Synthesis, structure-activity relationship and binding mode analysis of 4-thiazolidinone derivatives as novel inhibitors of human dihydroorotate dehydrogenase

Article abstract of DOI:10.1039/c7md00081b

A series of 4-thiazolidinone derivatives were synthesized and evaluated as novel human dihydroorotate dehydrogenase (hDHODH) inhibitors. Compounds 26 and 31 displayed IC₅₀ values of 1.75 and 1.12 μM, respectively. The structure-activity relationship was summarized. Further binding mode analysis revealed that compound 31 could form a hydrogen bond with Tyr38 and a water-mediated hydrogen bond with Ala55, which may be necessary for maintaining the bioactivities of the compounds in this series. Further structural optimization of the para- or meta-position of the phenyl group at R will lead to the identification of more potent hDHODH inhibitors.

Full text of DOI:10.1039/c7md00081b

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Synthesis, structure-activity relationship and binding mode analysis
of 4-thiazolidinone derivatives as novel inhibitors of human
dihydroorotate dehydrogenase†
Fanxun Zeng,a# Tiantian Qi,b# Chunyan Li,a Tingfang Li,a Honglin Li,b Shiliang Li,ab*
Lili Zhub* and Xiaoyong Xuac*
a Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China
University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
b Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor
Engineering, School of Pharmacy, East China University of Science & Technology,
Shanghai 200237, China
c
Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130
Meilong Road, Shanghai 200237, China
# Authors contributed equally to this work
* Corresponding author. Tel.: +86-21-64250213; fax: +86-21-64250213. E-mail:
slli403@163.com.
* Corresponding author. Tel.: +86-21-64253379; fax: +86-21-64250213. E-mail:
zhulfl@ecust.edu.cn.
* Corresponding author. Tel.: +86-21-64252945; fax: +86-21-64252603. E-mail:
xyxu@ecust.edu.cn.
† The authors declare no competing interests.
A series of 4-thiazolidinone derivatives were synthesized and evaluated as novel
human dihydroorotate dehydrogenase (hDHODH) inhibitors. Compounds 26 and 31
displayed IC50 values of 1.75 and 1.12 µM, respectively. The structure-activity
relationship was summarized. Further binding mode analysis revealed that compound
31 could form a hydrogen bond with Tyr38 and a water-mediated hydrogen bond with
Ala55, which may be necessary for maintaining the bioactivities of the compounds in
this series. Further structural optimization of the para- or meta-position of the phenyl
group at R will lead to the identification of more potent hDHODH inhibitors.
Introduction
Human dihydroorotate dehydrogenase (hDHODH), a critical rate-limiting enzyme
in pyrimidine de novo biosynthesis pathway, plays a key role in the biosynthesis of
nucleotide and cell proliferation.1-2 The significance of DHODH in rapidly
proliferating cells such as tumor cells and active T and B lymphocytes makes it
become an ideal target for pharmacological intervention.3 Some inhibitors of DHODH
have proven efficacy for the treatment of malaria,4-5 autoimmune diseases,6-8 cancer,9

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psoriasis,10 virus proliferation 11-13 and acute myeloid leukemia.14 Leflunomide (1) and
brequinar (3) are two representative examples of such DHODH inhibitors (Fig. 1)
Leflunomide and its active metabolite teriflunomide, have been approved for the
15-16
treatment of rheumatoid arthritis and multiple sclerosis.3,
However,
administration of leflunomide for an extended period would cause numerous adverse
effects including gastrointestinal symptoms, liver toxicity, hypertension, interstitial
lung disease and birth defect, preventing it from being utilized widely.17-19 Brequinar
was used as antitumor and immunosuppressive agent in phase II clinical trials but
failed due to its narrow therapeutic window.20-22 Compound 4 has already exhibited
promising results for inflammatory bowel disease in the phase IIa clinical trial, and it
is now focused on Crohn’s disease in a phase IIb trial.23 Consequently, there remains
intensively needs to discover novel and potent hDHODH inhibitors for further
development.
Figure 1. Structures of representative inhibitors of hDHODH.
4-Thiazolidinones, a class of heterocycle including nitrogen and sulfur atoms, have
been reported as a biologically important scaffold and possess broad biological
activities, such as anticonvulsant activity, cardiovascular effects, antibacterial activity,
anticancer activity, antihistaninic activity (H1-antagonist), and anti-inflammatory
activity et al.24-27 As part of our continuing studies on 4-thiazolidinones,28 compound
5 was found to have the inhibitory activity against hDHODH by random screening.
Then, a serious of 4-thiazolidinones were synthesized and evaluated for their
inhibitory activities against hDHODH.
Herein we described the discovery and the SAR study of 4-thiazolidinone
derivatives as novel hDHODH inhibitors. The binding modes of compounds 21 and
31 were also studied by molecular docking to help further elucidate the SAR.

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Results and discussion
Chemistry
The synthesis of starting materials aryl isothiocyanates was shown in Scheme 1.
Dithiocarbamate salts were prepared by reaction of triethylenediamine and
carbamodithioic acids which were formed by treatment of aromatic amines with
carbon bisulfide. Isothiocyanates were then obtained by treated dithiocarbamate salts
with BTC. 4-isothiocyanatobenzoic acid was prepared by reaction of 4-aminobenzoic
acid with TCDI in the presence of TEA.
4-Thiazolidinones and their analogs were prepared according to the routes depicted
in Scheme 2. Aryl isothiocyanates were treated with active methylene compounds and
potassium hydroxide in DMF to provide ketene-N,S-acetal salts. These
ketene-N,S-acetal salts were further reacted with 2-chloroacetyl chloride,
3-bromopropanoyl chloride or 1,2-dibromoethane to give compounds 5-11 and 13-31.
Compound 12 was prepared by de-protection of compound 11 with TFA in DCM.
Reaction of isothiocyanate with 2-mercaptoacetic acid offered an intermediate
2-(carbamothioylthio)acetic acid, which was subsequently cyclized to produce the
additional analogue 32. All the final compounds were fully characterized by
spectroscopic techniques.
Scheme 1. Synthesis of intermediates. (i) DABCO, CS2, acetone, r.t., 12 h; (ii) BTC,
CHCl3, r.t., 4 h, 70%-95%; (iii) TEA, DCM, r.t. 90%.

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Scheme 2. Synthesis of compounds 5-32. (i) KOH, DMF, r.t. 15-30 min; ClCH2COCl,
0 oC; r.t., 12 h, 68%-80%. (ii) KOH, DMF, r.t. 15 min; BrCH2CH2COCl, 0 oC; r.t., 12
o
h, 60%. (iii) KOH, DMF, r.t. 15 min; BrCH2CH2Br, 0 C; r.t., 12 h, 48%. (iv) TFA,
DCM, r.t. 85%. (v) TEA, dioxane, reflux, 65%.
Inhibitory activities against hDHODH and SAR study
Table 1 highlights SAR for the 4-thiazolidinone moiety. If 4-thiazolidinone was
replaced by 1,3-thiazin-4-one, the inhibitory activity of compound 6 decreased
dramatically. Replacement of the 4-thiazolidinone of 5 with thiazolidin provided 7,
with apparently decreased activity again. We next investigated the effect of the R2
group. Compounds 8-11 showed similar activity with 5, suggesting that carbon chain
length of the ester group probably had no apparent effect on the activity. When the
ester structures were transformed into their acid, the activity of compound 12 became
very poor with an inhibitory rate of only 14.867 % at 10 µM. Introducing a -CONH2
group to the R2 position also showed weak activity (compound 13), which implied
that polar groups were not tolerated at the R2 position. Compounds 14 and 15 with
ester groups at R1 also showed dramatically lower enzyme inhibitory activities than
that of the cyano group substituted counterparts (compounds 5 and 8). The above
discussions indicated that the 4-thiazolidinone scaffold, the cyano substitution for R1

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and the ester structure for R2 are key factors for potent hDHODH inhibitors.
Table 1
Structures and activities for 4-thiazolidinone analogs 5-15
Inhibitory Rate at
10 µM (%)
34.866
hDHODH
IC50 (µM)a
compd
R1
R2
R3
n
CN
CN
CN
CN
CN
CN
CN
CN
CN
CO2Me
CO2Me
CO2Me
CO2Et
=O
=O
H
1
2
1
1
1
1
1
1
1
1
1
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
0.0084
5
6
7
8
9
10
11
12
13
15.690
11.063
38.194
33.481
28.770
33.933
14.867
11.757
=O
=O
=O
=O
=O
=O
=O
=O
CO2Pr
CO2Bu
CO2tBu
COOH
CONH2
CO2Me
CO2Et
14
15
CO2Me
CO2Et
4.271
8.713
Brequinar
a Attempts to determine IC50 values were made if the inhibition rate at 10 µM was
larger than 50%.
In order to optimize the activity of lead compound 5, N-substituted derivatives
were then explored (Table 2). Compound 16 with o-chlorophenyl or compound 17
with o-iodophenyl group showed equal or lower enzyme inhibitory activities
compared with that of lead compound 5. When m-Cl, p-F and p-Br group were
introduced to the phenyl of the scaffold (compounds 19-21), the inhibitory activities
were higher than that of compound 5, which were shown in Table 2. Among them,
given the dramatically improved potency observed with 4-bromophenyl analog 21,
further investigations were performed to study the effect of various para-substituted
phenyls. Many para-substituted analogs displayed submicromolar potencies
(compounds 20-24 and 26). Compounds with hydrophobic groups (-F, -Br, -NO2,
-CF3, -OCH3 and -t-Bu) at the para-position of phenyl showed better potencies.
Compound 27 with hydrophilic group (-COOH) displayed decreased potencies.
Pyridinyl derivatives (28 and 29) were not beneficial for the increasing of inhibitory
activities. These results indicated that introduction of bulky hydrophobic groups to R1
might improve the activity. Based on this idea, naphthalenyl was introduced at the
N-position to give analogs 30 and 31. Gratifying, compound 31 (2-naphthyl) was
slightly more potent than 26 with IC50 value of 1.12 µM. The poor inhibitory activity
of compound 32 further verified the key effect of 2-cyanoacetate substitution for
potency.

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Table 2
Structures and activities for 4-thiazolidinone analogs 16-32
Inhibitory Rate at
10 µM (%)
hDHODH IC50
compd
R
(µM)a
40.010
18.377
34.109
56.856
49.438
68.979
74.431
62.932
52.475
40.378
>10
16
>10
>10
17
18
19
20
21
22
23
24
25
8.51
10.64
2.68
3.03
4.41
9.45
>10

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79.074
15.064
43.738
45.360
21.886
80.327
1.75
26
27
28
29
30
31
>10
>10
>10
>10
1.12
Cl
Cl
N
N
25.632
>10
32
a IC50 values were determined from three independent tests, and attempts to determine
IC50 values were made if the inhibition rate at 10 µM was larger than 50%.
Binding mode analysis
To further study the action mechanism of this series of derivatives, the binding
modes of compounds 21 and 31 were simulated by molecular docking (Fig. 2). Figure
2A tells that the carbonyl group of 4-thiazolidinone forms a hydrogen bond with
Tyr38. When 4-thiazolidinone was replaced by 1,3-thiazin-4-one (compound 6) or
thiazolidin (compound 7), the hydrogen bond mentioned above would be destroyed,
leading to a dramatically decreased inhibitory activity. The methyl ester of 21 is
located at the entrance of the binding site, interacting with hydrophobic residues like
Leu42, Leu46, Leu58 and Phe62. However, it should be noticed that the methyl
moiety of the ester in 21 is exposed to the bulk solvent (Fig. 2B), thus prolongation of
the carbon chain length of the ester group may contribute little to the bioactivity,
that’s why compounds 8-11 showed similar activity with 5. Because of the relatively
hydrophobic profile, hydrophilic substituents like -COOH and -CONH2 (compounds
12 and 13) are not favored at the entrance of the binding site. Figure 2A also shows
that the cyano group of 21 orients itself towards the inner side of the binding site,
forming a water-mediated hydrogen bond with Ala55. Limited space is left around the

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cyano group for substituting. Larger groups like -CO2Me and -CO2Et may clash with
residues Leu58 and Ala59, leading to sharply decreased bioactivity (14 and 15).
Additionally, the 4-bromophenyl group of 21 makes beneficial van der Waals (vdW)
interactions with the hydrophobic subsite formed by residues Met43, Ala59, Leu68,
Phe98, Met111, Leu359 and Pro364. Obviously, hydrophilic groups like -COOH are
disfavored at this hydrophobic subsite, thus compound 27 displayed seriously
decreased bioactivity against hDHODH compared with 21. The binding mode of the
phenyl group of 21 informs us that little space is remained for substitution at the
ortho-position of the phenyl, while larger hydrophobic groups are preferred at the
para- or meta-position. This is consistent with the decreased inhibitory activities of
16-17, 25 and 30, the increased inhibitory activities of 18-19, and the improved
inhibitory activities of 20-24, 26 and 31. As for compound 31, the large naphthalenyl
group accommodates the concave surface well (Fig. 2B) and displayed the most
potent bioactivity of this series. Collectively, the 4-thiazolidinone scaffold, the cyano
substitution for R1, the ester structure for R2 and the hydrophobic substitutions at
para- or meta-positions of the phenyl group for R are beneficial for maintaining the
bioactivities of the inhibitors in this series.
Compared with the ligand 3X2 in 4LS1 occupying both the hydrophobic and
hydrophilic sections of the ubiquinone-binding site of DHODH (Figure S1),
compound 31 mainly accommodates the hydrophobic subsite with its naphthalenyl
group contacting with residues Met43, Ala59, Leu68, Phe98, Met111, Leu359 and
Pro364 through favorable apolar interactions. This obviously distinct binding mode of
compound 31 and 3X2 informed us that polar group, such as carboxyl, formyl and
hydroxyl, which is connected to a proper linker that substituted to the naphthalenyl
group of 31, would generate hydrogen bond or salt bridge interactions with residue
Arg136 in the hydrophilic subsite of the ubiquinone-binding site, thus may bring us
compounds with improved binding affinity against DHODH. This structural
optimization work is undertaken.
Figure 2. The proposed binding modes for representative compounds 21 and 31. The

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X-ray crystal structure of hDHODH (PDB ID: 4LS1) is shown as transparent purple
cartoon (A) or solid surface (B), and the docked inhibitors are represented as sticks
with transparent surface. Compound 21 is shown as pink sticks, while compound 31 is
displayed as green sticks. For small molecules, oxygen atoms are colored red,
nitrogen atoms are colored blue, and the sulfur atoms are colored yellow. Key
residues (thin sticks) in the binding site are colored in purple. Potential intermolecular
hydrogen bonds are showed in black dashed lines. Water molecule W592 is depicted
as red balls.
Conclusions
In conclusion, a series of 4-thiazolidinone derivatives have been identified as
hDHODH inhibitors. Several compounds exhibited moderate activities against
hDHODH, especially compounds 26 and 31 with IC50 values of 1.75 and 1.12 µM,
respectively. The SAR study and binding mode investigation demonstrate that the
4-thiazolidinone scaffold, the cyano substitution for R1, the ester structure for R2 and
the hydrophobic substitutions at para- or meta-positions of the phenyl group for R are
favorable for improving inhibitory activity. For this series of 4-thiazolidinone
derivatives, the hydrogen bond with Tyr38 and the water-mediated hydrogen bond
with Ala55 were proposed to be indispensable to maintain the inhibitory activity for
hDHODH. The present SAR indicates that further decoration of the phenyl group at R
may bring us more potent hDHODH inhibitors.
Acknowledgments
This work was financial supported by Shanghai Foundation of Science and
Technology (15431902100). Shiliang Li is supported by China Postdoctoral Science
Foundation (Grant No.: 2016M600290).
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Graphical Abstract
A series of 4-thiazolidinone derivatives were synthesized and evaluated as novel
human dihydroorotate dehydrogenase (hDHODH) inhibitors.