this study, therefore, molecular docking calculations were then performed in
the presence of this cofactor. The docking studies were performed using Molegro Virtual Docker
(MVD) 2013.6.0.1 for Windows.26 First of all, we identified one cavity with a volume 188 Å3 located
in close proximity to GSH (glutathione) as a cofactor by the same software, which can automatically
detect cavities from protein surfaces. The putative active site of the enzyme was defined to include
residues within a 10 Å radius to this cavity. The docking wizard of 2013.6.0.1 was used to dock all
compounds together with MK-886 and NS398 as mPGES-1 inhibitor and COX-2 inhibitor,
respectively, for comparison. The best pose with the highest MolDock score by the MVD scoring
function was selected for each compound and inserted in Table 2. As shown in Table 2, the
appropriate correlation between IC50 value and MolDock Score was found for compound 1, 8l, 8n,
and MK-886. This docking result suggest that this series compounds rather inhibit PGE2 production
by blocking the active site (i.e., the binding site for PGH2) of mPGES-1 enzyme than of COX-2
enzyme. This possibility was also supported by the relatively lowest MolDock score (-117.9) for
NS398, a selective COX-2 inhibitor with an IC50 value of 7.0 nM against PGE2 production under our
assay condition. In particular, the most active compound 8n with IC50 value of 70 nM against
−
mPGES-1 was found to dock into the active site of mPGES-1 with higher MolDock Score of 168.8
compared to hit compound 1 (IC50 value of >10 µM and MolDock Score = -135.2). Based on these

results, we decided to further analyze the detailed binding modes of compounds 8n and 1 with
mPGES-1, respectively, because the understanding of their binding modes will be of great help in
further lead optimization studies in the future. According to the docking results, the three ring
systems of most active compounds 8n occupied the similar positions as those of hit compound 1 in
the active site of mPGES-1 enzyme as shown in Figure 3. Both hit compound 1 and active compound
8n interacted with GSH through two hydrogen bond interactions with the oxygen atom of carbamate
group in Figure 3 (a) and (c). In the case of compound 8n, however, the oxygen atom of the methoxy
group in P-1 region and the second nitrogen atom of the sulfonyl hydrazide group participated in
additional hydrogen bond interactions with Ala45 (2.91 Å) and Asn46 (3.11 Å) of chain 1, and
Ser127 (3.29 Å) of chain 2, respectively, which has been identified as a key residue in the catalytic
activity of human mPGES-1 enzyme.23 In addition, the indanyl ring in P-2 region of compound 8n
was well-positioned in the hydrophobic pocket, constituting of hydrophobic residues Ile32 (chain 1),
Gly35 (chain 1), Leu29 (chain 1), Gln36 (chain 1), Tyr130 (chain 2), and Thr131 (chain 2) in the
mPGES-1 active site when compared to the simple phenyl ring of hit compound 1 as shown in Figure
3 (b) and (d). The combination of additional hydrogen bonds and hydrophobic interactions could
possibly increase the ligand binding affinity and thus result in higher mPGES-1 inhibitory activity of
compound 8n than hit compound 1. In fact, compound 8n was more than 100-fold more potent than
hit compound 1 against mPGES-1 enzyme in a cell-free assay.27 The presence of an indanyl ring
could also explain why compound 8n was more active than compound 8j bearing simple 4-
ethylphenyl ring at P-2 region.
In conclusion, a series of novel phenylsulfonyl hydrazide derivatives have been synthesized
and evaluated for their inhibitory effects on LPS-induced PGE2 production in RAW 264.7 cells
through a preliminary hit-to-lead optimization strategy. Among them, compound 8n bearing an
anisole and indanyl ring at P-1 and P-2 regions, respectively, exhibited the most potent inhibition on
PGE2 production with an IC50 value of 4.5 nM and also was non-cytotoxic at up to 10 µM

concentration. Compound 8n also showed an IC50 value of 70 nM against mPGES-1 enzyme in a
cell-free assay. Molecular docking study revealed that 8n could inhibit PGE2 production by blocking
the PGH2 binding site of mPGES-1 enzyme and will serve as an important template for future
chemical modification. Further optimization including P-3 region in Figure 1 and application of this
series of compounds will be reported in due course.
Acknowledgment
This research was supported by Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2013R1A1A2058915)
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26. MVD 2013.6.0.1 for Windows in Molegro ApS: With this purpose, crystal structures of human
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the MVD’s Pose Viewer utility.
27. Spectral data of N-(5-indanoxycarbonyl)-N’-(phenyl)-4-methoxyphenylsulfonyl hydrazide
1
(8n): mp 134.7-139.0 °C; H NMR (400 MHz, DMSO-d6) δ 9.16 (1H, s), 7.94-7.91 (1H, m),
7.27-7.23 (2H, m), 7.22-7.18 (3H, m), 6.85 (1H, t, J = 7.2 Hz), 6.81-6.77 (3H, m), 6.72 (1H, dd,
J = 8.0 and 2.4 Hz,), 3.89 (3H, s), 2.81 (2H, t, J = 7.2 Hz), 2.80 (2H, t, J = 7.2 Hz), 2.00 (2H,
qu, J = 7.6 Hz); 13C NMR (100 MHz, DMSO-d6) δ 163.82, 151.40, 148.29, 146.87, 145.51,
141.85, 130.97, 129.09, 129.04, 124.84, 119.88, 118.72, 117.11, 114.46, 111.95, 55.94, 32.24,
31.62, 25.31; Low MS (ES): m/z 439.23 [M+H]+; HRMS (FAB): m/z calcd for C23H23N2O5S
[M+H]+ 439.1328, found 439.1322.

Graphical Abstract
Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent suppressor of PGE2
production: Synthesis, biological activity, and molecular docking study
Minju Kim, Sunhoe Lee, Eun Beul Park, Kwang Jong Kim, Hwi Ho Lee,
Ji-Sun Shin, Katrin Fischer, Andreas Koeberle, Oliver Werz*, Kyung-Tae Lee*, Jae Yeol Lee*