Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1

Article abstract of DOI:10.1016/j.ejmech.2016.03.017

There are currently no clinically available inhibitors of metallo-β-lactamases (MBLs). These enzymes confer resistance to bacteria against a broad range of commonly used β-lactam antibiotics, and are produced by an increasing number of bacterial pathogens. In this study, several thiol derivatives of l-amino acids were designed and synthesized, and their inhibitory effects against the metallo-β-lactamase IMP-1 (subclass B1) were investigated. The most potent compound, derived from l-tyrosine, exhibited competitive inhibition, with a K_i of 86 nM. The ability of this compound to render MBL-expressing bacteria susceptible to imipenem was examined. Reductions in MIC values up to 5.2 - fold were observed.

Full text of DOI:10.1016/j.ejmech.2016.03.017

European Journal of Medicinal Chemistry 114 (2016) 318e327
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Research paper
Design, synthesis, and in vitro and biological evaluation of potent
amino acid-derived thiol inhibitors of the metallo-b-lactamase IMP-1
,
Omid Khalili Arjomandi a, Waleed M. Hussein a b, Peter Vella a, Yusralina Yusof a,
,
*
Hanna E. Sidjabat c, Gerhard Schenk a, Ross P. McGeary a
a The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Qld, 4072, Australia
b Helwan University, Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Ein Helwan, Helwan, Egypt
c The University of Queensland, UQ Centre for Clinical Research, Building 71/918, Royal Brisbane & Women's Hospital Campus, Herston, QLD, 4029, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
There are currently no clinically available inhibitors of metallo-
confer resistance to bacteria against a broad range of commonly used
b
-lactamases (MBLs). These enzymes
-lactam antibiotics, and are
produced by an increasing number of bacterial pathogens. In this study, several thiol derivatives of
amino acids were designed and synthesized, and their inhibitory effects against the metallo- -lactamase
IMP-1 (subclass B1) were investigated. The most potent compound, derived from -tyrosine, exhibited
Received 30 November 2015
Received in revised form
4 March 2016
Accepted 5 March 2016
Available online 9 March 2016
b
L-
b
L
competitive inhibition, with a Ki of 86 nM. The ability of this compound to render MBL-expressing
bacteria susceptible to imipenem was examined. Reductions in MIC values up to 5.2dfold were observed.
© 2016 Elsevier Masson SAS. All rights reserved.
Keywords:
Metallo-b-lactamase
Enzyme inhibitor
Antibiotic resistance
1. Introduction
there are currently no clinically useful inhibitors against MBLs.
Accordingly, the development of new MBL inhibitors is urgent
The
for the treatment of bacterial infections, but in recent years the
emergence of pathogenic bacteria that can secrete -lactamases
(enzymes that deactivate these antibiotics by hydrolyzing their
lactam ring) has led to great concern regarding the continuing
ability of current drugs to adequately treat diseases caused by these
b
-lactam antibiotics are the most widely prescribed drugs
[14,15].
Various classes of MBL inhibitors have been reported [16],
b
including trifluoromethyl ketones and alcohols [17], dicarboxylic
acids [18e23], thiols [24e30], sulfates [31], hydroxamates [32],
tetrazoles [33] and sulfonamides [34]. The aim of this work was to
develop lead inhibitors of the MBL enzyme IMP-1 (subclass B1)
through docking studies, synthesis, kinetic enzyme assays and cell-
based assays. IMP-1, which may be secreted by both Pseudomonas
aeruginosa and Klebsiella pneumoniae [35e38], was selected as our
target since these pathogens have been responsible for outbreaks of
antibiotic-resistant bacterial infections in clinical settings. In
addition, this enzyme is well-characterized and its crystal structure
has been reported [39].
b
-
bacteria [1].
b
-Lactamases may be classified as either serine-
b-
lactamases (SBLs, Classes A, C and D) or metallo-
b-lactamases
(MBLs, Class B), according to their mechanisms of action. MBLs are
further divided into three subclasses, B1, B2 and B3, depending on
their amino acid sequences and metal occupancies [2], and we have
recently tentatively identified a fourth MBL subclass, B4 [3,4]. There
can be one or two zinc(II) ions in their active sites [3,5e10].
ꢀ
Since MBLs can deactivate most
b-lactam antibiotics, including
The design of this project was based on the work of Lienard et al.
such widely used drug families as the carbapenems, cephalosporins
and penams [11,12], the development of inhibitors of MBLs is an
[40]. That group reported that the N-(3-mercapto)propanoyl de-
rivative of unnatural
IMP-1, with a Ki of 0.088
focusses on the design, synthesis and testing of thiol derivatives of
the three natural aromatic amino acids, -phenylalanine, -tyrosine
and -tryptophan.
D-phenylalanine was a competitive inhibitor of
essential strategy for maintaining the usefulness of existing
b
-lac-
mM (Fig. 1). The work presented here
tam antibiotics. While clavulanic acid is a potent inhibitor of SBLs
[13], being widely prescribed in combination with amoxicillin,
L
L
L
* Corresponding author.
E-mail address: r.mcgeary@uq.edu.au (R.P. McGeary).
http://dx.doi.org/10.1016/j.ejmech.2016.03.017
0223-5234/© 2016 Elsevier Masson SAS. All rights reserved.

O.K. Arjomandi et al. / European Journal of Medicinal Chemistry 114 (2016) 318e327
319
3. Docking studies
For computational modeling, the crystal coordinates of the IMP-
1 enzyme (PDB code 1JJT) [19] were downloaded from the Protein
Data Bank (PDB) and used in all subsequent docking studies. The
IMP-1 MBL is functionally a monomeric protein but crystallizes as a
dimer with 221 amino acids in each chain. Both chain A and chain B
have identical amino acid residues and each has two zinc (II) ions in
the active site. The topologies of the active sites of both chain A and
chain B are identical and hence chain B was deleted from the crystal
coordinates and only chain A was used for the docking studies.
Since the enzyme kinetic assays (see Supplementary data) were
performed at pH 7, the carboxylic acid functional groups of the
docked inhibitors were deprotonated and anionic. As the thiol
groups of the inhibitors were anticipated to coordinate to the zinc
metal ions in the active site, these functional groups were also
deprotonated for the docking studies. MolDock was used for all
docking studies [46]. Calculated binding energies for all of the in-
hibitors (MolDock Scores) may be found in the Supplementary data.
Docking studies predicted that all of the inhibitors coordinated
to both zinc ions in the active site of IMP-1 via their thiolate groups,
with ZndS distances of around 2.0e3.0 Å. Fig. 2 shows the lowest
energy docking result for the most potent inhibitor in the series,
13a (see Section 4). In this example, ZndS distances are less than
2.0 Å. A hydrogen bond between the amide carbonyl oxygen atom
of 13a and the side chain amide NH2 group of Asn233 is present
(3.2 Å). Distances between the central aromatic ring of 13a and the
aromatic rings of Trp64 and His263 are approximately 4 Å, slightly
longer than the sum of the van der Waals radii of these groups.
ꢀ
Fig. 1. IMP-1 inhibitor reported by Lienard et al. [40].
2. Chemistry
The synthetic routes to compounds 1a-c are shown in Scheme 1.
Compounds 1a [41] and 1b [42] were synthesized by the reaction of
thioacetic acid with bromoacetic acid and acrylic acid, respectively.
Compound 1c [43] was prepared by the reaction of potassium
thioacetate with 4-chlorobutanoic acid. In all cases isolated yields
were around 60%.
Boc-protected
L
-tyrosine 3 was synthesized from -tyrosine 2 by
L
standard methods [44]. Benzylation of the phenolic group of 3
using benzyl bromide and sodium methoxide in methanol pro-
duced benzyl ether 4 in 64% yield (Scheme 2) [45]. Heating benzyl
ether 4 in refluxing methanol containing thionyl chloride produced
the methyl ester hydrochloride salt 5 in quantitative yield.
-Amino acid methyl esters 6e8 were synthesized by refluxing
the appropriate -amino acids in methanol containing thionyl
chloride. Compounds 9aec, 10aec, 11aec and 12aec were syn-
thesized by condensing the -amino acid methyl esters with
thioester-acid intermediates 1aec using HBTU/DIPEA as the
coupling reagent (Scheme 3). Hydrolyzed compounds 13aec,
14aec, 15aec and 16aec were prepared by treatment of in-
termediates 9aec, 10aec, 11aec and 12aec with degassed sodium
hydroxide solution to give the final thiol products. Thiols 13aec,
14aec, 15aec and 16aec are sensitive to aerial oxidation, readily
forming disulfides, which were apparent as trace impurities in the
mass spectra of all of these thiols, even after careful purification by
flash column chromatography.
L
L
L
4. Enzyme kinetics studies
The inhibitory activities (IC50 values) of the inhibitors against
IMP-1 were first evaluated by a screening assay which measured
the residual activity of the enzyme. In our previous work in the area
of MBL inhibitors [28e30], we have employed the chromogenic
cephalosporin CENTA [47] as substrate in our enzyme assays.
However, thiol-containing inhibitors react with this compound,
displacing the 5-nitro-2-sulfidobenzoate chromophore [38].
Therefore, in this study benzylpenicillin was used as the substrate.
Initial assay results showed that all of the thiol compounds
Scheme 1. Reagents and conditions: (a) NaHCO3, H2O, r.t., overnight, 65%; (b) neat, 100 ꢀC, 90 min, 62%; (c) DMF, r.t., 2 h, 59%.

320
O.K. Arjomandi et al. / European Journal of Medicinal Chemistry 114 (2016) 318e327
Scheme 2. Reagents and conditions: (a) Boc2O, NaOH, THF/H2O, r.t., overnight, 100%; (b) BnBr, NaOMe, MeOH, 40 ꢀC, 3 h, 64%; (c) SOCl2, MeOH,
D, 3 h, 100%.
Scheme 3. Reagents and conditions: (a) 1a, 1b or 1c, HBTU, DIPEA, THF, r.t., overnight; (b) NaOH, H2O/MeOH, r.t., 1 h.
exhibited more than 50% inhibition at 10
m
M. Further kinetic ana-
strains: 1) Escherichia coli expressing IMP-1 (i.e. blaIMP-1 expressed
in BL21 cells); 2) a clinical isolate of Enterobacter cloacae expressing
the very closely related MBL IMP-4 (95% homology) [48]; and 3) a
clinical isolate of E. cloacae expressing both IMP-4 and TEM-1, a
lyses then allowed the determination of the competitive (Kic) and
uncompetitive (Kiuc) values of these compounds (Table 1). A
representative inhibition curve of compound 13a is shown in the
Supplementary data.
Class A serine-
b
-lactamase [2]. The imipenem MIC in combination
L of 13a at a concentra-
All of the compounds demonstrated Kic values lower than 10
mM
with 13a was tested by incorporating 20 m
against IMP-1. It was observed that the shorter-chain thioacetic
acid-derived inhibitors (13a, 14a and 15a) were more potent than
their longer chain counterparts (Table 1). In most cases the inhib-
itory mode was exclusively competitive; the exception was com-
pound 15b which showed a mixed mode of inhibition, although its
tion of 50 mM into Mueller-Hinton (MH) agar. Bacterial suspen-
sions at 0.5 McFarland were spread onto the agar plates
supplemented with compound 13a. The imipenem E-test strip
(bioMerieux) was then placed on the media. As a control the imi-
penem MICs of the three test strains were also determined on plain
MH agar (i.e. in the absence of 13a).
Kiuc value (60 mM) was much larger than its Kic value (1.45 mM).
Compound 13a exhibited the most potent inhibitory activity with a
Kic value of 86 nM. Since several low-molecular weight thiols have
been reported to exhibit moderate inhibitory activities against
MBLs [24e26], we also assayed the thioacetate intermediates 1a-c.
Interestingly, compound 1a was a mixed-mode inhibitor of IMP-1
Table 2 summarizes the results of these trials. Administration of
13a to the E. cloacae strain expressing both IMP-4 and TEM-1
resulted in no difference in the growth of the bacteria when imi-
penem was administered. For the E. cloacae expressing only IMP-4,
a marked reduction in the imipenem MIC (3.9efold) was noted
(Fig. 3). For E. coli expressing only IMP-1, an even greater reduction
in the imipenem MIC was observed (5.2efold) (Fig. 4).
with a Kic value of 0.32
mM. Compounds 1b and 1c showed no
inhibitory activity towards IMP-1 (data not shown).
The results suggest that 13a, as well as being a potent in vitro
inhibitor of IMP-1, also significantly inhibits IMP-1 and IMP-4 in
strains of E. coli and E. cloacae that express this MBL and its variant.
The absence of an effect of 13a on the strain of E. cloacae that ex-
5. Biological evaluation
The effects of the most potent IMP-1 inhibitor, compound 13a,
were examined on the three following MBL-producing bacterial
presses the serine-b-lactamase TEM-1 is expected, as 13a would

O.K. Arjomandi et al. / European Journal of Medicinal Chemistry 114 (2016) 318e327
321
these compounds demonstrated promising in vitro inhibitory ac-
tivity against IMP-1. Among them, compound 13a is the most
potent inhibitor, with a competitive Ki of 86 nM. Importantly, this
inhibitor also significantly decreases the imipenem MIC for bacteria
expressing IMP-1 or IMP-4. We expect that this compound can be
used as a lead for further development of potent MBL inhibitors of
clinical relevance.
7. Experimental
All chemicals were purchased from SigmaeAldrich, Merck and
Fluka chemical companies. All NMR experiments were recorded on
Bruker AVANCE 500, 400 or 300 MHz spectrometers. Chemical
shifts are reported in parts per million (ppm) on a
d scale and
referenced to the residual solvent peak (1H, 7.24 ppm, 13C, 77.0 ppm
for CDCl3; 1H, 2.49 ppm, 13C, 39.5 ppm for DMSO-d6; 1H, 3.30 ppm,
13C, 49.5 ppm for CD3OD). Coupling constants (J) are reported in
Hertz. Multiplicities of the peaks are abbreviated as follows: s for
singlet, bs for broad singlet, d for doublet, t for triplet, and q for
quartet. Low- and high-resolution EI-MS were measured on a Fin-
nigan MAT 900 XL-Trap mass spectrometer in positive and negative
ionization mode. LR-ESI were recorded on a Bruker HCT 3D Ion Trap
and HR-ESI were performed on a BrukerMicrOTof-Q with the
DIONEX Ultimate 3000 LC in positive and negative electrospray
ionization mode, with CH3OH as solvent. For IR analyses samples
were measured neat on a PerkinElmer Frontier FT-IR Spectrometer.
Fig. 2. Interactions of docked ligand 13a at the active site of IMP-1 (PDB: 1JJT). Atom
colors are as follows: blueenitrogen, redeoxygen, greyecarbon and yellow-zinc atom
(of IMP-1), and redeoxygen, blueenitrogen, greenecarbon, and yellowesulfur (on
inhibitor). (For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)
Table 1
7.1. Enzyme expression
Inhibitory activities of the target compounds 13aec, 14aec, 15aec, 16aec and 1a
against IMP-1. Benzylpenicillin was used as the substrate.
The IMP-1 enzyme, lacking the first 21 signal peptide amino acid
residues, was expressed and purified using the protocol of Vella
et al. [38,49]. Details of the enzyme kinetic assays are presented in
the Supplementary data.
Compound
Kic
(
m
M)a
Kiuc (m
M)b
13a
13b
13c
14a
14b
14c
15a
15b
15c
16a
16b
16c
1a
0.086 0.024
9.39 4.60
5.85 1.30
0.47 0.09
5.02 1.64
8.62 3.30
0.25 0.20
1.45 0.67
2.82 1.98
4.55 1.96
5.18 1.55
5.63 4.50
0.32 4.50
ec
e
e
e
e
e
e
7.2. General procedure 1: esterification of amino acids
Compounds 6e8 were synthesized using the following general
procedure reported by Maiti and Banerjee [50]: a solution of amino
acid (18.2 mmol) in MeOH (20 mL) was stirred at 0 ꢀC. Thionyl
chloride (1.6 mL, 22 mmol) was added dropwise over 10 min. The
reaction mixture was then allowed to warm to room temperature
before being heated under reflux for 3 h. The solvent and volatiles
were evaporated under reduced pressure and the product was
triturated with ethyl acetate to give the methyl ester hydrochloride
salt as a colorless solid (100%).
60.25 20
e
e
e
e
2.64 0.46
a
Kic: Inhibition constant for competitive inhibition mode.
Kiuc: Inhibition constant for uncompetitive inhibition mode.
e: Insignificant (>1 mM) contribution of this mode.
b
c
7.3. General procedure 2: amide coupling reactions
not be anticipated to inhibit this enzyme, and hence would have no
effect on the ability of TEM-1 to degrade imipenem.
Compounds 9aec, 10aec, 11aec and 12aec were synthesized
using the following general procedure: L-amino acid methyl ester
6. Conclusions
hydrochlorides 5e8 (4.50 mmol), thioesters 1aec (4.95 mmol),
HBTU (1.88 g, 4.95 mmol), DIPEA (1.75 g, 2.35 mL,13.5 mmol) in THF
(40 mL) were stirred overnight. The THF was evaporated under
reduced pressure then either DCM or ethyl acetate (40 mL) was
added. The organic solution was washed with saturated sodium
We describe a straightforward and efficient synthesis of novel
thiol compounds based on naturally occurring aromatic amino
acids as inhibitors against the metallo-b-lactamase IMP-1. All of
Table 2
Imipenem MIC values in the absence or presence of compound 13a.
Strains
b
-Lactamases
Imipenem MICs (
m
g/mL)
Reduction in MIC
Without inhibitor
With 13a
E. coli BL21
E. cloacae ECL1
E. cloacae ECL2
IMP-1
IMP-4
IMP-4, TEM-1
2
1.5
0.5
0.38
0.38
0.5
5.2dfold
3.9dfold
None

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Fig. 3. Imipenem-induced growth inhibition of E. cloacae ECL1 expressing IMP-4 in the absence of an MBL inhibitor (A, left) and the presence of compound 13a (B, right).
Fig. 4. Imipenem-induced growth inhibition of E. coli BL21 expressing IMP-1 in the absence of an MBL inhibitor (A, left) and the presence of compound 13a (B, right).
bicarbonate solution (40 mL), dried (Na2SO4), filtered and evapo-
rated to give the crude product, which was purified by flash chro-
matography (30e100% EtOAc in petroleum ether).
to 1 using concentrated HCl. The solution was extracted with ethyl
acetate (40 mL) and washed with water (5 ꢁ 50 mL). The organic
phase was dried (Na2SO4), filtered and evaporated under reduced
pressure to give the pure products.
7.4. General procedure 3: saponification
7.5. 2-(Acetylthio)acetic acid (1a)
Compounds 13aec, 14aec, 15aec and 16aec were synthesized
using the following general procedure: Compounds 9aec, 10aec,
11aec and 12aec (2.4 mmol) were dissolved in degassed methanol
(10 mL), then degassed sodium hydroxide solution (1 M,10 mL) was
added and the solution was stirred under argon for one hour. The
organic solvent was evaporated under reduced pressure, then
degassed water (30 mL) was added and the water phase was
washed with degassed ethyl acetate (40 mL). The pH was adjusted
A variation of the method of Benary was used [41]. Sodium bi-
carbonate (15.7 g, 187 mmol) was added slowly to a stirred solution
of thioacetic acid (8.1 g, 7.5 mL, 106 mmol) and bromoacetic acid
(11.2 g, 80 mmol) in water (100 mL). The mixture was stirred at
room temperature overnight, then acidified to pH 1 with concen-
trated HCl and extracted with ethyl acetate (100 mL). The organic
layer was separated and washed with water (3 ꢁ 100 mL), then

O.K. Arjomandi et al. / European Journal of Medicinal Chemistry 114 (2016) 318e327
323
dried (Na2SO4), filtered and evaporated to give 2-(acetylthio)acetic
acid (1a) as a yellow oil (7.05 g, 65%). 1H NMR (300 MHz, CDCl3):
d
127.4 (Ar-C), 114.8 (Ar-C), 69.9 (PhCH2O), 53.5 (CHN), 52.3 (OCH3),
36.7 (CH2CHN), 32.7 (CH2S), 30.1 (CH3CO). HRMS calculated for
C
9.44 (1H, s, OH), 3.71 (2H, s, CH2), 2.37 (3H, s, CH3). 13C NMR
21H23NNaO5S [MþNa]þ 424.1189, found 424.1202.
(75 MHz, CDCl3):
d 193.9 (SCO), 174.5 (CO2), 31.2 (CH2), 30.0 (CH3).
The NMR spectra are in agreement with the literature [51].
7.10. (S)-3-(4-(Benzyloxy)phenyl)-2-(2-mercaptoacetamido)
propanoic acid (13a)
7.6. 3-(Acetylthio)propanoic acid (1b)
Colorless solid, 0.70 g (84%). IR nmax: 3676, 3325, 2989, 2598
A variation on the method of Li et al. was used [42]. Thioacetic
acid (10.8 g, 10 mL, 142 mmol) was added with stirring to acrylic
acid (7.9 g, 7.5 mL, 110 mmol). The mixture was stirred under argon
for 30 min at room temperature and then at 100 ꢀC for 90 min.
Crystals formed on cooling to room temperature. Excess thioacetic
acid was removed under reduced pressure then the residue was
dissolved in ethyl acetate (100 mL). The solution was washed with
water (3 ꢁ 100 mL) then dried (Na2SO4), filtered and evaporated to
give 3-(acetylthio)propanoic acid (1b) as a yellow hygroscopic solid
(SH), 2901, 1702 (CO2), 1610 (CON), 1543, 1512, 1235, 736 cmꢂ1. 1H
NMR (400 MHz, DMSO-d6):
d
8.22 (1H, d, J ¼ 8.2 Hz, NH), 7.40e7.27
(5H, m, Ar-H), 7.09 (2H, d, J ¼ 9.2 Hz, Ar-H), 6.87 (2H, d, J ¼ 9.2 Hz,
Ar-H), 5.01 (2H, s, PhCH2O), 4.31 (1H, dt, J ¼ 7.8, 5.8 Hz, CHNH), 3.06
(2H, s, CH2S), 2.93 (1H, dd, J ¼ 13.7, 5.0 Hz, CHAHBCHN), 2.77 (1H,
dd, J ¼ 13.7, 6.8 Hz, CHAHBCHN). 13C NMR (100 MHz, DMSO-d6):
d
172.7 (CO2), 169.4 (CON), 157.0 (Ar-C), 137.2 (Ar-C), 130.2 (Ar-C),
129.4 (Ar-C), 128.4 (Ar-C), 127.7 (Ar-C), 127.6 (Ar-C), 114.5 (Ar-C),
69.1 (CH2O), 53.8 (CHN), 35.9 (CH2CHN), 26.8 (CH2S). HRMS
calculated for C18H18NO4S [MꢂH]ꢂ 344.0962, found 344.0949.
(10.1 g, 62%). 1H NMR (400 MHz, CDCl3):
(2H, t, J ¼ 6.9 Hz, SCH2), 2.67 (2H, t, J ¼ 6.9 Hz, CH2CO), 2.31 (3H, s,
d 10.01 (1H, bs, OH), 3.08
CH3). 13C NMR (100 MHz, CDCl3):
d
195.5 (SCO), 177.7 (CO2), 34.1
7.11. (S)-Methyl 2-(3-(acetylthio)propanamido)-3-(4-(benzyloxy)
phenyl)propanoate (9b)
(CH2S), 30.5 (CH2CO), 23.8 (CH3). The 1H NMR spectrum is in
agreement with the literature [52].
Pale brown oil, 1.50 g (80%). IR nmax: 3675, 3304, 2989, 2901,
7.7. 4-(Acetylthio)butanoic acid (1c)
1740 (CO2), 1679 (COS), 1650 (CON), 1510, 1233, 1109, 737 cmꢂ1. 1H
NMR (400 MHz, CDCl3):
d 7.42e7.25 (5H, m, Ar-H), 7.00 (2H, d,
The method of Hogg et al. was adapted [43]. Potassium thio-
acetate (1.0 g, 8.8 mmol) was added portionwise to a solution of 4-
chlorobutyric acid (1.0 g, 8.2 mmol) in dry DMF (5 mL) at room
temperature. The reaction mixture was stirred under argon for 2 h
then the organic solvent was removed under reduced pressure. The
residue was taken up in ethyl acetate (50 mL) and washed with HCl
(5%, 2 ꢁ 50 mL) and water (3 ꢁ 50 mL). The organic phase was dried
(Na2SO4), filtered and evaporated to give 4-(acetylthio)butanoic
acid (1c) as a dark oil (0.78 g, 59%). 1H NMR (400 MHz, CDCl3):
J ¼ 8.5 Hz, Ar-H), 6.87 (2H, d, J ¼ 8.5 Hz, Ar-H), 6.04 (1H, d, J ¼ 7.7 Hz,
NH), 5.01 (2H, s, PhCH2O), 4.81 (1H, dt, J ¼ 7.8, 5.8 Hz, CHNH), 3.69
(3H, s, CH3O), 3.13e2.96 (4H, m, SCH2 and CH2CHN), 2.49 (2H, dt,
J ¼ 6.8, 3.0 Hz, CH2CO), 2.28 (3H, s, CH3CO). 13C NMR (100 MHz,
CDCl3):
d 195.9 (COS), 172.0 (CON), 170.2 (CO2), 158.0 (Ar-C), 136.9
(Ar-C), 130.3 (Ar-C), 128.6 (Ar-C), 127.98 (Ar-C), 127.97 (Ar-C), 127.5
(Ar-C), 114.9 (Ar-C), 70.0 (CH2O), 53.3 (CHNH), 52.3 (OCH3), 37.0
(CH2CHN), 36.0 (CH2S), 30.6 (CH2CO), 24.7 (CH3CO). HRMS calcu-
lated for C22H25NNaO5S [MþNa]þ 438.1346, found 438.1352.
d
2.91 (2H, t, J ¼ 7.1 Hz, CH2S), 2.42 (2H, t, J ¼ 7.4 Hz, CH2CO), 2.32
(3H, s, CH3), 1.91 (2H, quintet, J ¼ 7.2 Hz, CH2CH2CH2). 13C NMR
7.12. (S)-3-(4-(Benzyloxy)phenyl)-2-(3-mercaptopropanamido)
propanoic acid (13b)
(100 MHz, CDCl3):
d
195.6 (SCO), 178.3 (CO2), 32.5 (CH2CO), 30.6
(CH2S), 28.2 (CH3), 24.5 (CH2CH2CH2). The NMR spectra are in
agreement with the literature [43].
Pale yellow viscous oil, 0.71 g (82%). IR nmax: 3676, 3325, 2989,
2598 (SH), 2901, 1702 (CO2), 1610 (CON), 1543, 1511, 1232, 736 cmꢂ1
.
7.8. (S)-Methyl 2-amino-3-(4-(benzyloxy)phenyl)propanoate
1H NMR (400 MHz, CD3OD):
d 7.41e7.21 (5H, m, Ar-H), 7.13 (2H, d,
hydrochloride (5)
J ¼ 9.2 Hz, Ar-H), 6.84 (2H, d, J ¼ 9.2 Hz, Ar-H), 4.97 (2H, s, PhCH2O),
4.51 (1H, dd, J ¼ 7.5, 5.5 Hz, CHNH), 3.14 (1H, dd, J ¼ 14.0, 5.0 Hz,
CHAHBCHN), 2.88 (1H, dd, J ¼ 14.0, 7.9 Hz, CHAHBCHN), 2.62 (2H, dt,
J ¼ 6.5, 2.6 Hz, CH2S), 2.40 (2H, dt, J ¼ 7.5, 2.5 Hz, CH2CO). 13C NMR
White solid, 5.85 g (100%). 1H NMR (300 MHz, DMSO-d6):
d 8.63
(3H, bs, NH3), 7.47e7.25 (5H, m, Ar-H), 7.14 (2H, d, J ¼ 8.5 Hz, Ar-H),
6.96 (2H, d, J ¼ 8.5 Hz, Ar-H), 5.07 (2H, s, PhCH2O), 4.18 (1H, t,
J ¼ 6.9 Hz, CHNH3), 3.65 (3H, s, OCH3), 3.09e3.00 (2H, m, CH2CHN).
(100 MHz, CD3OD):
d 173.3 (CO2), 172.8 (CON), 158.9 (Ar-C), 138.9
(Ar-C), 131.64 (Ar-C), 131.55 (Ar-C), 128.7 (Ar-C), 128.5 (Ar-C), 115.69
(Ar-C), 115.66 (Ar-C), 70.9 (CH2O), 57.1 (CHN), 38.3 (CH2CHN), 37.4
(CH2CO), 28.3 (CH2S). HRMS calculated for C19H20NO4S [MꢂH]ꢂ
358.1119, found 358.1110.
13C NMR (75 MHz, DMSO-d6):
d 169.8 (CO2), 158.0 (Ar-C), 137.5 (Ar-
C), 131.0 (Ar-C), 128.8 (Ar-C), 128.2 (Ar-C), 128.1 (Ar-C), 127.0 (Ar-C),
115.3 (Ar-C), 69.6 (CH2O), 53.7 (CHN), 53.0 (OCH3), 35.4 (CH2CHN).
The NMR spectra are in agreement with the literature [53].
7.13. (S)-Methyl 2-(4-(acetylthio)butanamido)-3-(4-(benzyloxy)
7.9. (S)-Methyl 2-(2-(acetylthio)acetamido)-3-(4-(benzyloxy)
phenyl)propanoate (9c)
phenyl)propanoate (9a)
Brown viscous oil, 1.35 g (70%). IR nmax: 3676, 3292, 2989, 2901,
Yellow-brown oil, 1.63 g (90%). IR nmax: 3676, 3269, 2988, 2901,
1749, 1736 (CO2), 1688 (COS), 1650 (CON), 1610, 1544, 1242,
1733 (CO2), 1700 (COS) 1656 (CON), 1511, 733 cmꢂ1
.
1H NMR
697 cmꢂ1 1H NMR (400 MHz, CDCl3):
. d 7.43e7.26 (5H, m, Ar-H),
(400 MHz, CDCl3):
d
7.45e7.26 (5H, m, Ar-H), 6.98 (2H, d, J ¼ 8.5 Hz,
6.99 (2H, dt, J ¼ 8.5, 2.7 Hz, Ar-H), 6.88 (2H, dt, J ¼ 8.5, 2.4 Hz,
Ar-H), 6.03 (1H, d, J ¼ 7.8 Hz, NH), 5.01 (2H, s, PhCH2O), 4.82 (1H, dt,
J ¼ 7.8, 3.9 Hz, CHNH), 3.70 (3H, s, CH3O), 3.08 (1H, dd, J ¼ 14.0,
5.8 Hz, CHAHBCHN), 2.99 (1H, dd, J ¼ 14.0, 6.1 Hz, CHAHBCHN), 2.83
(2H, dt, J ¼ 7.1, 4.1 Hz, CH2S), 2.30 (3H, s, CH3CO), 2.22 (2H, dt,
Ar-H), 6.87 (2H, d, J ¼ 8.5 Hz, Ar-H), 6.58 (1H, d, J ¼ 7.8 Hz, NH), 5.02
(2H, s, PhCH2O), 4.76 (1H, dt, J ¼ 7.8, 5.8 Hz, CHNH), 3.71 (3H, s,
OCH3), 3.55 (1H, d, J ¼ 15.0 Hz, CHAHBS), 3.49 (1H, d, J ¼ 15.0 Hz,
CHAHBS), 3.08 (1H, dd, J ¼ 14.1, 5.7 Hz, CHAHBCHN), 3.00 (1H, dd,
J ¼ 14.1, 6.7 Hz, CHACHBCHN), 2.31 (3H, s, CH3CO). 13C NMR
J ¼ 5.4, 1.7 Hz, CH2CO), 1.86 (2H, quintet, J ¼ 7.2 Hz, CH2CH2CH2). 13
C
(100 MHz, CDCl3):
d
195.1 (COS), 171.5 (CO2), 167.5 (CON), 157.8 (Ar-
NMR (100 MHz, CDCl3): d 195.9 (COS), 172.2 (CON), 171.5 (CO2),
C), 136.9 (Ar-C), 130.2 (Ar-C), 128.5 (Ar-C), 127.9 (Ar-C), 127.8 (Ar-C),
157.9 (Ar-C), 136.9 (Ar-C), 130.2 (Ar-C), 128.5 (Ar-C), 128.1 (Ar-C),

324
O.K. Arjomandi et al. / European Journal of Medicinal Chemistry 114 (2016) 318e327
127.9 (Ar-C), 127.4 (Ar-C), 114.9 (Ar-C), 70.0 (CH2O), 53.1 (CHN), 52.3
(OCH3), 37.0 (CH2CHN), 34.8 (CH2CO), 30.6 (CH2S), 28.3 (CH3CO),
25.4 (CH2CH2CH2). HRMS calculated for C23H27NNaO5S [MþNa]þ
452.1502, found 452.1511.
[MꢂH]ꢂ 277.0652, found 277.0658.
7.18. (S)-Methyl 2-(3-(acetylthio)propanamido)-3-(1H-indol-3-yl)
propanoate (10b)
7.14. (S)-3-(4-(Benzyloxy)phenyl)-2-(4-mercaptobutanamido)
propanoic acid (13c)
Brown viscous oil, 1.49 g (95%). IR nmax: 3323, 2951, 1737 (CO2),
1680 (COS), 1658 (CON), 1527, 1435, 1216, 745 cmꢂ1 1H NMR
.
(300 MHz, CDCl3):
d
8.12 (1H, s, indole-NH), 7.50 (1H, d, J ¼ 8.1 Hz,
Brown semisolid, 0.72 g (80%). IR nmax: 3675, 3325, 2989, 2598
Ar-H), 7.34 (1H, d, J ¼ 9.6 Hz, Ar-H), 7.18 (1H, t, J ¼ 6.9 Hz, Ar-H), 7.09
(1H, t, J ¼ 7.8 Hz, Ar-H), 6.97 (1H, d, J ¼ 2.4 Hz, Ar-H), 6.00 (1H, d,
J ¼ 7.8 Hz, NHCO), 4.94 (1H, dt, J ¼ 7.8, 5.4 Hz, CHNH), 3.68 (3H, s,
OCH3), 3.30 (2H, dd, J ¼ 5.1, 2.6 Hz, CH2CHN), 3.09 (2H, t, J ¼ 6.9 Hz,
CH2S), 2.45 (2H, t, J ¼ 6.9 Hz, CH2CO), 2.30 (3H, s, CH3CO). 13C NMR
(SH), 2925, 1722 (CO2), 1611 (CON), 1510, 1226, 1176, 695 cmꢂ1. 1H
NMR (500 MHz, CD3OD):
d
7.40 (2H, t, J ¼ 7.9 Hz, Ar-H), 7.35 (2H, t,
J ¼ 7.1 Hz, Ar-H), 7.28 (1H, t, J ¼ 6.5 Hz, Ar-H), 7.12 (2H, d, J ¼ 7.8 Hz,
Ar-H), 6.90 (2H, d, J ¼ 8.8 Hz, Ar-H), 5.04 (2H, s, PhCH2O), 4.64 (1H,
dd, J ¼ 7.2, 4.8 Hz, CHNH), 3.21 (1H, dd, J ¼ 14.0, 4.4 Hz, CHAHBCHN),
2.85 (1H, dd, J ¼ 14.0, 9.8 Hz, CHAHBCHN), 2.31 (2H, t, J ¼ 7.0 Hz,
CH2CO), 2.28e2.21 (2H, m, CH2S), 1.79e1.70 (2H, m, CH2CH2CH2).
(75 MHz, CDCl3):
d 195.9 (COS), 172.2 (CON), 170.2 (CO2), 136.1 (Ar-
C), 127.7 (Ar-C), 122.7 (Ar-C), 122.3 (Ar-C), 119.8 (Ar-C), 118.5 (Ar-C),
111.3 (Ar-C), 110.0 (Ar-C), 53.0 (CHN), 52.4 (CH3O), 36.1 (CH2S), 30.5
(CH2CO), 27.6 (OCH3), 24.6 (CH2CHN). HRMS calculated for
13C NMR (125 MHz, CD3OD):
d 175.2 (CO2), 174.9 (CON), 159.2 (Ar-
C), 138.8 (Ar-C), 131.3 (Ar-C), 130.8 (Ar-C), 129.5 (Ar-C), 128.8 (Ar-C),
128.6 (Ar-C), 115.9 (Ar-C), 71.0 (CH2O), 55.0 (CHN), 37.6 (CH2CHN),
35.2 (CH2CO), 31.2 (CH2S), 24.2 (CH2CH2CH2). HRMS calculated for
C
17H20N2NaO4S [MþNa]þ 371.1052, found 371.1036.
7.19. (S)-3-(1H-Indol-3-yl)-2-(3-mercaptopropanamido)propanoic
acid (14b)
C
20H23NO4S [MꢂH]ꢂ 372.1275, found 372.1269.
7.15. (S)-Methyl 2-amino-3-(1H-indol-3-yl)propanoate
hydrochloride (6)
Brown waxy solid, 0.47 g (67%). IR nmax: 3379, 2940, 2550 (SH),
1718 (CO2), 1625 (CON), 1525, 1210, 742 cmꢂ1. 1H NMR (300 MHz,
DMSO-d6):
d
10.82 (1H, s, indole-NH), 8.20 (1H, d, J ¼ 7.7 Hz, NHCO),
White solid, 4.63 g (100%). 1H NMR (400 MHz, CD3OD):
d
7.53
7.52 (1H, d, J ¼ 8.1 Hz, Ar-H), 7.31 (1H, d, J ¼ 7.7 Hz, Ar-H), 7.13 (1H,
d, J ¼ 2.2 Hz, Ar-H), 7.05 (1H, dt, J ¼ 7.3 Hz,1.3 Hz, Ar-H), 6.96 (1H, dt,
J ¼ 7.3, 1.3 Hz, Ar-H), 4.47 (1H, dt, J ¼ 7.8, 5.4 Hz, CHNH), 3.16 (1H,
dd, J ¼ 15.0, 5.0 Hz, CHAHBCHN), 2.99 (1H, dd, J ¼ 15.0, 9.0 Hz,
CHAHBCHN), 2.69e2.52 (2H, m, CH2S), 2.44e2.30 (2H, m, CH2CO),
(1H, d, J ¼ 7.9 Hz, Ar-H), 7.39 (1H, d, J ¼ 8.1 Hz, Ar-H), 7.22 (1H, s, Ar-
H), 7.13 (1H, t, J ¼ 7.0 Hz, Ar-H), 7.06 (1H, t, J ¼ 7.0 Hz, Ar-H), 4.33
(1H, dd, J ¼ 7.2, 5.6 Hz, CHNH3), 3.77 (3H, s, OCH3), 3.45 (1H, dd,
J ¼ 15.0, 5.6 Hz, CHAHBCHN), 3.37 (1H, dd, J ¼ 15.0, 7.2 Hz,
CHAHBCHN). 13C NMR (100 MHz, CD3OD):
d
171.3 (CO), 138.8 (Ar-C),
2.17 (1H, t, J ¼ 9.3 Hz, SH). 13C NMR (75 MHz, DMSO-d6):
d 173.4
128.7 (Ar-C), 126.2 (Ar-C), 123.4 (Ar-C), 120.8 (Ar-C), 119.3 (Ar-C),
113.2 (Ar-C), 107.9 (Ar-C), 55.1 (CHNH3), 54.1 (OCH3), 28.0
(CH2CHN). The 1H NMR spectrum is in agreement with the litera-
ture [54].
(CO2), 170.2 (CON), 136.0 (Ar-C), 127.2 (Ar-C), 123.5 (Ar-C), 120.9 (Ar-
C), 118.3 (Ar-C), 118.1 (Ar-C), 111.3 (Ar-C), 109.9 (Ar-C), 52.9 (CHN),
30.7 (CH2CO), 27.1 (CH2CHN), 19.8 (CH2SH). HRMS calculated for
C
14H15N2O3S [MꢂH]ꢂ 291.0809, found 291.0812.
7.16. (S)-Methyl 2-(2-(acetylthio)acetamido)-3-(1H-indol-3-yl)
7.20. (S)-Methyl 2-(4-(acetylthio)butanamido)-3-(1H-indol-3-yl)
propanoate (10a)
propanoate (10c)
Orange oil, 1.44 g (96%). IR nmax: 3349, 2954, 1737 (CO2), 1680
Brown viscous oil, 1.47 g (90%). IR nmax: 3313, 2936, 1736 (CO2),
(COS), 1662 (CON), 1524, 1357, 1222, 847 cmꢂ1. 1H NMR (500 MHz,
1680 (COS), 1652 (CON), 1523, 1435, 1214, 744 cmꢂ1 1H NMR
.
CDCl3):
d
8.23 (1H, s, indole-NH), 7.52 (1H, d, J ¼ 8.1 Hz, Ar-H), 7.34
(400 MHz, CDCl3):
d
8.20 (1H, bs, indole-NH), 7.50 (1H, d, J ¼ 7.8 Hz,
(1H, d, J ¼ 8.5 Hz, Ar-H), 7.18 (1H, t, J ¼ 7.9 Hz, Ar-H), 7.11 (1H, t,
J ¼ 7.2 Hz, Ar-H), 7.00 (1H, d, J ¼ 2.4 Hz, Ar-H), 6.67 (1H, d, J ¼ 8.8 Hz,
CHNH), 4.89 (1H, dt, J ¼ 7.0, 5.5 Hz, CHNH), 3.69 (3H, s, OCH3), 3.54
(1H, d, J ¼ 15.0 Hz, CHACHBS), 3.50 (1H, d, J ¼ 15.0 Hz, CHACHBS),
3.29 (2H, m, CH2CHN), 2.24 (3H, s, CH3CO). 13C NMR (125 MHz,
Ar-H), 7.34 (1H, d, J ¼ 7.4 Hz, Ar-H), 7.17 (1H, t, J ¼ 7.1 Hz, Ar-H), 7.10
(1H, t, J ¼ 7.1 Hz, Ar-H), 6.97 (1H, d, J ¼ 2.3 Hz, Ar-H), 6.05 (1H, d,
J ¼ 7.7 Hz, NHCO), 4.93 (1H, dt, J ¼ 7.8, 5.5 Hz, CHNH), 3.68 (3H, s,
OCH3), 3.36e3.23 (2H, dd, J ¼ 8.4, 5.6 Hz, CH2CHN), 2.82 (2H, dt,
J ¼ 2.8, 7.3 Hz, CH2S), 2.29 (3H, s, CH3CO), 2.17 (2H, t, J ¼ 7.6 Hz,
CH2CO), 1.85 (2H, quintet, J ¼ 7.2 Hz, CH2CH2CH2). 13C NMR
CDCl3):
d 195.2 (COS), 172.1 (CO2), 167.8 (CON), 136.2 (Ar-C), 127.7
(Ar-C), 123.0 (Ar-C), 122.3 (Ar-C), 119.8 (Ar-C), 118.7 (Ar-C), 111.4 (Ar-
C), 109.9 (Ar-C), 53.3 (CHN), 52.6 (CH3O), 33.0 (CH2S), 30.2
(CH2CHN), 27.5 (CH3CO). HRMS calculated for C16H18N2NaO4S
[MþNa]þ 357.0879, found 357.0886.
(100 MHz, CDCl3): d 195.9 (COS), 172.4 (CON), 171.5 (CO2), 136.1 (Ar-
C), 127.7 (Ar-C), 122.7 (Ar-C), 122.3 (Ar-C), 119.7 (Ar-C), 118.5 (Ar-C),
111.3 (Ar-C), 110.1 (Ar-C), 52.9 (CHN), 52.4 (CH3O), 34.9 (CH2CO),
30.6 (CH2S), 28.3 (CH3CO), 27.6 (CH2CHN), 25.3 (CH2CH2CH2).
HRMS calculated for C18H22N2NaO4S [MþNa]þ 385.1192, found
385.1203.
7.17. (S)-3-(1H-Indol-3-yl)-2-(2-mercaptoacetamido)propanoic
acid (14a)
7.21. (S)-3-(1H-Indol-3-yl)-2-(4-mercaptobutanamido)propanoic
Yellow waxy solid, 0.47 g (70%). IR nmax: 3379, 2929, 2550 (SH),
acid (14c)
1717 (CO2), 1618 (CON), 1530, 1214, 742 cmꢂ1. 1H NMR (300 MHz,
CD3OD):
d
7.55 (1H, d, J ¼ 8.1 Hz, Ar-H), 7.31 (1H, d, J ¼ 8.1 Hz, Ar-H),
Brown viscous oil, 0.48 g (65%). IR nmax: 3287, 2971, 2901, 2550
7.13e6.92 (3H, m, Ar-H), 4.72 (1H, dd, J ¼ 7.0, 5.1 Hz, CHNH), 3.36
(SH), 1735 (CO2), 1634 (CON), 1527, 1230, 1066, 743 cmꢂ1. 1H NMR
(1H, dd, J ¼ 14.7, 5.2 Hz, CHAHBCHN), 3.22 (1H, dd, J ¼ 14.7, 7.2 Hz,
(500 MHz, CD3OD):
d
7.54 (1H, t, J ¼ 7.2 Hz, Ar-H), 7.31 (1H, t,
CHAHBCHN), 3.12 (2H, s, CH2S). 13C NMR (75 MHz, CD3OD):
d
175.3
J ¼ 7.2 Hz, Ar-H), 7.11e7.03 (2H, m, Ar-H), 6.99 (1H, q, J ¼ 7.0 Hz, Ar-
H), 4.75 (1H, dt, J ¼ 7.8, 5.5 Hz, CHNH), 3.36 (1H, dd, J ¼ 15.0, 4.5 Hz,
CHAHBCHN), 3.13 (1H, dd, J ¼ 15.0, 8.3 Hz, CHAHBCHN), 2.42 (2H, t,
J ¼ 7.2 Hz, CH2S), 2.27e2.21 (2H, m, CH2CO), 1.81 (2H, quintet,
(CO2),173.3 (CON),138.5 (Ar-C),129.4 (Ar-C),125.0 (Ar-C),122.9 (Ar-
C), 120.3 (Ar-C), 119.8 (Ar-C), 112.8 (Ar-C), 111.2 (Ar-C), 55.4 (CHNH),
28.8 (CH2SH), 28.6 (CH2CHN). HRMS calculated for C13H13N2O3S

O.K. Arjomandi et al. / European Journal of Medicinal Chemistry 114 (2016) 318e327
325
J ¼ 7.2 Hz, CH2CH2CH2). 13C NMR (125 MHz, CD3OD):
d
175.3 (CO2),
3.20 (1H, dd, J ¼ 14.1, 4.8 Hz, CHAHBCHN), 2.93 (1H, dd, J ¼ 14.1,
9.3 Hz, CHAHBCHN), 2.81e2.76 (2H, m, CH2S), 2.55e2.51 (2H, m,
175.2 (CON), 138.0 (Ar-C), 128.8 (Ar-C), 124.4 (Ar-C), 122.4 (Ar-C),
119.8 (Ar-C), 119.2 (Ar-C), 112.3 (Ar-C), 111.1 (Ar-C), 54.6 (CHN), 38.3
(CH2CHN), 35.1 (CH2CO), 28.5 (CH2S), 26.1 (CH2CH2CH2). HRMS
calculated for C15H17N2O3S [MꢂH]ꢂ 305.0965, found 305.0960.
CH2CO). 13C NMR (100 MHz, CD3OD):
d 175.2 (CO2), 174.1 (CON),
138.9 (Ar-C), 130.8 (Ar-C), 130.0 (Ar-C), 128.3 (Ar-C), 55.5 (CHN),
38.9 (CH2CHN), 36.7 (CH2CO), 35.4 (CH2S). HRMS calculated for
C
24H28N2NaO6S2 [2M þ Na]þ 527.1281, found 527.1275. The 1H NMR
7.22. (S)-Methyl 2-amino-3-phenylpropanoate hydrochloride (7)
spectrum is in agreement with that reported for the enantiomer
[40].
White solid, 3.92 g (100%). 1H NMR (300 MHz, DMSO-d6):
d 8.83
(3H, bs, NH3), 7.34e7.22 (5H, m, Ar-H), 4.20 (1H, dd, J ¼ 7.6, 5.5 Hz,
CHNH3), 3.63 (3H, s, OCH3), 3.23 (1H, dd, J ¼ 13.4, 5.0 Hz,
CHAHBCHN), 3.09 (1H, dd, J ¼ 13.4, 7.4 Hz, CHAHBCHN). 13C NMR
7.27. (S)-Methyl 2-(4-(acetylthio)butanamido)-3-
phenylpropanoate (11c)
(75 MHz, DMSO-d6):
d
169.3 (CO), 134.8 (Ar-C), 129.4 (Ar-C), 128.6
Brown oil, 1.31 g (90%). IR nmax: 3333, 2954, 1737 (CO2), 1680
(Ar-C), 127.2 (Ar-C), 53.3 (CHN), 52.5 (OCH3), 35.8 (CH2CHN). The
NMR spectra are in agreement with the literature [55].
(COS), 1658 (CON), 1531, 1221, 847 cmꢂ1. 1H NMR (500 MHz, CDCl3):
d
7.28e7.22 (3H, m, Ar-H), 7.07 (2H, d, J ¼ 7.0 Hz, Ar-H), 6.01 (1H, d,
J ¼ 7.7 Hz, NH), 4.87 (1H, dd, J ¼ 9.7, 5.0 Hz, CHNH), 3.71 (3H, s,
OCH3), 3.15 (1H, dd, J ¼ 14.0, 5.5 Hz, CHAHBCHN), 3.05 (1H, dd,
J ¼ 14.0, 6.5 Hz, CHAHBCHN), 2.87e2.80 (2H, m, CH2S), 2.30 (3H, s,
CH3CO), 2.21 (2H, dt, J ¼ 7.3, 2.5 Hz, CH2CO), 1.85 (2H, quintet,
7.23. (S)-Methyl 2-(2-(acetylthio)acetamido)-3-phenylpropanoate
(11a)
Orange oil, 1.30 g (98%). IR nmax: 3317, 2953, 1740 (CO2), 1680
J ¼ 7.2 Hz, CH2CH2CH2). 13C NMR (125 MHz, CDCl3):
d 195.9 (COS),
(COS),1662 (CON),1526,1215, 846 cmꢂ1. 1H NMR (300 MHz, CDCl3):
172.1 (CON), 171.4 (CO2), 135.9 (Ar-C), 129.2 (Ar-C), 128.6 (Ar-C),
127.1 (Ar-C), 53.0 (CHN), 52.3 (OCH3), 37.9 (CH2CHN), 34.8 (CH2CO),
30.6 (CH2S), 28.3 (CH3CO), 25.4 (CH2CH2CH2). HRMS calculated for
d
7.31e7.21 (3H, m, Ar-H), 7.10e7.06 (2H, m, Ar-H), 6.63 (1H, d,
J ¼ 7.3 Hz, NH), 4.81 (1H, dd, J ¼ 7.6, 6.2 Hz, CHNH), 3.72 (3H, s,
OCH3), 3.57 (1H, d, J ¼ 14.9 Hz, CHAHBS), 3.49 (1H, d, J ¼ 14.9 Hz,
CHAHBS), 3.15 (1H, dd, J ¼ 5.6, 14.0 Hz, CHAHBCHN), 3.06 (1H, dd,
J ¼ 6.2, 14.0 Hz, CHAHBCHN), 2.34 (3H, s, CH3CO). 13C NMR (75 MHz,
C
16H21NNaO4S [MþNa]þ 346.1083, found 346.1080.
7.28. (S)-2-(4-mercaptobutanamido)-3-phenylpropanoic acid
(15c)
CDCl3):
d
195.2 (COS), 171.5 (CO2), 167.6 (CON), 135.6 (Ar-C), 129.3
(Ar-C), 128.5 (Ar-C), 127.1 (Ar-C), 53.4 (CHN), 52.4 (OCH3), 37.6
(CH2CHN), 32.7 (CH2S), 30.1 (CH3CO). HRMS calculated for
C
Brown viscous oil, 0.42 g (65%). IR nmax: 3318, 2941, 2565 (SH),
14H17NNaO4S [MþNa]þ 318.0770, found 318.0769.
1718 (CO2), 1633 (CON), 1531, 1219, 699 cmꢂ1. 1H NMR (500 MHz,
CD3OD):
d
7.27e7.17 (5H, m, Ar-H), 4.68 (1H, dd, J ¼ 9.7, 5.0 Hz,
7.24. (S)-2-(2-Mercaptoacetamido)-3-phenylpropanoic acid (15a)
CHNH), 3.22 (1H, dd, J ¼ 14.0, 4.7 Hz, CHAHBCHN), 2.91 (1H, dd,
J ¼ 14.0, 10.0 Hz, CHAHBCHN), 2.48 (2H, t, J ¼ 7.3 Hz, CH2CO), 2.24
(2H, dt, J ¼ 4.7, 7.3 Hz, CH2S), 1.84 (2H, quintet, J ¼ 7.0 Hz,
Brown oil, 0.45 g (79%). IR nmax: 3318, 2947, 2565 (SH), 1719
(CO2),1632 (CON),1526,1208, 699 cmꢂ1. 1H NMR (400 MHz, DMSO-
CH2CH2CH2). 13C NMR (125 MHz, CD3OD):
d 175.1 (CO2), 174.8
d6):
d
8.36 (1H, d, J ¼ 9.0 Hz, NH), 7.27e7.17 (5H, m, Ar-H), 4.46e4.41
(CON), 138.5 (Ar-C), 130.2 (Ar-C), 129.5 (Ar-C), 127.8 (Ar-C), 54.9
(CHNH), 38.38 (CH2CHN), 38.36 (CH2SH), 35.1 (CH2CO), 26.2
(CH2CH2CH2). HRMS calculated for C13H17NNaO3S [MþNa]þ
290.0821, found 290.0827.
(1H, m, CHNH), 3.42 (2H, s, CH2S), 3.05 (1H, dd, J ¼ 14.1, 5.3 Hz,
CHAHBCHN), 2.87 (1H, dd, J ¼ 14.1, 8.4 Hz, CHAHBCHN). 13C NMR
(100 MHz, DMSO-d6): d 172.7 (CO2), 167.8 (CON), 137.3 (Ar-C), 129.2
(Ar-C), 128.2 (Ar-C), 126.5 (Ar-C), 53.8 (CHN), 41.8 (CH2CHN), 36.8
(CH2S). HRMS calculated for C11H12NO3S [MꢂH]ꢂ 238.0543, found
238.0543.
7.29. (S)-Methyl 2-amino-3-(4-hydroxyphenyl)propanoate
hydrochloride (8)
7.25. (S)-Methyl 2-(3-(acetylthio)propanamido)-3-
White solid, 4.21 g (100%). 1H NMR (300 MHz, DMSO-d6):
d 9.47
phenylpropanoate (11b)
(1H, bs, OH), 8.63 (3H, bs, NH3), 7.00 (2H, d, J ¼ 8.5 Hz, Ar-H), 6.71
(2H, d, J ¼ 8.5 Hz, Ar-H), 4.13 (1H, t, J ¼ 5.8 Hz, CHNH3), 3.65 (3H, s,
OCH3), 3.07 (1H, dd, J ¼ 15.0, 5.6 Hz, CHAHBCHN), 2.97 (1H, dd,
Tan solid, 1.34 g (96%). IR nmax: 3292, 2953, 1728 (CO2), 1696
(COS), 1642 (CON), 1545, 1131, 696 cmꢂ1. 1H NMR (300 MHz, CDCl3):
J ¼ 15.0, 7.2 Hz, CHAHBCHN). 13C NMR (75 MHz, DMSO-d6):
d 169.4
d
7.32e7.23 (3H, m, Ar-H), 7.12e7.08 (2H, m, Ar-H), 6.02 (1H, d,
(CO2), 156.7 (Ar-C), 130.3 (Ar-C), 124.3 (Ar-C), 115.4 (Ar-C), 53.4
(CHN), 52.5 (CH3O), 35.0 (CH2CHN). The NMR spectra are in
agreement with the literature [56].
J ¼ 7.0 Hz, NH), 4.89 (1H, dt, J ¼ 7.8, 5.8 Hz, CHNH), 3.73 (3H, s,
OCH3), 3.20e3.05 (4H, m, CH2CHN and CH2S), 2.51e2.46 (2H, m,
COCH2), 2.32 (3H, s, CH3CO). 13C NMR (75 MHz, CDCl3):
d 195.9
(COS), 171.9 (CONH), 170.2 (CO2), 135.7 (Ar-C), 129.2 (Ar-C), 128.6
(Ar-C), 127.1 (Ar-C), 53.1 (CHN), 52.3 (OCH3), 37.8 (CH2CHN), 36.0
(CH2S), 30.5 (COCH2), 24.7 (CH3CO). HRMS calculated for
7.30. (S)-Methyl 2-(2-(acetylthio)acetamido)-3-(4-hydroxyphenyl)
propanoate (12a)
C
15H19NNaO4S [MþNa]þ 332.0937, found 332.0919. The NMR
Pale yellow oil, 1.35 g (95%). IR nmax: 3675, 3304, 2989, 2901,
spectra are in agreement with those reported for the enantiomer
[40].
1740 (CO2), 1698 (COS), 1655 (CON), 1510, 1233, 1109, 737 cmꢂ1. 1H
NMR (300 MHz, CDCl3):
d
6.91 (2H, d, J ¼ 8.8 Hz, Ar-H), 6.70 (2H, d,
J ¼ 8.4 Hz, Ar-H), 6.66 (1H, d, J ¼ 8.9 Hz, NH), 4.82e4.70 (1H, dt,
J ¼ 7.8, 5.5 Hz, CHNH), 3.71 (3H, s, OCH3), 3.55 (1H, d, J ¼ 15.0 Hz,
CHAHBS), 3.49 (1H, d, J ¼ 15.0 Hz, CHAHBS), 3.06 (1H, dd, J ¼ 14.1,
5.7 Hz, CHAHBCHN), 2.93 (1H, dd, J ¼ 14.1, 6.7 Hz, CHAHBCHN), 2.33
7.26. (S)-2-(3-Mercaptopropanamido)-3-phenylpropanoic acid
(15b)
Brown oil, 0.43 g (70%). IR nmax: 3318, 2973, 2565 (SH), 1712
(3H, s, CH3CO). 13C NMR (75 MHz, CDCl3):
d 195.4 (COS), 171.7 (CO2),
(CO2), 1656 (CON), 1089, 1047, 879 cmꢂ1
.
1H NMR (400 MHz,
168.0 (CON), 155.2 (Ar-C), 130.3 (Ar-C), 127.0 (Ar-C), 115.5 (Ar-C),
53.6 (CHN), 52.5 (OCH3), 36.9 (CH2CHN), 32.7 (CH2S), 30.2 (CH3CO).
CD3OD):
d
7.27e7.18 (5H, m, Ar-H), 4.68 (1H, dd, J ¼ 9.1, 5.1, CHNH),

326
O.K. Arjomandi et al. / European Journal of Medicinal Chemistry 114 (2016) 318e327
HRMS calculated for C14H17NNaO5S [MþNa]þ 334.0720, found
7.35. (S)-3-(4-Hydroxyphenyl)-2-(4-mercaptobutanamido)
propanoic acid (16c)
334.0728.
Brown viscous oil, 0.41 g, 60%. IR nmax: 3314, 2973, 2550 (SH),
7.31. (S)-3-(4-Hydroxyphenyl)-2-(2-mercaptoacetamido)
1700 (CO2), 1614 (CON), 1379, 1045 cmꢂ1 1H NMR (500 MHz,
.
propanoic acid (16a)
CD3OD):
d
7.03 (2H, d, J ¼ 8.5 Hz, Ar-H), 6.69 (2H, d, J ¼ 8.5 Hz, Ar-H),
4.64e4.58 (1H, m, CHNH), 3.11 (1H, dd, J ¼ 14.0, 4.9 Hz, CHAHBCHN),
2.82 (1H, dd, J ¼ 14.0, 9.6 Hz, CHAHBCHN), 2.51 (2H, t, J ¼ 6.9 Hz,
CH2CO), 2.30e2.22 (2H, m, CH2S), 1.87 (2H, quintet, J ¼ 7.2 Hz,
Pale yellow viscous oil, 0.40 g (65%). IR nmax: 3314, 2972, 2550
(SH), 1721 (CO2), 1653 (CON), 1513, 1186 cmꢂ1. 1H NMR (400 MHz,
CD3OD):
d
7.03 (2H, d, J ¼ 8.4 Hz, Ar-H), 6.69 (2H, d, J ¼ 8.4 Hz, Ar-H),
CH2CH2CH2). 13C NMR (125 MHz, CD3OD):
d 175.2 (CO2), 175.0
4.59 (1H, dd, J ¼ 8.1, 5.2 Hz, CHNH), 3.13 (2H, s, CH2S), 3.10 (1H, dd,
J ¼ 14.1, 5.2 Hz, CHAHBCHN), 2.91 (1H, dd, J ¼ 14.1, 8.3 Hz,
(CON), 157.3 (Ar-C), 131.2 (Ar-C), 129.1 (Ar-C), 116.2 (Ar-C), 55.2
(CHN), 37.6 (CH2CHN), 35.2 (CH2CO), 31.2 (CH2S), 26.2
(CH2CH2CH2). HRMS calculated for C13H16NO4S [MꢂH]ꢂ 282.0806,
found 282.0795.
CHAHBCHN). 13C NMR (100 MHz, CD3OD):
d 174.5 (CO2), 172.9
(CON), 157.4 (Ar-C), 131.4 (Ar-C), 128.7 (Ar-C), 116.2 (Ar-C), 55.4
(CHN), 37.5 (CH2CHN), 28.0 (CH2S). HRMS calculated for
C
11H12NO4S [MꢂH]ꢂ 254.0493, found 254.0492.
Acknowledgments
We are grateful to Dr Tri Le for NMR support and Mr Graham
MacFarlane for all the low and high resolution mass spectra. We
thank Jed Burns, Daniel Tan and Siti Hajar Mohd Pahmi for helpful
discussions and Daniel Feder for instruction regarding the docking
software. O.K.A. gratefully acknowledges the receipt of a PhD
scholarship from The University of Queensland. The authors would
like to acknowledge the National Health and Medical Research
Council (NHMRC) of Australia for funding (Project Grant
APP1084778). G.S. also thanks the Australian Research Council for
the award of a Future Fellowship (FT120100694).
7.32. (S)-Methyl 2-(3-(acetylthio)propanamido)-3-(4-
hydroxyphenyl)propanoate (12b)
Brown viscous oil, 1.35 g (92%). IR nmax: 3675, 3317, 2974, 1736
(CO2), 1680 (COS), 1652 (CON), 1514, 1221, 844 cmꢂ1 1H NMR
.
(500 MHz, CDCl3):
d
6.91 (2H, d, J ¼ 8.5 Hz, Ar-H), 6.70 (2H, d,
J ¼ 8.6 Hz, Ar-H), 6.22 (1H, d, J ¼ 8.0 Hz, NH), 4.83 (1H, dt, J ¼ 7.7,
6.1 Hz, CHNH), 3.71 (3H, s, OCH3), 3.07e3.02 (3H, m, CH2S and
CHAHBCHN), 2.95 (1H, dd, J ¼ 14.2, 6.1 Hz, CHAHBCHN), 2.51e2.42
(2H, m, CH2CO), 2.29 (3H, s, CH3CO). 13C NMR (125 MHz, CDCl3):
d
196.4 (COS), 172.1 (CON), 170.8 (CO2), 155.4 (Ar-C), 130.3 (Ar-C),
Appendix A. Supplementary data
126.9 (Ar-C), 115.5 (Ar-C), 53.3 (CHN), 52.4 (OCH3), 37.0 (CH2CHN),
36.0 (CH2S), 30.5 (CH2CO), 24.7 (CH3CO). HRMS calculated for
C
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2016.03.017.
15H19NNaO5S [MþNa]þ 348.0876, found 348.0873.
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