Design and synthesis of α-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA synthetase inhibitors

Article abstract of DOI:10.1016/j.ejmech.2019.111827

Human African trypanosomiasis (HAT), caused by the parasitic protozoa Trypanosoma brucei, is one of the fatal diseases in tropical areas and current medicines are insufficient. Thus, development of new drugs for HAT is urgently needed. Leucyl-tRNA synthetase (LeuRS), a recently clinically validated antimicrobial target, is an attractive target for development of antitrypanosomal drugs. In this work, we report a series of α-phenoxy-N-sulfonylphenyl acetamides as T. brucei LeuRS inhibitors. The most potent compound 28g showed an IC₅₀ of 0.70 μM which was 250-fold more potent than the starting hit compound 1. The structure-activity relationship was also discussed. These acetamides provided a new scaffold and lead compounds for the further development of clinically useful antitrypanosomal agents.

Full text of DOI:10.1016/j.ejmech.2019.111827

European Journal of Medicinal Chemistry xxx (xxxx) xxx
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Research paper
Design and synthesis of a-phenoxy-N-sulfonylphenyl acetamides as
Trypanosoma brucei Leucyl-tRNA synthetase inhibitors
Weixiang Xin 1, Zezhong Li 1, Qing Wang, Jin Du, Mingyan Zhu, Huchen Zhou*
State Key Laboratory of Microbial Metabolism, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Human African trypanosomiasis (HAT), caused by the parasitic protozoa Trypanosoma brucei, is one of the
fatal diseases in tropical areas and current medicines are insufficient. Thus, development of new drugs
for HAT is urgently needed. Leucyl-tRNA synthetase (LeuRS), a recently clinically validated antimicrobial
target, is an attractive target for development of antitrypanosomal drugs. In this work, we report a series
Received 25 June 2019
Received in revised form
21 October 2019
Accepted 26 October 2019
Available online xxx
of
a-phenoxy-N-sulfonylphenyl acetamides as T. brucei LeuRS inhibitors. The most potent compound 28g
showed an IC50 of 0.70
m
M which was 250-fold more potent than the starting hit compound 1. The
structure-activity relationship was also discussed. These acetamides provided a new scaffold and lead
compounds for the further development of clinically useful antitrypanosomal agents.
© 2019 Elsevier Masson SAS. All rights reserved.
Keywords:
Human African trypanosomiasis (HAT)
Anti-trypanosomal agent
Leucyl-tRNA synthetase (LeuRS)
a
-phenoxy-N-Sulfonylphenyl acetamides
Structure-activity relationship
1. Introduction
Aminoacyl-tRNA synthetases (aaRSs) catalyze the attachment of
amino acids to the 30-hydroxyl of the terminal adenosine of the
Human African trypanosomiasis (HAT), also known as sleeping
sickness, is a parasitic disease caused by the protozoa Trypanosoma
brucei [1]. It is transmitted by the tsetse fly through biting and
threatens 61 million people in 36 countries in Africa. It is a fatal
disease if not treated effectively in a timely manner. Up to now,
there are only four drugs available in the clinics for the treatment of
HAT: pentamidine and suramin for the early stage; melarsoprol and
eflornithine for the late stage of the disease [2]. Although these
drugs have been used for decades, there are still limitations such as
serious toxic side effects, low efficacy, high cost, and difficulty of
administration. Fexinidazole, a nitroimidazole approved in 2019 for
the treatment of trypanosomiasis, will add to the existing arsenal
[3]. However, the discovery of antitrypanosomal drugs has been
challenging with eflornithine as the only new drug approved dur-
ing the past 28 year until the approval of fexinidazole this year.
Together with the emergence of drug resistance, thus new anti-
trypanosomal drugs are urgently needed [4,5].
corresponding tRNA to produce the aminoacyl-tRNA, which hap-
pens in the synthetic active site of aaRSs [6]. Since the accuracy of
the incorporation of the correct amino acid is essential in ensuring
the fidelity of the genetic code, many aaRS enzymes possess a
proofreading mechanism which happens in the editing active site
where the incorrect amino acids will be hydrolyzed. Due to its
crucial role in protein synthesis, aaRSs of pathogens are promising
targets for the development of anti-infective drugs [7e11]. In recent
years, leucyl-tRNA synthetase (LeuRS) has been paid much atten-
tion as a clinically validated antimicrobial target. Tavaborole, a
LeuRS inhibitor, was approved in 2014 as a topical treatment of
fungal infection of the toenails, and good selectivity between fungal
and human LeuRS was achieved in this case [12]. A number of
compounds have been reported as LeuRS inhibitors (Fig. 1). Boron-
containing compound a (GSK2251052) inhibits bacterial (E. coli)
LeuRS by targeting its editing site and has been evaluated clinically
[13e15], however, the development of this compound was
encumbered due to emergence of resistance. N-leucinylbenzene-
sulfonamides such as compound b, mimicking the endogenous
substrate, are reported as E. coli LeuRS inhibitors [10]. We have also
previously reported benzoxaborole-based T. brucei LeuRS (TbLeuRS)
inhibitors such as compound c which target the editing site [16].
We have also been making continuous efforts searching for in-
hibitors that target the synthetic site of TbLeuRS. In our previous
Abbreviations: HAT, human African trypanosomiasis; T. brucei, Trypanosoma
brucei; LeuRS, leucyl-tRNA synthetase; TbLeuRS, T. brucei LeuRS; aaRS, aminoacyl-
tRNA synthetases.
* Corresponding author.
E-mail address: hczhou@sjtu.edu.cn (H. Zhou).
These authors contributed equally to this work.
1
https://doi.org/10.1016/j.ejmech.2019.111827
0223-5234/© 2019 Elsevier Masson SAS. All rights reserved.
Please cite this article as: W. Xin et al., Design and synthesis of
a-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA
synthetase inhibitors, European Journal of Medicinal Chemistry, https://doi.org/10.1016/j.ejmech.2019.111827

2
W. Xin et al. / European Journal of Medicinal Chemistry xxx (xxxx) xxx
3. Results and discussion
Starting from the N-(4-sulfonylphenyl)thiourea hit compound 1,
which was identified from our laboratory collection as a new class
of TbLeuRS inhibitor that targets the synthetic site (Fig. 2), we
decided to replace the thiourea group with amide group that is
more desirable for further development. A direct replacement of
the thiourea by amide group resulted in acetamide 5 that showed
comparable activity to thiourea 1 (Table 1).
Next, we modified compound 5 by introducing various acyl
groups onto the terminal amino group (Table 1). First, a heteroaryl
compound 6 failed to improve potency, so we decided to make
effort on amino acid-derived substituents. The phenylalanyl, glu-
tamyl, glutaminyl, isoleucyl, leucyl-substituted compounds 7e19
were synthesized and tested for their TbLeuRS inhibitory activity. It
is rather interesting to see that the leucyl compound 19 showed the
Fig. 1. Chemical structures of known LeuRS inhibitors.
screening of a collection of compounds from our laboratory, a N-(4-
sulfonylphenyl)thiourea hit compound M) was
1
(IC50 ¼ 174
m
identified as a new class of TbLeuRS inhibitor which target the
synthetic site (Fig. 2) [17]. Considering that the solubility of thio-
urea group is known to be relatively low and its toxicity also pre-
sent an issue, which would limit further development of the
scaffold, we took on a task to change the thiourea group to amide,
and developed a series of a-phenoxy-N-sulfonylphenyl acetamides
best inhibitory activity (IC50 ¼ 38.4
mM), which is a 5-fold
as TbLeuRS inhibitors. The initially obtained acetamide 5 showed
comparable activity to thiourea 1. The terminal sulfonamide group
in compound 5, reminiscent of the leucyl area in the substrate
mimics Leu-AMS (Fig. 3), were modified to give a ~5-fold increase of
improvement as compared to the initial acetamide 5. In the case
of the phenylalanyl, glutamyl, and isoleucyl compounds 7e12 and
15e16, the benzyl or Boc-protected compounds showed better
inhibitory activity than the free amino compounds. Among them,
compounds 7 and 10 showed improved activity as compared to
compound 5. However, in the case of glutaminyl and leucyl com-
pounds 13e14 and 17e19, the compounds with free amino group
showed better activity. The leucyl compound 19 gave significant
improvement of inhibitory activity and represented the best com-
pound in this round of effort. Therefore, the leucyl group was
retained in the following study.
inhibitory activity (compound 19, IC50 ¼ 38.4
mM). The observation
that the 1,3-substitution pattern on the central phenyl ring would
better resembles the geometry of Leu-AMS led to significantly
improved potency as represented by compound 28g
(IC50 ¼ 0.70
mM). Thus, we successfully replaced thiourea with
amide group and obtained good TbLeuRS inhibitors with ~250-fold
improvement of inhibitory activity from the initial hit compound.
The molecule Leu-AMS mimicked the endogenous substrate
Leu-AMP but contained a stable sulfonamide linkage group in place
of the phosphate group (Fig. 3a). Thus, Leu-AMS is often used as a
substrate mimic in protein-ligand crystallization studies. When
compound 19 was superimposed with Leu-AMS, although the
leucyl end of the two molecules overlapped well, the other end of
the molecule deviated significantly from each other (Fig. 3b). This is
due to the fact that Leu-AMS has the two extending branches
spaced by a single oxygen atom in the sugar ring, while compound
19 has a 1,4-substitution pattern in its central phenyl ring. So, it was
suggested that a 1,3-substitution pattern should make the geome-
try of our compounds more closely resembles Leu-AMS. Indeed,
this strategy significantly improved the inhibitory activity as
exemplified by comparing 1,4-substituted compound 29
2. Chemistry
Synthesis of
a-phenoxy-N-(4-sulfonylphenyl)acetamides was
shown in Scheme 1. First, ester 3 was prepared from 4-bromo-2-
chlorophenol and ethyl 2-bromoacetate in the presence of potas-
sium carbonate, which was subsequently hydrolyzed to give acid 4.
After conversion of acid 4 to its acyl chloride, it was coupled with 4-
aminobenzenesulfonamide to yield compound 5. It was further
reacted with N-protected amino acids in the presence of EDCI and
DMAP to give acetamides 6e8, 10, 13, 15, and 17e18. Removal of the
Boc group using HCl gas gave acetamides 9, 14, 16, and 19. Hydro-
lysis of the benzyl ester 10 under basic condition followed by
acidification with HCl gas in dichloromethane gave acid 11, while
acidification with HCl gas in ethyl acetate gave ethyl ester 12.
(IC50 ¼ 43.6
m
M)
and
its
1,3-substituted
analog
28b
(IC50 ¼ 5.69
mM). The superimposed structures also showed that
Synthesis of a-phenoxy-N-(3-sulfonylphenyl)acetamides 28a-g
compound 28b better resembles the geometry of Leu-AMS (Fig. 3c).
A series of 1,3-substitued compounds 28a-g were synthesized and
evaluated as shown in Table 2. The phenyl and nitrophenyl com-
pounds 28a and 28c gave comparable potency. In the case of the
biphenyl compounds 28f and 28g, the 30-biphenyl compound 28g
gave significantly improved inhibitory activity with an IC50 value of
was shown in Scheme 2. Esters 21a-g were prepared from various
phenols and ethyl bromoacetate in the presence of potassium
carbonate, which was subsequently hydrolyzed to give acids 22a-g.
Cbz protection of aniline 23 gave compound 24 which was reacted
with N-Boc-L-leucine in the presence of EDCI and DMAP as coupling
reagent to give compound 25. Compound 26 was obtained after the
Cbz group was removed by 10% Pd/C and H2, and was subsequently
coupled with the acyl chlorides of 22a-g to give compounds 27a-g.
Removal of the Boc group by HCl gas eventually gave compounds
28a-g.
0.70 mM, which represented the most potent compound in this
study. Thus, we successfully replaced thiourea with amide group
and obtained good TbLeuRS inhibitors with ~250-fold improve-
ment of inhibitory activity from the initial hit compound. The
Fig. 2. Design of new LeuRS inhibitors with amide linkage group.
Please cite this article as: W. Xin et al., Design and synthesis of
a-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA
synthetase inhibitors, European Journal of Medicinal Chemistry, https://doi.org/10.1016/j.ejmech.2019.111827

W. Xin et al. / European Journal of Medicinal Chemistry xxx (xxxx) xxx
3
Fig. 3. a. Chemical structures of Leu-AMS and compounds 19, 28b, and 29. b. Overlay of Leu-AMS (cyan) and compound 19 (grey). c. Overlay of Leu-AMS (cyan), compound 28b
(orange), and compound 29 (green). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
compounds were also tested on the T. brucei parasites, and among
them compound 28f showed inhibition of parasite growth with an
chromatography was performed using Huanghai silica gel
(45e75 m). The preparative HPLC was conducted on Shanghai
m
IC50 of 33.33 3.41
optimized in terms of their physicochemical properties in order to
achieve satisfactory antiparasitic activity in the future efforts.
m
M (SI Fig. 2). These compounds will be further
Unimicro EasySep-1010 liquid chromatography using a C18 column
(30 mm ꢀ 250 mm), a 1 mL sample loop, a flow rate of 16 mL minꢁ1
,
and a gradient of 10% v/v MeOH in H2O (0.1% v/v TFA) (t ¼ 0 min) to
100% MeOH (t ¼ 30.0 min). NMR spectra were recorded on Bruker
Avance III 400 MHz. Chemical shifts are expressed in parts per
million (ppm) relative to residual solvent as an internal reference
(CDCl3: 7.26; MeOD: 3.31; DMSO‑d6: 2.50). High resolution mass
spectra were obtained on a Micromass GCT (electron ionization) or
an Agilent 6530 Accurate Mass Q-TOF LC-MS (electrospray ioniza-
tion). HPLC analysis was performed on an Agilent 1200 with a flow
rate of 1 mL minꢁ1 and two gradients: gradient A (10% v/v MeCN in
H2O (containing 0.1% v/v TFA) (t ¼ 0.0 min) to 100% MeCN
(t ¼ 15.0 min)); gradient B (10% v/v MeCN in H2O (t ¼ 0.0 min) to
100% MeCN (t ¼ 20.0 min)), stopping at 20 or 25 min using a DAD
detector. An Agilent Eclipse XDB-C18 column (4.6 mm ꢀ 150 mm,
4. Conclusions
As a neglected tropical disease, human African trypanosomiasis
is in urgent need of new treatment, especially those in new
chemical classes. LeuRS, as a clinically validated antimicrobial
target, should serve as a promising antitrypanosomal target. Here,
we reported the discovery of
a-phenoxy-N-(3-sulfonylphenyl)
acetamide as a new class of TbLeuRS inhibitors with compound 28g
representing the most potent inhibitor in this study. This work
successfully provided a new scaffold for further exploring new
TbLeuRS inhibitors, which may eventually become potential ther-
apeutics for the treatment of African trypanosomiasis.
5 mm) was used. Purity was based on the integrated UV chro-
matogram (254 nm). The purity of all biological assay compounds
was >95.0%.
5. Material and methods
5.1. Chemistry
5.1.1. Ethyl 2-(4-bromo-2-chlorophenoxy)acetate (3)
To a solution of 4-bromo-2-chlorophenol (2, 5.2 g, 25.0 mmol)
and ethyl 2-bromoacetate (4.3 g, 25.7 mmol) in 50 mL DMF, anhy-
drous K2CO3 (3.5 g, 25.0 mmol) was added. After stirring overnight
at 70 ꢂC, the mixture was poured into 150 mL water and extracted
All solvents and reagents were purchased from commercial
sources and used without further purification unless otherwise
noted. Reactions were not optimized for maximum yields. Column
Please cite this article as: W. Xin et al., Design and synthesis of
a-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA
synthetase inhibitors, European Journal of Medicinal Chemistry, https://doi.org/10.1016/j.ejmech.2019.111827

4
W. Xin et al. / European Journal of Medicinal Chemistry xxx (xxxx) xxx
Scheme 1. Synthesis of N-(4-sulfamoylphenyl)thiourea derivatives. Condition and reagents: (a) ethyl 2-bromoacetate, K2CO3, DMF; (b) 1 M NaOH, dioxane; (c) SOCl2, 4-
aminobenzenesulfon amide; (d) RCOOH, EDCI, DMAP, DCM; (e) HCl gas, DCM; (f) 2.5 M NaOH, MeOH; (g) HCl gas, EtOAc.
with ethyl acetate (70 mL ꢀ 4). The organic layer was combined,
washed with brine (100 mL ꢀ 3) and dried over anhydrous Na2SO4.
The residue after rotary evaporation was purified by column
chromatography to give 3 as an oil (6.18 g, 84.1% yield). 1H NMR
(101 MHz, DMSO‑d6) d 166.74, 153.51, 141.72, 139.29, 132.52, 131.41,
127.23,123.28,119.47,116.33,112.89, 68.12. Mp: 209e210 ꢂC. HRMS:
[MþNa]þ calcd [C14H12BrClN2O4S
þ
Na]þ 440.9288, found
440.9306. HPLC: gradient A, 98.0% purity, 18.5 min.
(400 MHz, CDCl3)
d
7.53 (s, 1H), 7.30 (d, J ¼ 8.4 Hz, 1H), 6.72 (d,
J ¼ 8.4 Hz, 1H), 4.68 (s, 2H), 4.26 (q, J ¼ 7.2 Hz, 2H), 1.29 (t, J ¼ 7.2 Hz,
3H).
5.1.4. General procedure for preparation of 6e8, 10, 13, 15, 17e18
To a mixture of compound 5 (1.0 eq.) and corresponding car-
boxylic acid (1.2e2.0 eq.) in DCM EDCI (5.0 eq.) and DMAP (3.0 eq.)
were added at 0 ꢂC, then the mixture was warmed to r.t. and stirred
overnight. The mixture was washed with 0.5 M HCl (30 mL ꢀ 3) and
brine (30 mL), dried over anhydrous Na2SO4 and concentrated to
give the residue which was purified by appropriate method to give
the product.
5.1.2. 2-(4-Bromo-2-chlorophenoxy)acetic acid (4)
To a solution of 3 (5.0 g, 17.0 mmol) in 50 mL dioxane, 1 M NaOH
(50 mL) was added. After stirring at r.t. overnight, the mixture was
acidified with 1 M HCl to pH ¼ 3. After extracted with ethyl acetate
(50 mL ꢀ 4), the organic layer was washed with brine (50 mL), dried
over anhydrous Na2SO4 and concentrated to give 4 as a white solid
(4.69 g, 94.3% yield). 1H NMR (400 MHz, DMSO‑d6)
d 7.66 (s, 1H),
7.44 (d, J ¼ 8.8 Hz, 1H), 6.97 (d, J ¼ 8.8 Hz, 1H), 4.72 (s, 2H). Mp:
150e151 ꢂC.
5.1.5. N-((4-(2-(40-Bromo-20-chlorophenoxy)acetamido)phenyl)
sulfonyl)furan-2-carboxamide (6)
5.1.3. 2-(40-Bromo-20-chlorophenoxy)-N-(40-sulfamoylphenyl)
acetamide (5)
Compound 6 (151 mg, 61.7% yield) was prepared from 5
(200 mg, 0.48 mmol) and furan-2-carboxylic acid (106 mg,
0.95 mmol) following the general procedure. The crude product
was washed with DCM to give 6 as a white solid (151 mg, 61.7%
To a solution of compound 4 (300 mg, 1.13 mmol) in 6 mL SOCl2
was added 2 drops DMF and heated to reflux. After 3 h, SOCl2 was
removed by atmospheric distillation. The residue, after dried in
vacuo for 5 min, was dissolved in 15 mL dry acetone and added
dropwise into sulfanilamide (182 mg,1.07 mmol) in 225 mL acetone
at 0 ꢂC. The mixture was warmed to r.t. and continued stirring for
2 h. After the reaction completed, the mixture was filtered and the
cake was washed with ether (10 mL ꢀ 2) to give compound 5
yield). 1H NMR (400 MHz, DMSO‑d6)
d 12.43 (s, 1H), 10.64 (s, 1H),
7.95 (d, J ¼ 9.1 Hz, 3H), 7.83 (d, J ¼ 8.8 Hz, 2H), 7.71 (d, J ¼ 2.4 Hz,
1H), 7.51 (d, J ¼ 3.6 Hz, 1H), 7.48 (dd, J ¼ 8.9, 2.4 Hz, 1H), 7.06 (d,
J ¼ 8.9 Hz, 1H), 6.68 (dd, J ¼ 3.4, 1.4 Hz, 1H), 4.92 (s, 2H). 13C NMR
(101 MHz, DMSO‑d6) d 166.96, 153.47, 148.31, 145.37, 143.41, 134.09,
132.51, 131.41, 129.56, 123.24, 119.37, 118.34, 116.28, 112.84, 68.06,
(405 mg, 85.4% yield). 1H NMR (400 MHz, DMSO‑d6)
d
10.54 (s, 1H),
55.38.
[C19H14BrClN2O6S
gradient A, 98.4% purity, 14.7 min.
Mp:
262e263
þ
ꢂC.
HRMS:
[MþNa]þ
calcd
7.83e7.73 (m, 4H), 7.71 (d, J ¼ 2.4 Hz, 1H), 7.49 (dd, J ¼ 8.9, 2.4 Hz,
Na]þ 534.9342, found 534.9352. HPLC:
1H), 7.27 (s, 2H), 7.08 (d, J ¼ 8.9 Hz, 1H), 4.92 (s, 2H). 13C NMR
Please cite this article as: W. Xin et al., Design and synthesis of
a-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA
synthetase inhibitors, European Journal of Medicinal Chemistry, https://doi.org/10.1016/j.ejmech.2019.111827

W. Xin et al. / European Journal of Medicinal Chemistry xxx (xxxx) xxx
5
R
R
a
b
HO
O
R
O
O
HO
O
O
20a-g
21a-g
22a-g
O
O
d
c
O
O
S
O
NHCbz
N
H
S
O
NH2
S
O
NHCbz
H2N
H2N
NHBoc
24
25
23
O
O
O
O
O
O
e
f
S
O
N
H
S
O
NH2
R
N
N
H
H
22a-g
NHBoc
NHBoc
26
27a-g
O
O
S
H
N
O
R
g
N
O
H
NH2
O
28a-g
Scheme 2. Synthesis of N-(3-sulfamophenyl)amide derivatives. Reagent and conditions: (a) ethyl bromoacetate, K2CO3, DMF, 70 ꢂC; (b) 1 M NaOH, dioxane; (c) CbzCl, NaHCO3, H2O/
acetone; (d) N-Boc-leucine, EDCI, DMAP, DCM; (e) 10% Pd/C, H2, MeOH; (f) oxalyl chloride, DCM; (g) HCl gas, EtOAc.
5.1.6. 2-(40-Bromo-20-chlorophenoxy)-N-((4’-((N-carbobenzoxy-L-
phenyl alanyl)amino)sulfonyl)phenyl)acetamide (7)
(s, 2H), 4.21e4.06 (m, 1H), 2.84e2.79 (m, 1H), 2.60e2.54 (m, 1H),
1.24 (s, 9H). 13C NMR (101 MHz, DMSO‑d6)
166.96, 155.72, 153.46,
d
Compound 7 (61.6 mg, 15.2% yield) was prepared from 5
137.66, 132.53, 131.41, 129.67, 129.34, 128.50, 126.86, 123.25, 119.28,
116.27, 112.90, 78.82, 68.11, 56.62, 36.57, 28.52. Mp: 218e219 ꢂC.
HRMS: [MþNa]þ calcd [C28H29BrClN3O7S þ Na]þ 688.0496, found
688.0521. HPLC: Gradient A, 100.0% purity, 17.2 min.
(200 mg,
0.48 mmol)
and
L-Cbz-phenylalanine
(135 mg,
0.71 mmol) following the general procedure. The crude product
was washed with DCM to give 7 as a white solid. 1H NMR (400 MHz,
DMSO‑d6)
d
12.41 (s, 1H), 10.66 (s, 1H), 7.89 (d, J ¼ 8.9 Hz, 2H), 7.83
5.1.8. 2-(40-Bromo-20-chlorophenoxy)-N-(4’-((
L-
phenylalanylamino) sulfonyl)phenyl)acetamide (9)
(d, J ¼ 8.9 Hz, 2H), 7.71 (d, J ¼ 2.4 Hz, 1H), 7.61 (d, J ¼ 8.2 Hz, 1H),
7.48 (dd, J ¼ 8.9, 2.4 Hz, 1H), 7.34e7.28 (m, 3H), 7.26e7.16 (m, 7H),
7.07 (d, J ¼ 8.9 Hz, 1H), 4.93 (s, 2H), 4.92 (s, 2H), 4.32e4.19 (m, 1H),
2.91 (dd, J ¼ 13.5, 4.0 Hz, 1H), 2.61 (dd, J ¼ 13.4, 10.8 Hz, 1H). 13C
Compound 8 (102 mg, 0.15 mmol) was treated with HCl gas in
DCM to give 9 as a white solid (80 mg, 86.7% yield). 1H NMR
NMR (101 MHz, DMSO‑d6)
d 171.29, 166.99, 156.30, 153.47, 143.46,
(400 MHz, DMSO‑d6)
d 12.87 (s, 1H), 10.88 (s, 1H), 8.25 (s, 3H), 7.87
137.54, 137.21, 133.63, 132.53, 131.41, 129.66, 129.43, 128.76, 128.54,
128.23, 128.05, 126.94, 123.26, 119.37, 116.29, 112.90, 68.09, 65.91,
56.88, 36.73. Mp: 191e192 ꢂC. HRMS: [MþNa]þ calcd
(d, J ¼ 9.0 Hz, 2H), 7.83 (d, J ¼ 8.9 Hz, 2H), 7.71 (d, J ¼ 2.4 Hz, 1H),
7.48 (dd, J ¼ 8.8, 2.4 Hz, 1H), 7.21e7.20 (m, 3H), 7.07 (d, J ¼ 8.9 Hz,
1H), 7.04e7.01 (m, 2H), 4.95 (s, 2H), 4.03 (s, 1H), 3.04 (dd, J ¼ 13.6,
5.4 Hz, 1H), 2.96e2.91 (m, 1H). 13C NMR (101 MHz, DMSO‑d6)
[C31H27BrClN3O7S
þ
Na]þ 722.0339, found 722.0497. HPLC:
Gradient B, 97.0% purity, 14.1 min.
d
168.05, 167.10, 153.48, 143.77, 134.29, 132.54, 131.39, 130.01,
129.69, 128.92, 127.69, 123.24, 119.43, 116.22, 112.87, 68.05, 54.20,
ꢂC.
HRMS:
[MþH]þ
calcd
5.1.7. 2-(40-Bromo-20-chlorophenoxy)-N-(4’-((N-tert-
butoxycarbonyl-L- phenylalanylamino)sulfonyl)phenyl)acetamide
(8)
36.37.
Mp:
224e225
[C23H21BrClN3O5S þ H]þ 566.0152, found 566.0173. HPLC: Gradient
A, 100.0% purity, 11.2 min.
Compound 8 (170 mg, 54.3% yield) was prepared from 5
(197 mg, 0.47 mmol) and L-Boc-phenylalanine (249 mg, 0.95 mmol)
following the general procedure. The crude product was purified
with column chromatography and to give 8 as a white solid. 1H
5.1.9. N-(4’-(((5’’-Benzoxy-2’’-(S)-((tert-butoxycarbonyl)amino)-
5’’-oxo) pentanoicylamino)sulfonyl)phenyl)-2-(40-bromo-20-
chlorophenoxy) acetamide (10)
NMR (400 MHz, DMSO‑d6)
d
12.31 (s, 1H), 10.64 (s, 1H), 7.85 (d,
Compound 10 (224 mg, 84.8% yield) was prepared from 5
(150 mg, 0.36 mmol) and (S)-5-benzyloxy-2-(tert-butoxycarbonyl)
amino- 5-oxopentanoic acid (242 mg, 0.72 mmol) following the
J ¼ 8.8 Hz, 2H), 7.79 (d, J ¼ 8.7 Hz, 2H), 7.70 (d, J ¼ 2.2 Hz, 1H), 7.47
(dd, J ¼ 8.9, 2.2 Hz, 1H), 7.28e7.13 (m, 5H), 7.07e7.03 (m, 2H), 4.91
Please cite this article as: W. Xin et al., Design and synthesis of
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6
W. Xin et al. / European Journal of Medicinal Chemistry xxx (xxxx) xxx
Table 1
Table 2
The inhibitory activity of phenoxy-N-(4-sulfamoylphenyl)acetamides against
The inhibitory activity of phenoxy-N-(3-sulfamoylphenyl)acetamides against
TbLeuRS.
TbLeuRS.
Compd
28a
R
TbLeuRS
IC50 M)
Compd
R
TbLeuRS
IC50 M)
(
m
(
m
5.51
5
6
191.1
251.1
28b
5.69
28c
6.81
7
8
115.5
280.8
28d
28e
2.68
3.58
9
>1000
28f
7.28
0.70
10
98
28g
11
428.2
12
13
14
>1000
685.3
285.4
5.1.10. (S)-4-Amino-5-(4-(2-(40-bromo-20-chlorophenoxy)
acetamido)phenylsulfonamido)-5-oxopentanoic acid hydrochloride
(11)
To the solution of 10 (80 mg, 0.108 mmol) in 5 mL MeOH was
added dropwise NaOH (8.6 mg, 0.215 mmol) in 2 mL water with ice
bath. After stirring for 3 h under ice bath, the mixture was diluted
with water, acidified to pH 2e3 and extracted with ethyl acetate
(20 mL ꢀ 3). The organic layer was dried over anhydrous Na2SO4
and evaporated to give 84 mg residue. The residue was treated with
HCl gas in DCM and purified by preparative HPLC to give 11 as a
white solid (9 mg, 14.3% yield). 1H NMR (400 MHz, DMSO‑d6)
15
16
17
346.1
>1000
110.4
d
10.68 (s, 1H), 8.13 (s, 3H), 7.88 (d, J ¼ 8.3 Hz, 2H), 7.78 (d, J ¼ 8.6 Hz,
2H), 7.71 (d, J ¼ 2.4 Hz, 1H), 7.48 (dd, J ¼ 8.9, 2.3 Hz, 1H), 7.05 (d,
J ¼ 8.8 Hz, 1H), 4.91 (s, 2H), 3.78 (s, 1H), 2.37e2.26 (m, 2H),
1.98e1.87 (m, 2H). 13C NMR (101 MHz, DMSO‑d6)
d 173.30, 168.43,
167.03, 153.43, 143.80, 132.49, 131.37, 129.61, 123.18, 119.39, 116.20,
112.83, 67.96, 52.46, 29.31, 26.11. Mp: 167e168 ꢂC. HRMS: [MþH]þ
calcd [C19H19BrClN3O7S þ H]þ 547.9894, found 547.9903. HPLC:
Gradient B, 95.6% purity, 10.0 min.
18
19
403.6
38.4
5.1.11. (S)-Ethyl-4-amino-5-(4-(2-(40-bromo-20-chlorophenoxy)
acetamido) phenylsulfonamido)-5-oxopentanoate hydrochloride
(12)
general procedure. The crude product was purified with column
chromatography to give 10 as a white solid. 1H NMR (400 MHz,
To the solution of 11 (202 mg, 0.27 mmol) in 10 mL MeOH was
added dropwise NaOH (49.8 mg, 1.24 mmol) in 0.5 mL water with
ice bath. After stirring for 3 h with ice bath, the mixture was diluted
with water, acidified with 1 M HCl to pH 2e3 and extracted with
ethyl acetate (20 mL ꢀ 3). The organic layer was dried over anhy-
drous Na2SO4 and evaporated to give 117 mg residue. The residue
was treated with HCl gas in ethyl acetate subsequently. After the
reaction was completed, the solvent was removed. The residue was
purified by preparative HPLC to give 12 as a white solid (11 mg, 6.6%
DMSO‑d6)
d
12.17 (s, 1H), 10.63 (s, 1H), 7.85 (d, J ¼ 8.9 Hz, 2H), 7.79
(d, J ¼ 8.7 Hz, 2H), 7.70 (d, J ¼ 2.4 Hz, 1H), 7.46 (dd, J ¼ 8.9, 2.4 Hz,
1H), 7.40e7.27 (m, 5H), 7.10 (d, J ¼ 7.1 Hz, 1H), 7.04 (d, J ¼ 8.9 Hz,
1H), 5.06 (s, 2H), 4.90 (s, 2H), 3.96e3.87 (m, 1H), 2.32e2.30 (m, 1H),
2.27e2.22 (m, 1H),1.82e1.75 (m,1H),1.72e1.64 (m,1H),1.31 (s, 9H).
13C NMR (101 MHz, DMSO‑d6)
d 172.21, 166.88, 155.69, 153.41,
136.56, 132.48, 131.36, 129.25, 129.21, 128.85, 128.42, 128.27, 123.19,
119.13, 119.10, 116.22, 112.84, 109.98, 78.86, 68.01, 65.95, 30.42,
yield). 1H NMR (400 MHz, DMSO‑d6)
d 10.93 (s, 1H), 8.32 (s, 3H),
28.53.
[C31H33BrClN3O9S
Gradient A, 100.0% purity, 17.7 min.
Mp:
164e165
þ
ꢂC.
HRMS:
[MþNa]þ
calcd
7.89 (d, J ¼ 8.9 Hz, 2H), 7.83 (d, J ¼ 8.8 Hz, 2H), 7.70 (d, J ¼ 2.3 Hz,
1H), 7.47 (dd, J ¼ 8.8, 2.3 Hz, 1H), 7.06 (d, J ¼ 8.9 Hz, 1H), 4.94 (s, 2H),
4.03 (q, J ¼ 7.0 Hz, 2H), 3.86 (s,1H), 2.37e2.25 (m,1H), 2.21e2.11 (m,
Na]þ 760.0707, found 760.0701. HPLC:
Please cite this article as: W. Xin et al., Design and synthesis of
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synthetase inhibitors, European Journal of Medicinal Chemistry, https://doi.org/10.1016/j.ejmech.2019.111827

W. Xin et al. / European Journal of Medicinal Chemistry xxx (xxxx) xxx
7
1H), 1.96 (d, J ¼ 7.7 Hz, 2H), 1.16 (t, J ¼ 7.1 Hz, 3H). 13C NMR
1H), 1.06e0.95 (m, 1H), 0.85e0.69 (m, 6H). 13C NMR (101 MHz,
DMSO‑d6) 168.54, 167.03, 153.48, 143.54, 132.52, 131.39, 129.56,
(101 MHz, DMSO‑d6)
d
172.56, 166.36, 153.47, 140.75, 140.26, 132.47,
d
131.37, 128.32, 123.20, 118.55, 116.22, 112.80, 68.08, 60.39, 54.24,
123.22, 119.24, 116.23, 112.84, 68.01, 57.40, 36.58, 24.19, 14.97, 11.63.
Mp: 259e260 ꢂC. HRMS: [MþH]þ calcd [C20H23BrClN3O5S þ H]þ
532.0308, found 532.0319. HPLC: Gradient A, 100.0% purity,
10.8 min.
29.72, 26.89, 14.52. Mp: 115e117 ꢂC. HRMS: [MþNa]þ calcd
[C21H23BrClN3O7S
þ
Na]þ 598.0027, found 598.0025. HPLC:
Gradient B, 97.7% purity, 10.0 min.
5.1.12. (S)-Tert-butyl(5-amino-1-(4-(2-(40-bromo-20-
chlorophenoxy)acetamido) phenylsulfonamido)-1,5-dioxopentan-2-
yl)carbamate (13)
Compound 13 (141 mg, 30.4% yield) was prepared from 5
(300 mg, 0.71 mmol) and (S)-5-amino-2-((tert-butoxycarbonyl)
amino)-5- oxopentanoic acid (264 mg, 1.07 mmol) following the
general procedure. The residue was dissolved in DCM and washed
with 0.5 M NaOH solution (20 mL). The aqueous phase was acidified
and filtered to give a white solid. The solid was recrystallized from
DCM/MeOH/hexane to give 13 as a white solid. 1H NMR (400 MHz,
5.1.16. 2-(40-Bromo-20-chlorophenoxy)-N-(4’-(((N-carbobenzoxyl-
L-leucyl)amino)sulfonyl)phenyl)acetamide (17)
Compound 17 (173 mg, quantitative yield) was prepared from 5
(100 mg, 0.24 mmol) and L-Cbz-leucine (126 mg, 0.48 mmol)
following the general procedure. The crude product was purified by
column chromatography to give 17 as a white solid. 1H NMR
(400 MHz, DMSO‑d6)
d
12.23 (s, 1H), 10.61 (s, 1H), 7.85 (d, J ¼ 8.8 Hz,
2H), 7.79 (d, J ¼ 9.2 Hz, 2H), 7.70 (d, J ¼ 2.4 Hz, 1H), 7.47 (dd, J ¼ 8.9,
2.4 Hz, 1H), 7.34e7.29 (m, 5H), 7.05 (d, J ¼ 8.9 Hz, 1H), 4.97 (s, 2H),
4.91 (s, 2H), 4.03 (s, 1H), 1.60e1.49 (m, 1H), 1.39e1.29 (m, 2H), 0.81
DMSO‑d6)
d
12.12 (s, 1H), 10.63 (s, 1H), 7.86 (d, J ¼ 8.3 Hz, 2H), 7.80
(dd, J ¼ 8.5, 6.8 Hz, 6H). 13C NMR (101 MHz, DMSO‑d6)
d 166.90,
(d, J ¼ 8.4 Hz, 2H), 7.71 (d, J ¼ 2.3 Hz, 1H), 7.48 (dd, J ¼ 8.7, 2.2 Hz,
1H), 7.24 (s, 1H), 7.08e7.02 (m, 2H), 6.77 (s, 1H), 4.92 (s, 2H),
3.91e3.79 (m, 1H), 2.12e1.93 (m, 2H), 1.80e1.65 (m, 1H), 1.64e1.51
156.37, 153.48, 137.33, 132.51, 131.41, 129.25, 128.79, 128.23, 123.25,
119.22, 116.29, 112.88, 68.07, 65.95, 53.91, 24.67, 23.42, 21.51. Mp:
71e72 ꢂC. HRMS: [MþNa]þ calcd [C28H29BrClN3O7S
þ
Na]þ
(m, 1H), 1.33 (s, 9H). 13C NMR (101 MHz, DMSO‑d6)
d
173.89, 166.85,
688.0496, found 688.0499. HPLC: Gradient A, 97.3% purity, 17.3 min.
153.48, 132.51, 131.42, 129.10, 123.24, 119.11, 116.28, 112.87,þ78.70,
68.09, 55.06, 31.84, 28.59. Mp: 171e172 ꢂC. HRMS: [MþNa] calcd
5.1.17. 2-(40-Bromo-20-chlorophenoxy)-N-(4’-(((N-tert-
[C24H28BrClN4O8S
Gradient A, 100.0% purity, 13.2 min.
þ
Na]þ 669.0398, found 669.0383. HPLC:
butoxycarbonyl-L- leucyl)amino)sulfonyl)phenyl)acetamide (18)
Compound 18 (382 mg, quantitative yield) was prepared from 5
(252 mg, 0.6 mmol) and L-Boc-leucine (278 mg, 1.2 mmol)
following the general procedure. The crude product was purified
with column chromatography to give 18 as a white solid. 1H NMR
5.1.13. 2-(40-Bromo-20-chlorophenoxy)-N-(4’-((
sulfonyl)phenyl)acetamide (14)
L-glutaminylamino)
Compound 13 (97 mg, 0.15 mmol) was treated with HCl gas in
(300 MHz, CDCl3)
d
9.60 (s, 1H), 8.80 (s, 1H), 8.05 (d, J ¼ 8.7 Hz, 2H),
DCM to give 14 as a white solid (69 mg, 78.7% yield). 1H NMR
7.78 (d, J ¼ 8.8 Hz, 2H), 7.60 (d, J ¼ 2.3 Hz, 1H), 7.41 (dd, J ¼ 8.7,
2.2 Hz, 1H), 6.86 (d, J ¼ 8.7 Hz, 1H), 4.74 (s, 1H), 4.66 (s, 2H),
4.08e3.94 (m, 1H), 1.69e1.58 (m, 1H), 1.44 (s, 9H), 0.88 (dd, J ¼ 10.9,
(400 MHz, DMSO‑d6)
d
10.76 (s, 1H), 8.22 (s, 3H), 7.91 (d, J ¼ 8.8 Hz,
2H), 7.82 (d, J ¼ 8.5 Hz, 2H), 7.70 (d, J ¼ 2.3 Hz, 1H), 7.48 (dd, J ¼ 8.6,
2.3 Hz, 2H), 7.07 (d, J ¼ 8.9 Hz, 1H), 6.98 (s, 1H), 4.93 (s, 2H), 3.80 (s,
1H), 2.15 (t, J ¼ 7.7 Hz, 2H), 1.94e1.85 (m, 2H). 13C NMR (101 MHz,
6.1 Hz, 6H). 13C NMR (101 MHz, DMSO‑d6)
d 166.92, 155.80, 153.46,
132.52, 131.40, 129.25, 123.25, 119.19, 116.27, 112.89, 78.70, 68.09,
53.53, 28.58, 24.68, 23.33, 21.64. Mp: 85e86 ꢂC. HRMS: [MþNa]þ
calcd [C25H31BrClN3O7S þ Na]þ 654.0653, found 654.0655. HPLC:
Gradient A, 96.2% purity, 17.1 min.
DMSO‑d6)
d 177.52, 173.52, 167.04, 153.48, 143.58, 133.50, 132.53,
131.41, 129.58, 123.22, 119.41, 116.24, 112.86, 68.01, 56.08, 52.97,
30.69.
Mp:
165e166
ꢂC.
HRMS:
[MþH]þ
calcd
[C19H20BrClN4O6S þ H]þ 547.0053, found 547.0046. HPLC: Gradient
A, 97.3% purity, 8.4 min.
5.1.18. 2-(40-Bromo-20-chlorophenoxy)-N-(4’-((
sulfonyl)phenyl)acetamide (19)
L-leucylamino)
5.1.14. 2-(40-Bromo-20-chlorophenoxy)-N-(4’-(((N-tert-
Compound 18 (193 mg, 0.30 mmol) was treated with HCl gas in
butoxycarbonyl- L-isoleucyl)amino)sulfonyl)phenyl)acetamide (15)
Compound 15 (369 mg, 97.1% yield) was prepared from 5
(249 mg, 0.59 mmol) and L-Boc-isoleucine (278 mg, 1.18 mmol)
following the general procedure. The crude product was purified
with column chromatography to give 15 as a white solid. 1H NMR
DCM to give 19 as a white solid (139 mg, 80.6% yield). 1H NMR
(400 MHz, DMSO‑d6)
d 12.85 (s, 1H), 10.88 (s, 1H), 8.23 (s, 3H), 7.90
(d, J ¼ 8.9 Hz, 2H), 7.83 (d, J ¼ 8.8 Hz, 2H), 7.70 (d, J ¼ 2.4 Hz, 1H),
7.47 (dd, J ¼ 8.9, 2.4 Hz, 1H), 7.06 (d, J ¼ 8.9 Hz, 1H), 4.94 (s, 2H), 3.79
(s, 1H), 1.57 (dt, J ¼ 12.6, 6.4 Hz, 1H), 1.49 (t, J ¼ 6.8 Hz, 2H), 0.82 (dd,
(400 MHz, CDCl3)
d
9.29 (s, 1H), 8.81 (s, 1H), 8.06 (d, J ¼ 8.7 Hz, 2H),
J ¼ 6.2, 2.0 Hz, 6H). 13C NMR (101 MHz, DMSO‑d6)
d 169.46, 167.06,
7.79 (d, J ¼ 8.8 Hz, 2H), 7.61 (d, J ¼ 2.3 Hz, 1H), 7.41 (dd, J ¼ 8.7,
2.3 Hz, 1H), 6.86 (d, J ¼ 8.8 Hz, 1H), 4.87 (d, J ¼ 7.6 Hz, 1H), 4.66 (s,
2H), 3.88 (s, 1H), 1.64e1.59 (m, 2H), 1.43 (s, 9H), 1.16e1.02 (m, 1H),
153.48, 143.67, 133.40, 132.52, 131.39, 129.58, 123.22, 119.37, 116.23,
112.84, 68.01, 51.83, 23.87, 23.10, 22.04. Mp: 263e264 ꢂC. HRMS:
[MþH]þ calcd [C20H23BrClN3O5S þ H]þ 532.0308, found 532.0314.
HPLC: Gradient A, 100.0% purity, 10.9 min.
0.95e0.80 (m, 6H). 13C NMR (101 MHz, DMSO‑d6)
d 171.93, 166.94,
155.90, 153.47, 143.38, 133.72, 132.52, 131.40, 129.39, 123.25, 119.14,
116.28, 112.89, 78.78, 68.09, 59.30, 36.21, 28.58, 24.72, 15.40, 11.08.
Mp: 187e188 ꢂC. HRMS: [MþNa]þ calcd [C25H31BrClN3O7S þ Na]þ
654.0653, found 654.0667. HPLC: Gradient A, 95.2% purity, 17.0 min.
5.1.19. General procedure for the synthesis of 22a-g
Anhydrous K2CO3 (1.1 eq) was added to a solution of 20a-g (1.0
eq.) and ethyl 2-bromoacetate (1.0 eq.) in DMF. After stirring
overnight at 70 ꢂC, the mixture was poured into water and
extracted with ethyl acetate. The organic layers were combined,
washed with brine, dried over anhydrous Na2SO4, and concentrated
to obtain 21a-g as a colorless oil without further purification.
1 M NaOH was added dropwise to a solution of 21a-g in dioxane
at 0 ꢂC. After stirring at r.t. for 1 h, the dioxane was evaporated and
the residue was washed with ethyl acetate. Then the water layer
was acidified with 1 M HCl to pH ¼ 3 and extracted with ethyl ac-
etate. The combined organic layer was washed with brine (50 mL),
5.1.15. 2-(40-Bromo-20-chlorophenoxy)-N-(4’-((
sulfonyl)phenyl)acetamide (16)
L-isoleucylamino)
Compound 15 (170 mg, 0.27 mmol) was treated with HCl gas in
DCM to give 16 as a white solid (148 mg, 96.8% yield). 1H NMR
(400 MHz, DMSO‑d6)
d 12.81 (s, 1H), 10.92e10.83 (m, 1H), 8.22 (s,
3H), 7.90 (d, J ¼ 8.8 Hz, 2H), 7.83 (d, J ¼ 8.6 Hz, 2H), 7.70 (d,
J ¼ 2.3 Hz, 1H), 7.47 (dd, J ¼ 8.8, 2.3 Hz, 1H), 7.06 (d, J ¼ 8.9 Hz, 1H),
4.99e4.88 (m, 2H), 3.67 (s, 1H), 1.83e1.78 (m, 1H), 1.26e1.18 (m,
Please cite this article as: W. Xin et al., Design and synthesis of
a-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA
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8
W. Xin et al. / European Journal of Medicinal Chemistry xxx (xxxx) xxx
dried over anhydrous Na2SO4, and concentrated or directly filtered
the solid to give 22a-g as a white solid.
5.1.28. Benzyl (3-(((N-Boc-L-leucyl)amino)sulfonyl)phenyl)
carbamate (25)
EDCI (2.00 g, 10.5 mmol) and DMAP (1.27 g, 10.5 mmol) were
added to a solution of 24 (1.07 g, 3.5 mmol) and L-Boc-leucine
(1.61 g, 7.0 mmol) in DCM at 0 ꢂC, then the mixture was slowly
warmed to r.t. and stirred overnight. The mixture was washed with
1 M HCl for three times and brine for once, dried over anhydrous
Na2SO4 and concentrated to give the residue which can be purified
by chromatography on silica gel, to afford 25 (1.1 g, 60.6% yield). 1H
5.1.20. 2-Phenoxyacetic acid (22a)
Compound 22a (635 mg, 73.4% yield for two steps) was pre-
pared from phenol (532 mg, 5.7 mmol) and ethyl 2-bromoacetate
(967 mg, 5.9 mmol) following the general procedure. 1H NMR
(400 MHz, DMSO‑d6)
d 12.95 (br. s, 1H), 7.27e7.31 (m, 2H),
6.89e6.97 (m, 3H), 4.66 (s, 2H).
NMR (400 MHz, CDCl3)
d
9.54 (s, 1H), 7.92 (s, 2H), 7.72 (d, J ¼ 6.9 Hz,
1H), 7.46 (t, J ¼ 8.1 Hz, 1H), 7.40e7.34 (m, 5H), 7.06 (s, 1H), 5.21 (s,
2H), 4.78 (s, 1H), 4.06 (s, 1H), 1.41 (s, 9H), 1.33e1.24 (m, 3H),
0.91e0.83 (m, 6H).
5.1.21. 2-(2-Chlorophenoxy)acetic acid (22b)
Compound 22b (1.2 g, 87.3% yield) was prepared from 2-
chlorophenol (945 mg, 7.39 mmol) and ethyl 2-bromoacetate
(1256 mg, 7.7 mmol) following the general procedure. 1H NMR
(400 MHz, DMSO‑d6)
7.25e7.29 (m, 1H), 6.94e7.03 (m, 2H), 4.80 (s, 2H).
d
13.07 (br. s, 1H), 7.43 (dd, J ¼ 7.6, 1.2 Hz, 1H),
5.1.29. N-(3-((Boc-L-leucyl)amino)sulfonyl)phenylamine(26)
To a solution of 25 (4.2 g, 8.0 mmol) in methanol (100 mL), 10%
Pd/C was added under N2 atmosphere. After 5 h, 30 mL DCM was
added to quench the reaction. Then filtered to afford 26 (3.0 g,
5.1.22. 2-(4-Nitrophenoxy)acetic acid (22c)
quantitative yield). 1H NMR (400 MHz, DMSO‑d6)
d 11.96 (br. s, 1H),
Compound 22c (446 mg, 37.6% yield) was prepared from 4-
nitrophenol (836 mg, 6.02 mmol) and ethyl 2-bromoacetate
(1023 mg, 6.2 mmol) following the general procedure. 1H NMR
(400 MHz, DMSO‑d6)
(d, J ¼ 9.2 Hz, 2H), 4.88 (s, 2H).
7.09e7.21 (m, 2H), 6.95e6.99 (m, 2H), 6.79 (d, J ¼ 8.0 Hz, 1H), 5.63
(s, 2H), 3.96e4.02 (m, 1H), 1.48e1.53 (m, 1H), 1.34 (s, 9H), 1.90 (s,
2H), 0.81 (t, J ¼ 7.6 Hz, 6H).
d
13.19 (br. s, 1H), 8.20 (d, J ¼ 9.2 Hz, 2H), 7.14
5.1.30. General procedures for the synthesis 28a-g
5.1.23. 2-(3-Methoxyphenoxy)acetic acid (22d)
To a solution of the acid (22a-g) (1.2 eq.) in DCM, oxalyl chloride
and 1 drop DMF were added dropwise at 0 ꢂC. After 3 h, DCM was
removed by rotary evaporation. The resulting acyl chloride dis-
solved in THF and pyridine was added dropwise into a solution of
26 (1.0 eq.) in THF at 0 ꢂC, then slowly warmed to r.t. and continued
stirring for 5e6 h. 1 M HCl was added and extracted with ethyl
acetate for three times. The organic layer was combined, washed
with brine for once, dried over anhydrous Na2SO4 and concentrated
to afford compounds 27a-g. To the solution of 27a-g in ethyl ace-
tate, HCl gas was added for 0.5 h, and the resulting solid was filtered
to obtain desired compounds 28a-g.
Compound 22d (890 mg, 75.9% yield) was prepared from 3-
methoxyphenol (798 mg, 6.45 mmol) and ethyl 2-bromoacetate
(1094 mg, 6.6 mmol) following the general procedure. 1H NMR
(400 MHz, DMSO‑d6)
6.47e6.55 (m, 3H), 4.65 (s, 2H), 3.72 (s, 3H).
d
12.98 (br. s, 1H), 7.17 (t, J ¼ 8.0 Hz, 1H),
5.1.24. 2-(4-Methylphenoxy)acetic acid (22e)
Compound 22e (1.2 g, 78.7% yield) was prepared from 4-
methylphenol (1038 mg, 8.37 mmol) and ethyl 2-bromoacetate
(1423 mg, 8.6 mmol) following the general procedure. 1H NMR
(400 MHz, DMSO‑d6)
(d, J ¼ 8.4 Hz, 2H), 4.62 (s, 2H), 3.72 (s, 3H).
d
12.90 (br. s, 1H), 7.08 (d, J ¼ 8.0 Hz, 2H), 6.79
5.1.31. 2-Phenoxy-N-((3-((L-leucyl)amino)sulfonyl)phenyl)
acetamide (28a)
5.1.25. 2-(4-Phenylphenoxy)acetic acid (22f)
Compound 28a (51.0 mg, 28.4% yield) was prepared from 22a
(71 mg, 0.48 mmol) and 26 (151 mg, 0.41 mmol) following the
Compound 22f (759 mg, 69.0% yield) was prepared from 4-
phenylphenol (820 mg, 4.8 mmol) and ethyl 2-bromoacetate
(819 mg, 5.0 mmol) following the general procedure. 1H NMR
general procedure. 1H NMR (400 MHz, DMSO‑d6)
d 12.96 (s, 1H),
10.76 (s, 1H), 8.44 (s, 1H), 8.34 (s, 3H), 7.95 (d, J ¼ 8.1 Hz, 1H),
7.68e7.64 (m, 1H), 7.59 (t, J ¼ 8.0 Hz, 1H), 7.36e7.29 (m, 2H), 7.02 (d,
J ¼ 8.7 Hz, 2H), 6.98 (d, J ¼ 7.3 Hz, 1H), 4.77 (s, 2H), 3.84 (s, 1H),
1.67e1.45 (m, 3H), 0.83 (dd, J ¼ 6.1, 2.8 Hz, 6H). 13C NMR (101 MHz,
(400 MHz, DMSO‑d6)
d
7.59 (d, J ¼ 7.6 Hz, 2H), 7.52 (d, J ¼ 8.8 Hz,
2H), 7.42 (t, J ¼ 7.6 Hz, 2H), 7.29 (t, J ¼ 7.6 Hz, 1H), 6.87 (d, J ¼ 7.6 Hz,
2H), 4.11 (s, 2H).
DMSO‑d6)
d 168.96, 167.20, 157.71, 139.25, 139.03, 129.54, 129.44,
124.34, 122.52, 121.13, 118.15, 114.58, 66.84, 51.27, 23.32, 22.50,
21.55. Mp: 239e242 ꢂC. HRMS: [MþH]þ calcd [C20H25N3O5S þ H]þ
420.1593, found 420.1582. HPLC: Gradient A, 97.6% purity, 7.6 min.
5.1.26. 2-(3-Phenylphenoxy)acetic acid (22g)
Compound 22g (768 mg, 70.3% yield) was prepared from 3-
phenylphenol (815 mg, 4.8 mmol) and ethyl 2-bromoacetate
(815 mg, 5.0 mmol) following the general procedure. 1H NMR
(400 MHz, DMSO‑d6)
d
7.65 (d, J ¼ 8.0 Hz, 2H), 7.46 (t, J ¼ 7.6 Hz, 2H),
5.1.32. 2-(2-Chlorophenoxy)-N-((3-((L-leucyl)amino)sulfonyl)
phenyl) acetamide (28b)
7.35e7.39 (m, 2H), 7.25 (d, J ¼ 7.6 Hz, 1H), 7.16 (s, 1H), 6.91 (dd,
J ¼ 8.4, 2.4 Hz, 1H), 4.76 (s, 2H).
Compound 28b (90 mg, 37.4% yield) was prepared from 22b
(109 mg, 0.6 mmol) and 26 (188 mg, 0.5 mmol) following the gen-
5.1.27. Benzyl (3-sulfamoylphenyl)carbamate(24)
eral procedure. 1H NMR (400 MHz, DMSO‑d6)
d 13.01 (s, 1H), 11.05
CbzCl (10 mL, 114.4 mmol) was added dropwise to a solution of
23 (10.0 g, 58.0 mmol) and sodium bicarbonate (7.4 g, 88.0 mmol)
in H2O/acetone (40/150 mL) at 0 ꢂC, then slowly warmed to r.t. After
stirred overnight, acetone was removed by rotary evaporation and
dried. The white residue was triturated with H2O and filtered. The
dried precipitate was washed with cold DCM and ether to afford 24
(s, 1H), 8.43 (t, J ¼ 1.7 Hz, 1H), 8.40 (s, 2H), 7.91 (d, J ¼ 8.2 Hz, 1H),
7.69e7.64 (m, 1H), 7.59 (t, J ¼ 8.0 Hz, 1H), 7.46 (dd, J ¼ 7.9, 1.5 Hz,
1H), 7.32e7.26 (m, 1H), 7.12 (dd, J ¼ 8.3, 1.2 Hz, 1H), 6.99 (td, J ¼ 7.8,
1.2 Hz, 1H), 4.94 (s, 2H), 3.86 (s, 1H), 1.62e1.53 (m, 3H), 0.83 (dd,
J ¼ 6.0, 4.5 Hz, 6H). 13C NMR (101 MHz, DMSO‑d6)
d 169.51, 167.10,
153.88,139.85,139.58,130.58,130.16,128.70,124.62,123.05,122.59,
121.90, 118.43, 114.46, 67.90, 51.83, 23.85, 23.04, 22.05. Mp:
257e259 ꢂC. HRMS: [MþH]þ calcd [C20H24ClN3O5S þ H]þ 454.1203,
found 454.1189. HPLC: Gradient A, 97.0% purity, 8.1 min.
(8.4 g, 95.9% yield). 1H NMR (400 MHz, DMSO‑d6)
d 10.08 (s, 1H),
8.06 (s, 1H), 7.5e7.55 (m, 1H), 7.51e7.34 (m, 7H), 7.32 (s, 2H), 5.18 (s,
2H).
Please cite this article as: W. Xin et al., Design and synthesis of
a-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA
synthetase inhibitors, European Journal of Medicinal Chemistry, https://doi.org/10.1016/j.ejmech.2019.111827

W. Xin et al. / European Journal of Medicinal Chemistry xxx (xxxx) xxx
9
5.1.33. 2-(4-Nitrophenoxy)-N-((3-((L-leucyl)amino)sulfonyl)
NMR (101 MHz, DMSO‑d6)
d
169.52, 167.75, 158.75, 142.18, 140.33,
phenyl)acetamide (28c)
139.54, 130.51, 130.09, 129.40, 128.13, 127.22, 124.92, 123.11, 120.20,
118.75, 114.17, 113.61, 67.54, 51.84, 23.85, 23.03, 22.06. Mp:
235e237 ꢂC. HRMS: [MþH]þ calcd [C26H29N3O5S þ H]þ 496.1906,
found 496.1891. HPLC: Gradient A, 99.3% purity, 9.5 min.
Compound 28c (79 mg, 33.8% yield) was prepared from 22c
(110 mg, 0.55 mmol) and 26 (179 mg, 0.46 mmol) following the
general procedure. 1H NMR (400 MHz, DMSO‑d6)
d 13.07 (s, 1H),
11.11e10.86 (m,1H), 8.42 (s, 1H), 8.33 (s, 2H), 8.24 (d, J ¼ 9.2 Hz, 2H),
7.97e7.90 (m, 1H), 7.67 (d, J ¼ 8.1 Hz, 1H), 7.60 (t, J ¼ 8.0 Hz, 1H),
7.27e7.16 (m, 2H), 5.00 (s, 2H), 3.84 (s, 1H), 1.65e1.45 (m, 3H), 0.83
5.2. TbLeuRS assay [16]
(t, J ¼ 5.6 Hz, 6H). 13C NMR (101 MHz, DMSO‑d6)
d 169.52, 166.73,
163.59, 141.75, 139.45, 130.15, 126.28, 124.81, 123.13, 118.64, 115.80,
Radioactivity was measured using a scintillation counter
(Beckman LS 6500). Brewer’s yeast tRNA was purchased from
Roche.
T. brucei LeuRS was cloned and expressed using pET21a vector in
E. coli strain BL21 (DE3)-RIPL. The concentration of LeuRS with the
CPM value of 1000 was defined as 1 activity unit (1 U).
67.63, 51.84, 23.85, 23.04, 22.02. Mp: 259e261 ꢂC. HRMS: [MþH]þ
calcd [C20H24N4O7S
Gradient A, 96.5% purity, 7.7 min.
þ
H]þ 465.1444, found 465.1427. HPLC:
5.1.34. 2-(3-Methoxyphenoxy)-N-((3-((L-leucyl)amino)sulfonyl)
phenyl)acetamide (28d)
LeuRS inhibition IC50 measurement was performed in 70 mL
Compound 28d (79 mg, 36.9% yield) was prepared from 22d
(89 mg, 0.5 mmol) and 26 (158 mg, 0.41 mmol) following the gen-
reaction mixtures containing 50 mM HEPES-KOH (pH 7.8), 5 mM
MgCl2 and 45 mM KCl, 1 mM DTT, 0.02% (w/v) BSA, 0.4 mg/mL
eral procedure. 1H NMR (400 MHz, DMSO‑d6)
d
10.61 (s, 1H), 8.43 (s,
brewer’s yeast tRNA (Roche), 1 U T. brucei LeuRS, 3 m
Ci/mL [14C]
1H), 8.21 (s, 3H), 7.93 (d, J ¼ 7.7 Hz, 1H), 7.66 (d, J ¼ 7.9 Hz, 1H), 7.59
(t, J ¼ 7.9 Hz, 1H), 7.24e7.19 (m, 1H), 6.62e6.55 (m, 3H), 4.74 (s, 2H),
3.79 (s, 1H), 3.75 (s, 3H), 1.63e1.51 (m, 3H), 0.84 (dd, J ¼ 6.1, 2.9 Hz,
leucine (318 mCi/mmol, PerkinElmer), ddH2O, and compounds at
different concentrations. The mixture was pre-incubated at 37 ꢂC
without ATP for 20 min, then added 4 mM ATP at 37 ꢂC for 15 min.
6H). 13C NMR (101 MHz, DMSO‑d6)
d
169.52, 167.66, 160.93, 159.44,
Then three 20 mL aliquots were spotted on 3 mm filter paper
139.52, 130.49, 130.07, 118.72, 116.18, 115.07, 107.35, 107.23, 101.61,
67.51, 55.63, 51.85, 23.86, 23.04, 22.04. Mp: 231e233 ꢂC. HRMS:
[MþH]þ calcd [C21H27N3O6S þ H]þ 450.1699, found 450.1680.
HPLC: Gradient A, 96.7% purity, 7.7 min.
(Whatman), washed 3 times in 5% trichloroacetic acid and 3 times
in alcohol. Filter papers were then dried in oven under 85 ꢂC for
20 min and the precipitated [14C] leucine tRNALeu were quantified
by liquid scintillation counting using a Beckman Coulter LS 6500
liquid scintillation counter. Data was averaged to generate an IC50
value using GraphPad 5 for each test compound.
5.1.35. 2-(4-Methoxyphenoxy)-N-((3-((L-leucyl)amino)sulfonyl)
phenyl)acetamide (28e)
A 70
mL reaction system containing 50 mM HEPES-KOH (pH 7.8),
Compound 28e (51 mg, 24.1% yield) was prepared from 22e
(95 mg, 0.52 mmol) and 26 (167 mg, 0.43 mmol) following the
5 mM MgCl2, 45 mM KCl, 1 mM DTT, 0.02% (w/v) BSA, 0.4 mg/mL
tRNA (Roche), 0.1 mL DMSO, 3 m
Ci/mL [14C] leucine, T. brucei LeuRS at
general procedure. 1H NMR (400 MHz, DMSO‑d6)
d
10.64 (s, 1H),
37 ꢂC, then 4 mM ATP induced reaction for 20 min [14C] leucine was
activated and transferred to the tRNALeu. Then it was quantified by
liquid scintillation counting using a Beckman Coulter LS 6500 liquid
scintillation counter.
8.44 (s, 1H), 8.29 (s, 3H), 7.93 (t, J ¼ 8.3 Hz, 1H), 7.66 (d, J ¼ 7.8 Hz,
1H), 7.59 (t, J ¼ 8.0 Hz, 1H), 6.99e6.94 (m, 2H), 6.89 (d, J ¼ 9.1 Hz,
2H), 4.69 (s, 2H), 3.84e3.76 (m, 1H), 3.71 (s, 3H), 1.64e1.42 (m, 3H),
0.84 (dd, J ¼ 6.0, 2.7 Hz, 6H). 13C NMR (101 MHz, DMSO‑d6)
d 169.52,
167.96, 154.32, 152.25, 139.56, 130.05, 124.89, 123.05, 118.71, 116.17,
115.07, 68.19, 55.85, 51.82, 23.86, 23.04, 22.07. Mp: 258e260 ꢂC.
5.3. In vitro T. brucei assay
HRMS: [MþH]þ calcd [C21H27N3O6S
þ
H]þ 450.1699, found
450.1685. HPLC: Gradient A, 96.5% purity, 7.6 min.
All in vitro anti-parasite assays were conducted with the
bloodstream-form Trypanosoma brucei brucei 221 strain. Parasites
were cultured in T-25 vented cap flasks and kept in humidified
incubators at 37 ꢂC and 5% CO2. The parasite culture media was
complete HMI-11 medium [18]. To ensure log growth phase, try-
panosomes were sub-cultured at appropriate dilutions every 2e3
5.1.36. 2-([1,10-Biphenyl]-4-yloxy)-N-((3-((L-leucyl)amino)
sulfonyl)phenyl)acetamide (28f)
28f (73 mg, 34.4% yield) was prepared from 22f (109 mg,
0.48 mmol) and 26 (153 mg, 0.41 mmol) following the general
procedure. 1H NMR (400 MHz, DMSO‑d6)
d
10.72 (s,1H), 8.45 (s,1H),
days. Log phase cultures were diluted 1:10 in HMI-11 and 10 mL was
8.26 (s, 3H), 7.95 (d, J ¼ 8.1 Hz, 1H), 7.70e7.57 (m, 6H), 7.44 (t,
J ¼ 7.7 Hz, 2H), 7.32 (t, J ¼ 7.3 Hz, 1H), 7.14e7.09 (m, 2H), 4.83 (s, 2H),
3.81 (s, 1H), 1.65e1.46 (m, 3H), 0.83 (dd, J ¼ 6.1, 3.0 Hz, 6H). 13C NMR
counted using hemocytometer to determine parasite concentra-
tion. Parasites were diluted to 2 ꢀ 105/mL in HMI-11 to generate a
2-fold working concentration for assay. Compounds to be tested
(101 MHz, DMSO‑d6)
d
169.53, 167.69, 157.92, 140.17, 139.57, 133.74,
were serially diluted in DMSO, and 0.5 mL added to 49.5 mL HMI-11
130.10, 129.34, 128.25, 127.30, 126.70, 124.86, 123.07, 118.69, 115.61,
in triplicate 96-well plates. Parasites from the diluted stock were
67.51, 51.83, 23.86, 23.05, 22.06. Mp: 266e268 ꢂC. HRMS: [MþH]þ
added to each well (50
m
L) to give a final concentration of 1.0 ꢀ 105/
calcd [C26H29N3O5S
þ
H]þ 496.1906, found 496.1910. HPLC:
mL parasites in 0.4% for DMSO. Trypanosomes were incubated with
Gradient A, 98.4% purity, 9.4 min.
compounds for 72 h at 37 ꢂC with 5% CO2. Resazurin (20
mL of
12.5 mg/mL stock) from Sigma-Aldrich was added to each well and
plates were incubated for an additional 5 h. Assay plates were read
using a plate reader (Thermo Varioskan Flash) at an excitation
wavelength of 544 nm and emission of 590 nm. Triplicate data
points were averaged to generate sigmoidal dose response curve
and determine IC50 values using GraphPad Prism 5.0. IC50 values
5.1.37. 2-([1,10-Biphenyl]-3-yloxy)-N-((3-((L-leucyl)amino)
sulfonyl)phenyl)acetamide (28g)
Compound 28g (110 mg, 40.1% yield) was prepared from 22g
(141 mg, 0.62 mmol) and 26 (198 mg, 0.52 mmol) following the
general procedure. 1H NMR (400 MHz, DMSO‑d6)
d 10.85 (s, 1H),
8.47 (s, 1H), 8.39 (s, 3H), 7.99 (d, J ¼ 8.1 Hz, 1H), 7.68 (d, J ¼ 7.7 Hz,
3H), 7.60 (t, J ¼ 8.0 Hz, 1H), 7.47 (t, J ¼ 7.6 Hz, 2H), 7.43e7.36 (m, 2H),
7.30 (dd, J ¼ 10.2, 4.9 Hz, 2H), 7.03 (dd, J ¼ 8.1, 2.0 Hz, 1H), 4.88 (s,
were measured in triplicate with an error range of 0.2
amin and pentamidine are used as positive control and typical
average IC50 values are 0.007 g/mL (0.005 M) and 0.009 g/mL
(0.026 M), respectively.
mM. Sur-
m
m
m
2H), 3.86 (s, 1H), 1.65e1.50 (m, 3H), 0.82 (dd, J ¼ 6.0, 3.0 Hz, 6H). 13
C
m
Please cite this article as: W. Xin et al., Design and synthesis of
a-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA
synthetase inhibitors, European Journal of Medicinal Chemistry, https://doi.org/10.1016/j.ejmech.2019.111827

10
W. Xin et al. / European Journal of Medicinal Chemistry xxx (xxxx) xxx
[9] B. Gadakh, A. Van Aerschot, Aminoacyl-tRNA synthetase inhibitors as anti-
Declaration of competing interests
microbial agents: a patent review from 2006 till present, Expert Opin. Ther.
Pat. 22 (2012) 1453e1465.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
[10] M.H. Charlton, R. Aleksis, A. Saint-Leger, A. Gupta, E. Loza, L.R. de Pouplana,
I. Kaula, D. Gustina, M. Madre, D. Lola, K. Jaudzems, G. Edmund, C.P. Randall,
L. Kime, A.J. O’ Neill, W. Goessens, A. Jirgensons, P.W. Finn, N-leucinyl ben-
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[12] F.L. Rock, W. Mao, A. Yaremchuk, M. Tukalo, T. Crepin, H.C. Zhou, Y.K. Zhang,
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Acknowledgments
We thank National Key Research and Development Program of
China (2017YFA0505200), National Science Foundation of China
(81573264 and 81222042), and E-Institutes of Shanghai Univer-
sities (EISU) Chemical Biology Division for financial support of this
work.
ꢀ
[13] V. Hernandez, T. Crepin, A. Palencia, S. Cusack, T. Akama, S.J. Baker, W. Bu,
L. Feng, Y.R. Freund, L. Liu, M. Meewan, M. Mohan, W. Mao, F.L. Rock,
H. Sexton, A. Sheoran, Y. Zhang, Y.K. Zhang, Y. Zhou, J.A. Nieman,
M.R. Anugula, E.M. Keramane, K. Savariraj, D. Shekhar Reddy, R. Sharma,
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.ejmech.2019.111827.
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Please cite this article as: W. Xin et al., Design and synthesis of
a-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA
synthetase inhibitors, European Journal of Medicinal Chemistry, https://doi.org/10.1016/j.ejmech.2019.111827