Discovery of 3-aryl substituted benzoxaboroles as broad-spectrum inhibitors of serine- and metallo-β-lactamases

Article abstract of DOI:10.1016/j.bmcl.2021.127956

The production of β-lactamases represents the main cause of resistance to clinically important β-lactam antibiotics. Boron containing compounds have been demonstrated as promising broad-spectrum β-lactamase inhibitors to combat β-lactam resistance. Here we report a series of 3-aryl substituted benzoxaborole derivatives, which manifested broad-spectrum inhibition to representative serine-β-lactamases (SBLs) and metallo-β-lactamases (MBLs). The most potent inhibitor 9f displayed an IC₅₀ value of 86 nM to KPC-2 SBL and micromolar inhibitory activity towards other tested enzymes. Cell-based assays further revealed that 9f was able to significantly reduce the MICs of meropenem in clinically isolated KPC-2-producing bacterial strains and it showed no apparent toxicity in HEK293T cells.

Full text of DOI:10.1016/j.bmcl.2021.127956

Bioorg. Med. Chem. Lett. 41 (2021) 127956
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of 3-aryl substituted benzoxaboroles as broad-spectrum
inhibitors of serine- and metallo-β-lactamases
Yu-Hang Yana, Zhao-Feng Lia, Xiang-Li Ninga, Ji Denga, Jun-Lin Yua, Yubin Luob,
,
,*
Zhenling Wangc, Guo Lia, Guo-Bo Lia *, You-Cai Xiaoa
a Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Department of Medicinal Chemistry, West China School of
Pharmacy, Sichuan University, Chengdu 610041, China
b Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China
c State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
The production of β-lactamases represents the main cause of resistance to clinically important β-lactam antibi-
otics. Boron containing compounds have been demonstrated as promising broad-spectrum β-lactamase inhibitors
to combat β-lactam resistance. Here we report a series of 3-aryl substituted benzoxaborole derivatives, which
manifested broad-spectrum inhibition to representative serine-β-lactamases (SBLs) and metallo-β-lactamases
(MBLs). The most potent inhibitor 9f displayed an IC50 value of 86 nM to KPC-2 SBL and micromolar inhibitory
activity towards other tested enzymes. Cell-based assays further revealed that 9f was able to significantly reduce
the MICs of meropenem in clinically isolated KPC-2-producing bacterial strains and it showed no apparent
toxicity in HEK293T cells.
Boron compounds
β-Lactamases
Antibiotic resistance
Introduction
there are currently no clinically available MBL inhibitors. Of particular
interest is to develop new agents with the ability to inhibit all β-lacta-
The β-lactams are the most widely used antibiotics in clinic for the
treatment of bacterial infections.1 However, the emergence and wide
spread of resistance in bacteria compromised their efficacy, posing a
great threat to public health.2,3 The most important β-lactam’s resis-
tance determinant in bacteria is the production of β-lactamases, which
hydrolyze the β-lactam ring to enable the β-lactams ineffective.4,5 The
β-lactamases can be classified into class A, B, C and D, according to their
sequence and structural diversity.6 Class A, C and D are nucleophilic
serine β-lactamases (SBLs), while class B are metallo β-lactamases
(MBLs) which utilize one or two zinc ions to catalyze the hydrolysis of
β-lactam antibiotics.7
mase producers, including MBLs.
Boron-containing compounds have been proved to have potential in
broadly inhibiting both SBLs and MBLs.13,14 Early work on boronic acid
derivatives has led to the introduction of the first cyclic boronate-based
SBL inhibitor, vaborbactam, which is approved by U.S. FDA for use in
co-administration with meropenem for the treatment of adult patients
with complicated urinary tract infections.15 In addition, several other
cyclic boronates, e.g. taniborbactam, RPX-7350, and QPX7728, (Fig. 1),
are now in clinical or preclinical pipeline as broad-spectrum inhibitors
for SBLs and MBLs.13,16 As another important class of boronic acid de-
rivatives, benzoxaboroles have been developed as anti-bacterial, anti-
viral, anti-fungal, anti-protozoal and anti-inflammatory agents with
interesting drug development perspectives;17 we recently tested the
FDA-approved anti-inflammatory drug crisaborole against SBLs, and
identified that crisaborole had broad-spectrum SBL inhibition, particu-
The combination of a β-lactam antibiotic with a β-lactamase inhibitor
has been demonstrated as a clinically effective strategy to counter
β-lactamase-mediated resistance.8,9 The β-lactam ring-containing mar-
keted inhibitors, clavulanic acid, sulbactam, and tazobactam, are mainly
active against class A SBLs.10 The clinical introduction of non-lactam-
based inhibitor avibactam and its derivative relebactam was an impor-
tant step because of their broad-spectrum inhibition against class A, C
and D SBLs.11,12 In contrast with the clinical success of SBL inhibitors,
larly with an IC50 value of 0.67 μM to clinically important K. pneumoniae
carbapenemase-2 (KPC-2) (Fig. S1). Based on the initial results and our
previous efforts on the development of β-lactamase inhibitor (BLI),18–20
we herein report the synthesis of a series of benzoxaboroles with various
* Corresponding authors.
E-mail addresses: liguobo@scu.edu.cn (G.-B. Li), xiaoliguo1987@scu.edu.cn (Y.-C. Xiao).
https://doi.org/10.1016/j.bmcl.2021.127956
Received 12 January 2021; Received in revised form 26 February 2021; Accepted 7 March 2021
Available online 17 March 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

Y.-H. Yan et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127956
Fig. 1. Representative boron-containing SBL and MBL inhibitors.
Scheme 1. Synthesis of compounds 3a–3b.ǂ ǂReaction conditions: (a) (i) ArMgBr, diethyl ether, 0 ◦C, overnight; (ii) NH4Cl (aq.); (b) Pd(PPh3)2Cl2, KOAc, DMSO,
B2Pin2, 90 ◦C, 8 h.
Scheme 2. Synthesis of compounds 7a–7i.ǂ ǂReaction conditions: (a) Pd(PPh3)2Cl2 KOAc, 1,4-dioxane, B2Pin2, 90 ◦C, 8 h; (b) (i) 1) NaIO4, THF/H2O, rt, 20 min; (ii)
HCl (aq.), 2 h; (c) THF, 6a–6g, 60 ◦C, 24 h.
aryl substituents at C-3 position (Fig. 1) and investigation of their
structure-activity relationship (SAR) with representative SBLs and
MBLs. These benzoxaboroles can potently inhibit all of the tested SBLs
and class B1/B2 MBLs, and the most potent compounds could restore
meropenem resistance in clinically isolated KPC-2-producing bacterial
strains, which provided a new starting point for the development of drug
candidates against antibacterial resistance.
bromobenzaldehyde 1a with Grignard reagent could afford the 2-bro-
mobenzyl alcohols 2a–2b, which were converted to the corresponding
3-aryl substituted benzoxaboroles 3a–3b via palladium-catalyzed
Miyaura borylation/cyclization cascade (Scheme 1).
On the other hand, 2-bromobenzaldehyde 1a–1c could also be used
for the synthesis of 3-indoxyl substituted benzoxaboroles 7a–7i. In the
first step, aryl boronates 4a–4c could be accessed through Palladium-
mediated borylation. After hydrolysis of the pinacol ester group to the
corresponding 2-formylbenzeneboronic acid derivatives 5a-–5c, final
products 7a–7i could be obtained by nucleophilic addition/cyclization
cascade using substituted indoles 6a–6g as nucleophile (Scheme 2).22
Following the same synthetic sequence, 3-aniline substituted benzox-
aboroles 9a–9j were obtained using N-substituted anilines 8a–8c as
nucleophile (Scheme 3).
Results and discussion
Synthesis of 3-aryl substituted benzoxaborole derivatives
The synthesis of compounds 3a–3b started from commercially
available substituted 2-bromobenzaldehyde 1a.21 The reaction of 2-
2

Y.-H. Yan et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127956
Scheme 3. Synthesis of compounds 9a–9j.ǂ ǂReaction conditions: (a) Pd(PPh3)2Cl2 KOAc, 1,4-dioxane, B2Pin2, 90 ◦C, 8 h; (b) (i) 1) NaIO4, THF/H2O, rt, 20 min; (ii)
HCl (aq.), 2 h; (c) THF, 8a–8c, 60 ◦C, 24 h.
Biochemical evaluation and SAR analyses
(i.e., compound 9a) at C-3 position, we observed a significant increase in
inhibitory activity (Table 1), particularly for KPC-2 (IC50 = 0.18 µM),
TEM-1 (IC50 = 0.73 µM), and NDM-1 (IC50 = 8.44 µM). Correspondingly,
9b (with methylaminophenyl) and 9c (with piperidinylphenyl) showed
comparable inhibitory activity to OXA-48, VIM-1 and Sfh-I, but slightly
lower activity to KPC-2, TEM-1, AmpC and NDM-1. These results sug-
gested that dimethylaminophenyl is a preferred fragment to extensively
accommodate with the active sites of all the tested enzymes. Thus,
several analogs (9d, 9f, 9g, 9h, 9i, and 9j) with C-3 dimethylamino-
phenyl were further synthesized and evaluated. Compared with 9a, 9d
with fluorine at C-4 position showed reduced activity against all the
tested enzymes except for Sfh-I, which is similar as that of the pair 7a/7h
(Table 1), suggesting that the fluorine substituent at C-4 position is not
favorable for the inhibition to the tested β-lactamases (except for Sfh-I).
Compound 9f with the chlorine substituent at C-5 position showed
better or comparable inhibitory potency compared with 9a. Especially,
9f had an IC50 value of 86 nM to the clinically important KPC-2.
Compared to 9a, 9g (a fluorine substituent at C-5) and 9h (a methoxy
substituent at C-5) exhibited slightly decreased inhibitory activity
against tested enzymes, with an exception of KPC-2. Compared with the
moderate inhibition of 9a and 9b on VIM-1, the weak inhibition of 9d–9j
on VIM-1 indicated that the substitution on the phenyl group of the
benzoxaborol core is unfavorable for binding with VIM-1. The intro-
duction of a chlorine atom at C-6 position (i.e., compound 9i) was
harmful for the inhibition of tested class A SBLs and B1 MBL but bene-
ficial to inhibit class C SBL and B2 MBL. As a marketed beta-lactamase
inhibitor, avibactam exhibited nanomolar to submicromolar inhibition
potency against tested SBLs and B2 Sfh-I, but showed weak inhibitory
activity against tested B1 MBLs. Compared to avibactam, the benzox-
aborole compounds had less potent inhibition to tested SBLs. Never-
theless, some compounds showed good inhibition towards both tested
SBLs and MBLs, e.g. 3b and 9f, indicating their potentiation for further
optimization as broad-spectrum MBL/SBL inhibitors.
To investigate the inhibitory activity of the synthesized 3-substituted
benzoxaborole derivatives to β-lactamases, we selected a panel of
representative MBLs and SBLs, including serine enzymes class A KPC-2
and penicillinase TEM-1, class C AmpC, class D Oxacillinase-48 (OXA-
48), and metalloenzymes class B1 New Delhi MBL-1 (NDM-1), B1 Ver-
ona integron-encoded MBL-1 (VIM-1) and class B2 Serratia fonticola
MBL (Sfh-I). The protein production/purification are well-documented
in our previous work20,23–25; all enzyme inhibition assays were carried
out using the reported fluorescent substrate FC-5.26 All the results are
summarized in Tables 1 and 2.
Compound 3a with phenyl substituent at C-3 position showed broad-
spectrum inhibition to all the tested β-lactamases at micromolar level.
(Table 1). Compound 3b, possessing a thiophene group substituent at C-
3 position, exhibited comparable or slightly better inhibitory potency
against SBLs and MBLs compared with 3a (Table 1).
Compounds 7a–7i, which bear 5-indole substituents at C-3 position,
were then evaluated against these SBLs and MBLs. Compound 7a dis-
played potent inhibition against KPC-2, AmpC, NDM-1, VIM-1 and Sfh-I
with IC50 values of low micromolar level, while it had much lower in-
hibition to TEM-1 and OXA-48. Similar tendency were observed for
compounds 7b–7e (with fluoro-, chloro-, or methyl group at the indole
substituent, please see Table 1); notably, 7b, 7c, and 7e manifested IC50
of 0.36 µM, 0.20 µM, and 0.22 µM to KPC-2, respectively. Comound 7b
showed less potent inhibition than 7b, 7c and 7e towards tested SBLs,
probably indicated the size and electronegativity of the substituent may
influent interaction with residues in the active site. Compounds 7f and
7g, with a large benzyl group at of 3-indole, had low inhibition against
tested SBL enzymes, probably due to its steric hindrance with the active
sites of these enzymes. Interestingly, 7g had substantial inhibitory ac-
tivity on the tested MBLs but 7f did not. This may be due to the steric
clash between the C-5 substitution on the indole ring of 7f and the
residues on the L10 loop of the MBL active site, while N-1 substituted
indole ring of 7g may enhance the interactions with the L3 loop. For
compounds 7h and 7i, which had fluorine at C-4 and C-6 position
respectively, we observed that 7h showed stronger inhibitory activity
than 7i against KPC-2, AmpC and tested MBLs.
In order to investigate how 9f binds with KPC-2 and NDM-1, we
carried out docking simulations to predict the possible binding mode of
9f with KPC-2 and NDM-1. Since the flexibility of Trp105 at L3 loop of
KPC-2 was observed in our previous crystallographic analyses,20 we
selected the two crystal structures (PDB codes 6J8Q and 6JN3) as the
docking templates. The best predicted binding mode is shown in Fig. 2A.
By replacement of the aromatic ring with the dimethylaminophenyl
3

Y.-H. Yan et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127956
Table 1
Inhibitory Activity of synthesized 3-substituted benzoxaborole derivatives against representative SBLs and MBLs.†
Cpd ID
Chemical Structure
SBLs IC50 values (µM)
MBLs IC50 values (µM)
Class B1 NDM-1
89.02
Class A KPC-2
1.00
Class A TEM-1
Class C AmpC
29.22
Class D OXA-48
8.67
Class B1 VIM-1
73.76
Class B2 Sfh-I
3.56
3a
4.46
3b
7a
0.41
2.58
6.97
18.74
3.66
5.45
22.41
6.04
17.39
15.15
2.47
8.50
>100
>100
7b
7c
7d
0.36
0.20
9.43
88.83
>100
>100
7.27
5.66
25.87
>100
>100
>100
>100
>100
23.97
62.47
NDǂ
6.58
18.58
14.93
13.13
7e
7f
0.22
>100
>100
8.52
>100
>100
68.00
16.25
19.44
>100
>100
>100
>100
>100
7g
7h
>100
>100
>100
>100
>100
>100
15.87
25.40
10.64
89.68
9.60
2.17
6.56
10.75
7i
>100
>100
>100
>100
>100
>100
>100
9a
0.18
0.73
8.27
2.41
8.44
39.36
2.52
9b
9c
0.10
0.51
3.20
13.88
32.22
2.37
3.44
57.39
11.69
26.45
18.44
3.02
5.27
32.96
9d
1.91
20.73
15.09
7.48
25.59
>100
1.83
9e
9f
2.41
37.87
1.54
15.27
22.69
6.49
2.34
51.38
9.05
>100
>100
1.15
3.81
0.086
(continued on next page)
4

Y.-H. Yan et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127956
Table 1 (continued)
Cpd ID
Chemical Structure
SBLs IC50 values (µM)
MBLs IC50 values (µM)
Class A KPC-2
0.35
Class A TEM-1
Class C AmpC
39.29
Class D OXA-48
3.58
Class B1 NDM-1
11.20
Class B1 VIM-1
Class B2 Sfh-I
3.64
9g
5.68
1.54
4.34
>100
9h
9i
0.18
0.81
11.39
3.60
2.93
1.96
38.39
61.73
>100
>100
4.23
0.47
9j
0.76
1.15
5.23
6.40
0.17
16.58
51.03
2.77
Aviǂ
0.0037
0.0019
0.024
>100
>100
0.025
Avi: avibactam.
†
ǂ
All the IC50 curves (errors among triplet tests) are shown in Supporting Information Fig. S2.
ND: not determined.
susceptibility testing according to the CLSI guideline. We observed that
3b and 9f at 100 µM could significantly potentiated the activity of
meropenem against the two KPC-2 producing Escherichia coli strains, i.e.,
reducing the MIC of meropenem by 32-fold to 8-fold. Even, 3b and 9f at
10 µM could restore meropenem activity to combat KPC-2 producing
Escherichia coli BAA-2340 (Table 2). Unfortunately, 3b and 9f were
unable to potentiate meropenem activity in AmpC/TEM-1 producing
K. pneumoniae (Table 2). The variable susceptibility on different bacte-
rial strains may reflects the possible effect of other resistance mecha-
nisms, e.g. active efflux pumps.
Table 2
MICs of meropenem against bacterial strains expressing KPC-2, AmpC, and TEM-
1 in the presence of 3b and 9f.ǂ
Bacterial
strain
Characterized
MEM
(µg/
ml)
MEM
+
MEM
+ 10
MEM
+
MEM
+ 10
µM 9f
β-lactamase
100
µM 3b
100
µM 9f
µM 3b
ATCC 25922
K. pneumonia
C692
–
0.06
–
–
–
–
AmpC, TEM-1
>128
>128
>128
>128
>128
In addition, the cytotoxicity of these two compounds was also eval-
uated using human HEK293T cells. Compound 3b and 9f showed no
apparent cytotoxicity to HEK293T cells at 100 µM and 10 µM (Fig. S3),
suggesting this series of compounds are a good starting point for further
structural optimization to develop more potent inhibitors to multiple
clinically relevant SBLs and MBLs.
Escherichia
coli BAA-
2340
KPC-2
16
0.5
2
0.5
2
Escherichia
KPC-2
64
2
32
8
32
coli 11119
ǂ
MEM: meropenem.
We observed that similar to previous reports,7,27,28 9f is likely to form a
covalent bond with the catalytically important Ser70 of KPC-2, and make
hydrogen bonds with Asn170 and Glu166. The benzoxaborole likely binds
near to Leu167 and Asn170, and the chlorine is likely positioned to make
Trp105 away from Leu167 (Fig. 2A). This binding mode may explain why
substituents at C-6 position (e.g., 7i and 9i) or big substituents on C-3
indole (e.g., 7g) lead to decreased inhibitory activity to KPC-2. For NDM-
1, we observed that the sp3 hybridized benzoxaborole of 9f is likely to
interact with zinc ions and form hydrogen bonding with Asn220
(Fig. 2B).
Conclusions
In summary, a series of 3-aryl substituted benzoxaborole derivatives
were synthesized and evaluated against a panel of representative SBLs
and MBLs. Most compounds have moderate to good inhibitory activity
against all the tested enzymes, and some of them had nanomolar inhi-
bition to clinically important KPC-2. The structurally distinct com-
pounds 3b and 9f significantly reduced the MICs of meropenem against
KPC-2 expressing clinical isolates and showed no apparent cytotoxicity
to HEK293T cells at 100 µM. This study provided new chemotypes for
developing broad-spectrum β-lactamase inhibitors, and suggested great
potential of benzoxaboroles in inhibiting both MBLs and SBLs.
Cell-based activity of 3b and 9f
Considering structural diversity and inhibitory activity, we chose
compound 3b and 9f for further investigation of their activity in cells.
Three SBL-producing clinical isolates, including K. pneumoniae C692
(with AmpC and TEM-1), Escherichia coli BAA-2340 (with KPC-2), and
Escherichia coli 11119 (with KPC-2), were selected for antimicrobial
Declaration of Competing Interest
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.
5

Y.-H. Yan et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127956
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