Discovery of mercaptopropanamide-substituted aryl tetrazoles as new broad-spectrum metallo-β-lactamase inhibitors

Article abstract of DOI:10.1039/d0ra06405j

β-Lactam antibiotic resistance mediated by metallo-β-lactamases (MBL) has threatened global public health. There are currently no available inhibitors of MBLs for clinical use. We previously reported the ruthenium-catalyzed meta-selective C-H nitration synthesis method, leading to some meta-mercaptopropanamide substituted aryl tetrazoles as new potent MBL inhibitors. Here, we described the structure-activity relationship of meta- and ortho-mercaptopropanamide substituted aryl tetrazoles with clinically relevant MBLs. The resulting most potent compound 13a showed IC50 values of 0.044 μM, 0.396 μM and 0.71 μM against VIM-2, NDM-1 and IMP-1 MBL, respectively. Crystallographic analysis revealed that 13a chelated to active site zinc ions via the thiol group and interacted with the catalytically important residues Asn233 and Tyr67, providing further structural information for the development of thiol based MBL inhibitors. This journal is

Full text of DOI:10.1039/d0ra06405j

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Discovery of mercaptopropanamide-substituted
aryl tetrazoles as new broad-spectrum metallo-b-
lactamase inhibitors†
Cite this: RSC Adv., 2020, 10, 31377
Yu-Hang Yan, Jian Chen, Zhen Zhan, Zhu-Jun Yu, Gen Li, Li Guo, Guo-Bo Li,
*
Yong Wu
and Yongxiang Zheng
b-Lactam antibiotic resistance mediated by metallo-b-lactamases (MBL) has threatened global public
health. There are currently no available inhibitors of MBLs for clinical use. We previously reported the
ruthenium-catalyzed meta-selective C–H nitration synthesis method, leading to some meta-
mercaptopropanamide substituted aryl tetrazoles as new potent MBL inhibitors. Here, we described the
structure–activity relationship of meta- and ortho-mercaptopropanamide substituted aryl tetrazoles with
clinically relevant MBLs. The resulting most potent compound 13a showed IC50 values of 0.044 mM,
0.396 mM and 0.71 mM against VIM-2, NDM-1 and IMP-1 MBL, respectively. Crystallographic analysis
revealed that 13a chelated to active site zinc ions via the thiol group and interacted with the catalytically
important residues Asn233 and Tyr67, providing further structural information for the development of
thiol based MBL inhibitors.
Received 23rd July 2020
Accepted 14th August 2020
DOI: 10.1039/d0ra06405j
rsc.li/rsc-advances
Subclass B1 MBLs contain the most clinically signicant types,
such as the New Delhi MBL (NDMs), imipenemase (IMPs), and
Introduction
Verona integron-encoded MBL (VIMs), representing the major
targets for developing inhibitors with therapeutic value.13 So far,
various types of MBL inhibitors have been reported, such as
thiol-containing compounds, cyclic boronates, succinic acids,
carboxylates and others.14–20 Most MBL inhibitors work via
active-site metal chelation manner, and more importantly, the
broad-spectrum MBL inhibitors have metal chelation and
anchor residue binding features.14 Despite progress has been
made, there is still a need to develop new broad-spectrum MBL
inhibitors to provide candidates for the development of clini-
cally useful MBL inhibitors.
In our previous study, we described a new synthesis
method, namely ruthenium-catalyzed meta-selective C–H
nitration, which led to new potent MBL inhibitors; these
inhibitors contain an aryl tetrazole fragment and a mercapto-
propanamide moiety as the metal binding pharmacophore.21
This work presents structure–activity relationship (SAR)
studies of mercaptopropanamide substituted aryl tetrazoles
with clinically relevant MBLs and crystallographic analyses of
the mechanism-of-inhibition of this chemotype inhibitors. We
synthesized a series of ortho- and meta-mercaptopropanamide
substituted aryl tetrazole derivatives through C–H activation
methods, and tested for their inhibitory activity against three
MBL enzymes, including VIM-2, NDM-1 and IMP-1. Among all
the synthesized target compounds, meta-mercapto-2-
methylpropanamide substituted aryl tetrazole 13a had the
strongest inhibitory activity against clinically relevant VIM-2,
NDM-1 and IMP-1 with IC50 values of 0.044 mM, 0.396 mM
b-Lactam antibiotics remain the most important class of anti-
biotics due to their safety, high efficacy and broad-spectrum
antibacterial activity.1 The emergence and rapid worldwide
distribution of b-lactam-resistant bacteria pathogens poses an
increasing clinical threat to human health and life.2–4 b-Lactam
hydrolysis mediated by b-lactamase is a major contributor to
the resistance in bacteria.5,6 Based on different catalytic mech-
anisms, b-lactamases are categorized into two groups: serine b-
lactamases (SBLs) and metallo-b-lactamases (MBLs).5 SBLs
employ an active-site nucleophilic serine to hydrolyze the b-
lactam ring, while MBLs utilize a Zn(II)-bound hydroxyl group to
achieve nucleophilic attack on the b-lactam carbonyl, ultimately
leading to the cleavage of the b-lactam ring.7,8 Several SBL
inhibitors, such as clavulanic acid, tazobactam, sulbactam,
avibactam, and vaborbactam, have been successfully applied in
combination with beta-lactam antibiotics to treat infections
caused by SBL-producing bacteria in clinics.9,10 However, there
are no FDA-approved MBL inhibitors.11,12
On the basis of sequence and structural similarities, MBL
enzymes can be divided into three subclasses (B1, B2, B3).7
Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education,
Sichuan Engineering Laboratory for Plant-Sourced Drug, Sichuan Research Center for
Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan
University, Sichuan 610041, China. E-mail: yongxiangzheng@scu.edu.cn; Tel: +86
199 3880 2868
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra06405j
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and 0.71 mM, respectively. Crystallographic analyses showed hydroxide to produce 2-(2H-tetrazol-5-yl)anilines (5a–5h).21
that 13a chelated to both active site zinc ions via thiol group Subsequently, Compounds 5a–5h were treated with different
and interacted with catalytically important residues on the L1 carboxylic acids, giving the thioesters (6a–6i) in high yields.
and L3 loop.
Finally, the desired compounds 7a–7i were furnished through
the hydrolysis reactions of 6a–6i in the presence of NH3$H2O
under argon atmosphere. Compound 5a was subjected to the
condensation reaction by isobutyryl chloride to give the desired
compound 8.
Results and discussion
Chemistry
Scheme 2 shows the synthetic route for target compounds
12a, 13a–13k and 14. Compounds 9a–9j were reacted with
Cu(NO3)2$3H2O to afford the meta-nitrated products 10a–10j via
the C–H activation strategy, followed by the reduction reactions
to give the compounds 11a–11j.24 Then, the thioesters 12a–12k
were readily synthesized by the condensation reactions of 11a–
11j with different carboxylic acids. Subsequently, the hydrolysis
reactions of 12a–12k produced the target compounds 13a–13k.
Compound 14 was obtained by the condensation reaction of
compound 9a and isobutyryl chloride.
Schemes 1 and 2 show the synthetic routes and total yields of all
target compounds. Compounds 6a, 7a–7i and 8 were synthe-
sized using the reaction sequence shown in Scheme 1.
Compound 2 was obtained by using benzonitrile to reacꢀt with
NaN3 in the presence of ZnBr2 and H2O stirring at 100 C for
24 h.22 Compounds 3a–3h were synthesized by the reactions of
compound 2 and different iodoalkanes.23 Then, compounds 3a–
3h were reacted with 3-phenyloxazolidinone to afford the cor-
responding amides 4a–4h via the C–H activation strategy as
described previously, followed by reacting with sodium
Scheme 1 Preparation of target compounds 7a–7i, 6a and 8. Reagents and conditions: (a) NaN3, ZnBr2, H2O, reflux, 24 h; (b) K2CO3, rt, 5 min; R–
I, 85 ꢀC, 4 h; (c) [Cp*RhCl2]2, Ag2SO4, DCE, 80 ꢀC, 24 h; (d) NaOH, EtOH, reflux, 1 h; (e) IBCF, NMM, dry DCM, rt, 24 h; (f) NH3$H2O, Ar, rt, 2 h. The
overall yield for each target compound is shown in brackets behind the compound number.
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Scheme 2 Preparation of target compounds 13a–13k and 14. Reagents and conditions: (a) Ru3(CO)12, PPh3, PhI(TFA)2, HFIP, 100 ꢀC, 24 h; (b) H2,
10% Pd/C, MeOH; (c) IBCF, NMM, dry DCM, rt, 24 h; (d) NH3$H2O, Ar, rt, 2 h.
that of 7a, which was reduced by about 5 times. Two examples
showed that the thiol group was important for interacting with
the active site: (1) the product 6a with acetylation modication
on the thiol group exhibited signicantly reduced inhibitory
activity; (2) no inhibition against tested MBL enzymes was
observed for 8 without the thiol group.
Then, we investigated the activity of compounds with mer-
captopropionamide substitutions on the meta position of the
phenyl ring (Table 2, Fig. S1†). Among all the synthesized
mercaptopropanamide derivatives, 13a manifested the most
potent inhibition, displaying IC50 values of 0.044 mM, 0.396 mM
and 0.71 mM against VIM-2, NDM-1 and IMP-1, respectively.
Introduction of alkane chain on the 2-N of tetrazole resulted in
13b–13d. Compared to 13a, 13b–13d exhibited compared inhi-
bition on VIM-2 and decreased inhibition on NDM-1 and IMP-1.
Mercaptopropionamide substituted compound 13e showed
IC50 values of 0.021 mM, 6.10 mM and 0.44 mM against VIM-2,
NDM-1 and IMP-1, respectively, indicating that the methyl
SAR of mercaptopropanamide substituted aryl tetrazole
derivatives with MBLs
We evaluated the inhibitory activity of all the targeted
compounds against clinically important VIM-2, NDM-1 and
IMP-1 by using a uorescence-based assay (Fig. S1†).25 As shown
in Table 1, 7a–7g contain mercapto-2-methylpropanamide
substituents on the ortho position of the phenyl ring. 7a dis-
played potent inhibition on VIM-2 with IC50 value of 0.035 mM
and moderate inhibition on NDM-1 and IMP-1. Addition of alkyl
or benzyl substituents to the N-2 of tetrazole of 7a slightly
decreased the inhibitory activity of VIM-2, but increased the
inhibitory activity on NDM-1 and IMP-1, except for 7b with
methyl substitution on the tetrazole, which showed less potent
inhibition against all the tested enzymes, especially for NDM-1.
The ortho-mercaptopropionamide-substituted derivatives 7h
and 7i showed comparable inhibition with 7a. Comparison of
7a, 7h, and 7i indicated that the effect of methyl substitution on
the tetrazole of 7h on the activity of NDM-1 was not as great as
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Table 1 Inhibitory activities of ortho-mercaptopropanamide substituted aryl tetrazole derivatives against representative MBL enzymes
IC50 value (mM)/pIC50/s.e. pIC50
Cpds
Chemical structure
VIM-2
NDM-1
IMP-1
7a
0.035/7.45/0.039
10.75/4.97/0.046
9.87/5.01/0.118
7b
7c
1.82/5.74/0.050
0.06/7.22/0.050
>100/—/—
12.26/4.90/0.127
0.13/6.89/0.107
1.84/5.74/0.048
7d
7e
7f
0.49/6.37/0.024
0.16/6.81/0.062
1.70/5.77/0.039
0.16/6.81/0.047
0.83/6.08/0.138
2.0/5.69/0.056
2.59/5.59/0.076
1.46/5.84/0.036
0.88/6.056/0.057
1.49/5.83/0.084
1.34/5.87/0.099
1.36/5.87/0.043
7g
7h
7i
0.028/7.55/0.044
0.026/7.59/0.033
3.16/5.50/0.041
19.52/4.70/0.094
10.17/4.99/0.076
4.68/5.33/0.166
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Table 1 (Contd.)
IC50 value (mM)/pIC50/s.e. pIC50
Cpds
Chemical structure
VIM-2
NDM-1
IMP-1
6a
0.63/6.20/0.049
30.16/4.52/0.077
30.41/4.52/0.088
8
>100/—/—
>100/—/—
>100/—/—
substitution on the a-C of the carbonyl group had a great charged group to interact with the positively charged residue
inuence on the activity of NDM-1. For the methyl substituted Arg228, it manifested potent MBL inhibition via specic
on N-1 or N-2 of 13e derivatives 13f and 13g, no signicant binding with the exible L1 loop, which provide new insights
impact of the substitution position on NDM-1 and IMP-1 inhi- into inhibitor design of MBL inhibitors.
bition was found, but methyl substitution on N-1 was unfavor-
able for VIM-2 activity. In addition, the shortening of the alkyl
chain was also adverse to the inhibition on VIM-2, as exempli-
Conclusions
In conclusion, a series of mercaptopropionamide-substituted
aryl tetrazole derivatives were synthesized via the C–H activa-
tion strategy, which will provide new strategies to readily derive
new meta- and ortho- substituted aryl tetrazoles or other related
derivatives. The SAR studies of these synthesized derivatives
with three representative MBL enzymes led to the identication
of 13a as a potent, broad-spectrum MBL inhibitor with IC50
values of 0.044 mM, 0.396 mM and 0.71 mM against VIM-2, NDM-
1 and IMP-1, respectively. The crystal structure of VIM-2 in
complex with 13a revealed that 13a was positioned to bridge the
active site zinc ions via the thiol group and interacted with
catalytically important residues on the L1 and L3 loop. Notably,
13a was observed to t well with the exible L1 loop, providing
new insights for further development of potent MBL inhibitors
of clinical relevance.
ed by 13h. Furthermore, we also explored the effect of different
heterocycles-replacing biphenyltetrazole (13i–13k) on MBL
inhibitory activity. Obviously, substitution of aromatic ring had
the greatest effect on NDM-1 and IMP-1 inhibition, which led to
at least 3-fold drop in activity. The activity of 13i–13k on VIM-2
was comparable to or slightly weaker than that of 13a. Similar to
what was observed before, 14 without thiol group had very low
inhibitory activity on tested MBLs.
Moreover, we assessed the effect of the most potent inhibitor
13a on a cellular level through minimum inhibitory concen-
trations (MIC) assay (Table S2†). The results indicated that 13a
potentiated the efficacy of meropenem at 100 mM against
laboratory-constructed VIM-2 expressing E. coli strain with MIC
value of 4 mg mLÀ1
.
Crystallographic analysis
Experimental
Protein expression and purication
In order to investigate the binding mode of the most potent
compound 13a, we obtained the X-ray structure of VIM-2 in
complex with 13a by co-crystal experiments. The VIM-2: 13a
VIM-2 (27–266 aa), NDM-1 (1–270 aa) and IMP-1 (19–246 aa)
were expressed and puried as previously published
procedures.15
ꢀ
(PDB ID 7CJL) complex structure was solved to 1.79 A resolution
(Table S1†). The VIM-2:13a complex crystallized in a P 212121
space group with two molecules in the asymmetric unit (ASU)
and was rened to Rwork/Rfree value of 20.53/24.64% (Table S1†).
Inhibition assays
The crystal structure revealed that 13a was positioned to bridge The experiments were carried out by using Tecan microplate
two active site zinc ions replacing the nucleophilic water the reader and at-bottom 96-well black plates at room tempera-
thiol group, which was common for the binding of thiol- ture. Compounds were dissolved into 100 mM with DMSO. All
containing MBL inhibitors with VIM-2 (Fig. 1).15,17,19 And the the MBL enzymes were dissolved in the assay buffer: 20 mM
carbonyl group makes hydrogen-bonding interactions with Tris–HCl (pH 7.5), 200 mM NaCl. The compounds (with 10
catalytically important residue Asn233 on the L3 loop. In addi- different concentrations in 3-fold dilution) pe-incubated with
tion, the phenyl group forms face-to-face p–p interactions with appropriate amount of MBL enzymes for 10 min. The reactions
Tyr67 on the L1 loop. Although 13a did not have negatively were initiated by adding of the substrate FC5. The IC50 values
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Table 2 Inhibitory activities of meta-mercaptopropanamide substituted benzoheterocycle derivatives against representative MBL enzymes
IC50 value (mM)/pIC50/s.e. pIC50
Cpds
Chemical structure
VIM-2
NDM-1
IMP-1
13a
0.044/7.35/0.022
0.396/6.40/0.036
0.71/6.15/0.089
13b
13c
0.082/7.08/0.026
0.018/7.74/0.039
3.02/5.52/0.032
2.37/5.63/0.040
6.23/5.21/0.153
1.23/5.91/0.050
13d
0.025/7.60/0.066
2.65/5.58/0.030
4.97/5.30/0.384
13e
13f
0.021/7.67/0.038
0.48/6.32/0.056
6.10/5.21/0.028
3.23/5.49/0.023
0.44/6.30/0.192
1.54/5.81/0.106
13g
13h
0.079/7.10/0.040
1.38/5.86/0.091
4.19/5.38/0.065
3.22/5.49/0.024
1.18/5.93/0.067
0.94/6.03/0.053
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Table 2 (Contd.)
IC50 value (mM)/pIC50/s.e. pIC50
Cpds
Chemical structure
VIM-2
NDM-1
IMP-1
13i
0.11/6.97/0.036
0.025/7.60/0.034
2.10/5.68/0.048
3.70/5.43/0.062
13j
1.27/5.90/0.058
1.27/5.90/0.067
4.19/5.38/0.399
1.56/5.81/0.199
13k
0.056/7.25/0.041
14
>100/—/—
>100/—/—
>100/—/—
for the compounds were determined by monitoring the uo-
rescence at lex of 380 nm and lem of 460 nm. All determinations
were tested in triplicate. The IC50 values were tted by using
GraphPad Prism5 soware.
Microdilution broth minimum inhibitory concentrations
(MICs) assay
Strains of E. coli DH5a containing plasmids pET28-lacUV5-VIM-
2 (E. coli-VIM-2) and pET28-lacUV5 (as control) were used to
assess the inhibitors.17 Single colonies of the E. coli-VIM-2 strain
on MH agar plates were transferred to 5 mL of MH liquid
medium, and grown at 37 ꢀC to an OD630 of ꢁ0.5. The
concentrations of E. coli-VIM-2 and E. coli strains were diluted to
ꢁ106 colony forming units (CFU) per mL in the MH medium,
then transferred to the microtiter plates, and treated with
meropenem (nal concentrations of 128 mg mLÀ1 to 0.25 mg
mLÀ1 in 2-fold dilution) or/and the inhibitors 13a (nal
concentrations of 25–200 mM, 2-fold concentration gradient).
ꢀ
The microtiter plates were incubated for 16–20 h at 37 C and
visually evaluated for bacterial growth. Each determinate was
performed in duplicate.
Crystallization and data collection
Fig. 1 Crystallographic analyses reveal the binding modes of 13a to
VIM-2. The active-site zinc ions are shown as pink spheres. The key
residues and 13a are shown as sticks. View from crystal structures of
VIM-2 in complex with 13a (PDB ID 7CJL) reveal that the inhibitor binds
to chelate with active site zinc ions and form interactions with residues
on the L1 and L3 loops.
X-ray structure of VIM-2 in complex with inhibitors 13a was
obtained as previously described. Briey, the mixture of 10 mg
mLÀ1 VIM-2 protein and 5 mM inhibitor was incubated in
crystallization buffer (20 mM Tris–HCl, pH 7.5, 200 mM NaCl,
0.5 mM tris(2-carboxyethyl)phosphine (TCEP)) for 60 min at
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4
ꢀC. The crystallization drops constituted of a 1 : 1 ratio of
protein-inhibitor mixture : reservoir solutions (25–32% PEG
9 D. Y. Wang, M. I. Abboud, M. S. Markoulides, J. Brem and
C. J. Schoeld, Future Med. Chem., 2016, 8, 1063–1084.
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(Otinowski and Minor, 1997). The molecular replacement and 12 A. Krajnc, J. Brem, P. Hinchliffe, K. Calvopina,
renement were carried out by using Phenix and Wincoot.15
T. D. Panduwawala, P. A. Lang, J. Kamps, J. M. Tyrrell,
E. Widlake, B. G. Saward, T. R. Walsh, J. Spencer and
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13 R. R. Watkins and R. A. Bonomo, Expert Rev. Anti-Infect.
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Conflicts of interest
There are no conicts to declare.
14 Y. H. Yan, G. Li and G. B. Li, Med. Res. Rev., 2020, 40(5), 1558–
1592.
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The authors thank the nancial support from the National
Natural Science Foundation (81874291), Sichuan Science and
Technology Program (2018HH0100), and Outstanding Inter-
discipline Project of West China Hospital of Sichuan University
(grant no: ZYJC18024).
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