Diaryl-Substituted Azolylthioacetamides: Inhibitor Discovery of New Delhi Metallo-β-Lactamase-1 (NDM-1)

Article abstract of DOI:10.1002/cmdc.201402249

The emergence and spread of antibiotic-resistant pathogens is a global public health problem. Metallo-β-lactamases (MβLs) such as New Delhi MβL-1 (NDM-1) are principle contributors to the emergence of resistance because of their ability to hydrolyze almost all known β-lactam antibiotics including penicillins, cephalosporins, and carbapenems. A clinical inhibitor of MBLs has not yet been found. In this study we developed eighteen new diaryl-substituted azolylthioacetamides and found all of them to be inhibitors of the MβL L1 from Stenotrophomonas maltophilia (K_i<2M), thirteen to be mixed inhibitors of NDM-1 (K_i<7M), and four to be broad-spectrum inhibitors of all four tested MβLs CcrA from Bacteroides fragilis, NDM-1 and ImiS from Aeromonas veronii, and L1 (K_i<52M), which are representative of the B1a, B1b, B2, and B3 subclasses, respectively. Docking studies revealed that the azolylthioacetamides, which have the broadest inhibitory activity, coordinate to the Zn^II ion(s) preferentially via the triazole moiety, while other moieties interact mostly with the conserved active site residues Lys224 (CcrA, NDM-1, and ImiS) or Ser221 (L1).

Full text of DOI:10.1002/cmdc.201402249

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DOI: 10.1002/cmdc.201402249
Diaryl-Substituted Azolylthioacetamides: Inhibitor
Discovery of New Delhi Metallo-b-Lactamase-1 (NDM-1)
Yi-Lin Zhang,[a] Ke-Wu Yang,*[a] Ya-Jun Zhou,[a] Alecander E. LaCuran,[b] Peter Oelschlaeger,[b]
and Michael W. Crowder[c]
The emergence and spread of antibiotic-resistant pathogens is
a global public health problem. Metallo-b-lactamases (MbLs)
such as New Delhi MbL-1 (NDM-1) are principle contributors to
the emergence of resistance because of their ability to hydro-
lyze almost all known b-lactam antibiotics including penicillins,
cephalosporins, and carbapenems. A clinical inhibitor of MBLs
has not yet been found. In this study we developed eighteen
new diaryl-substituted azolylthioacetamides and found all of
them to be inhibitors of the MbL L1 from Stenotrophomonas
maltophilia (Ki <2 mm), thirteen to be mixed inhibitors of NDM-
1 (Ki <7 mm), and four to be broad-spectrum inhibitors of all
four tested MbLs CcrA from Bacteroides fragilis, NDM-1 and
ImiS from Aeromonas veronii, and L1 (Ki <52 mm), which are
representative of the B1a, B1b, B2, and B3 subclasses, respec-
tively. Docking studies revealed that the azolylthioacetamides,
which have the broadest inhibitory activity, coordinate to the
ZnII ion(s) preferentially via the triazole moiety, while other
moieties interact mostly with the conserved active site residues
Lys224 (CcrA, NDM-1, and ImiS) or Ser221 (L1).
suggested owing to significant sequence diversity.[6] The emer-
gence of NDM-1 heralds a new era of antibiotic resistance be-
cause of this enzyme’s ability to hydrolyze almost all known b-
lactam-containing antibiotics and the rapid spread of the plas-
mid-encoded NDM-1 gene.[7] Bacteria harboring the NDM-
1 gene are not susceptible to any common antibiotics, except
colistin and tigecycline, because they contain multiple antibiot-
ic resistance genes.[8] Both B1- and B3-subclass enzymes con-
tain two ZnII ions and have broad-spectrum substrate profiles
that include penicillins, cephalosporins, and carbapenems. Sub-
class-B1 enzymes have been found in strains of Bacillus, Bacter-
oides, Pseudomonas, Serratia, and Chryseobacterium, and sub-
class-B3 enzymes in strains of Stenotrophomonas, Legionella,
Fluoribacter, Janthinobacterium, and Caulobacter.[9,10] In con-
trast, the B2-subclass enzymes contain only one ZnII ion and
primarily hydrolyze carbapenems, which have been called one
of the “last resort” antibiotics.[11] The co-administration of b-
lactam antibiotics with b-lactamase inhibitors has proven to be
an effective strategy for combating antibiotic-resistant bacterial
infections,[12] but b-lactamase inhibitors such as clavulanate,
sulbactam, and tazobactam do not inhibit MbLs, and there are
no clinically useful inhibitors of MbLs yet available.[13] Conse-
quently, there is a pressing need for broad-spectrum MbL in-
hibitors.
Antibiotic resistance is an emerging worldwide epidemic,[1] and
b-lactamases are the most significant threat to the continued
use of b-lactam antibiotics.[2] There have been more than 1000
distinct b-lactamases identified, and these enzymes have been
categorized into classes A–D, based on their primary sequence
homologies.[3] Class A, C, and D enzymes are collectively called
serine b-lactamases, which use an active site serine as a nucleo-
phile. Class B enzymes are called metallo-b-lactamases (MbLs),
and these enzymes use either one or two equivalents of ZnII to
catalyze b-lactam hydrolysis.[4] MbLs have been further divided
into subclasses B1–B3, based on primary sequence homologies
and ZnII content,[3–5] and separation of the B1 subclass into B1a
(all B1 enzymes but NDM-1) and B1b (NDM-1) was recently
Given the enormous biomedical importance of MbLs, there
has been a large amount of effort in identifying novel inhibi-
tors of these enzymes.[12,14] The succinic acid derivatives,[15a] d-
captopril,[15b] thiomandelic acid,[15c] picolinic acid,[15d] hydroxa-
mic acid derivatives,[15b] propionic acid,[15e] penicillin-based in-
hibitors,[15f] N-arylsulfonyl hydrazones,[15b] and pyrrole-based in-
hibitors have recently been reported.[15g] However, most of
these reports involved studies on one or two of the MbLs, and
to the best of our knowledge, only three classes of sulfur com-
pounds—thiols,[15b,c] thiophosphonates,[15h] and analogues of
penams[2]—have been reported to be broad-spectrum inhibi-
tors of the MbLs. Our research group has been engaged in the
synthesis and development of MbL inhibitors. We recently de-
veloped thioazoles which show inhibitory activity against MbLs
with Ki values in the micromolar range.[16] Based on this infor-
mation we decided to develop new diaryl-substituted azolylth-
ioacetamides by conjugation of the thioazoles with arylaceta-
mide in an attempt to find broad-spectrum inhibitors of MbLs.
Eventually, these compounds could be used in drug/inhibitor
combinations to combat bacterial infections.
[a] Y.-L. Zhang, Prof. K.-W. Yang, Y.-J. Zhou
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of
Ministry of Education, College of Chemistry and Materials Science
Northwest University, 229 North Taibai Road, Xi’an 7100679 (P.R. China)
E-mail: kwyang@nwu.edu.cn
[b] A. E. LaCuran, Prof. P. Oelschlaeger
Department of Pharmaceutical Sciences, College of Pharmacy
Western University of Health Sciences
309 East Second Street, Pomona, CA 91766 (USA)
[c] Prof. M. W. Crowder
Department of Chemistry and Biochemistry, Miami University
160 Hughes Laboratories, Oxford, OH 45056 (USA)
Toward this goal, 18 diaryl-substituted azolylthioacetamides
were synthesized as shown in Supporting Information
Scheme S1 and characterized by NMR and MS. The structures
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201402249.
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Table 1. Inhibition constants of metallo-b-lactamases by diaryl-substitut-
ed azolylthioacetamides.
Compd
Ki [mm]
B2, ImiS[b]
B1a, CcrA[a]
B1b, NDM-1[a]
B3, L1[a]
1
2
3
4
5
6
7
8
6.3Æ0.1
0.35Æ0.01
6.1Æ0.2
0.81Æ0.07
0.43Æ0.03
0.60Æ0.07
0.64Æ0.03
5.6Æ0.1
45Æ6
>300
0.25Æ0.03
0.65Æ0.09
1.8Æ0.1
7Æ1
15Æ2[c]
–
–
0.30Æ0.09
2.2Æ0.2
3.3Æ0.2[d]
0.073Æ0.007
0.34Æ0.02
0.51Æ0.03
52Æ5
–
>300
8.5Æ0.2
0.75Æ0.02 0.34Æ0.05
1.10Æ0.03 0.82Æ0.08
–
–
–
–
–
–
–
–
–
–
–
9
6.8Æ0.4
0.42Æ0.02
0.23Æ0.01
1.2Æ0.1
5.3Æ0.3
–
>300
1.3Æ0.4
>300
0.33Æ0.02
0.25Æ0.04
0.43Æ0.09
0.38Æ0.02
0.86Æ0.09
1.0Æ0.1
10
11
12
13
14
15
16
17
18
–
>300
>300
–
–
Figure 1. Structures of the synthesized diaryl-substituted azolylthioaceta-
mides as potential broad-spectrum inhibitors of metallo-b-lactamases.
–
1.4Æ0.4
4.3Æ0.3
–
–
0.54Æ0.04
0.51Æ0.04
0.39Æ0.06
–
–
Inhibition was assessed by monitoring [a] cefazolin and [b] imipenem hy-
drolysis; values are meansÆSD of n=3 experiments. [c] Noncompetitive
inhibition. [d] Uncompetitive inhibition; –: no inhibition.
of the synthesized compounds are shown in Figure 1. Briefly,
arylcarboxylates were prepared by esterifying aromatic carbox-
ylic acids and converting them into hydrazides by condensing
with hydrazine. The hydrazides reacted with NH4SCN or CS2
under basic conditions to give aroylthiourea or aroyldithiocar-
bazates, respectively.[17] The dithiocarbazates were treated with
cold concentrated sulfuric acid to give 2-thio-1,3,4-thiadiazoles,
which were held at reflux with potassium hydroxide to afford
2-thio-1,3,4-oxadiazoles,[18] and the thiourea was stirred with
potassium hydroxide at reflux to afford 2-thio-1,3,4-triazoles.[19]
N-Benzothiazolyl-2-chloroacetamide and N-phenyl-2-chloroace-
tamide were prepared as previously reported[20] and cross-
linked with the thiadiazoles, oxadiazoles, and triazoles under
various basic conditions to give the diaryl-substituted azolyl-
thioacetamides 1–18 (detailed synthetic procedures are avail-
able in the Supporting Information).
interact with the cysteine residues to form a disulfide bridge in
L1 rather than binding to the active site.[21]
Recently, structural and mechanistic studies on NDM-1 have
been reported,[5,22a–d] but no tight-binding inhibitors of the
enzyme have been reported to date. In this work, we found
the azolylthioacetamides 1–13 and 16 to be inhibitors of
NDM-1, exhibiting Ki values <7 mm, except 8, with a Ki value of
45 mm. However, 14, 15, 17, and 18 had no inhibition observed
against CcrA, NDM-1, and ImiS, whereas they showed Ki values
<2 mm against L1, suggesting the 2-(3-pyridyl)-1,3,4-thiadiazol-
yl and 2-(3-pyridyl)-1,3,4-oxadiazolyl moieties on the com-
pounds may play an important role in selecting B3-subclass
enzymes.
To test whether compounds 1–18 are inhibitors or even
broad-spectrum inhibitors of the MbLs, the following represen-
tative enzymes from the distinct MbL subclasses were chosen
for evaluation: CcrA (B1a), NDM-1 (B1b), ImiS (B2), and L1 (B3).
The data listed in Table 1 summarize Ki values and modes of in-
hibition for the azolylthioacetamides.
Inhibition of ImiS was also observed, and the most potent
inhibitors were 2, 4, 5, 7, 8, and 10, exhibiting Ki values
<15 mm. Compounds 1, 2, 4, 5, and 7 were found to be inhibi-
tors of CcrA, with Ki values <10 mm. It is not clear why 3, 6, 8–
13, and 16 inhibited NDM-1 and L1, but not CcrA, although
these three enzymes are all dinuclear MbLs.
The azolylthioacetamides 2, 4, 5, and 7 were found to be
broad-spectrum inhibitors of all four MbLs tested, exhibiting Ki
values <16 mm, except 5 against CcrA with a Ki value of 52 mm.
Compound 4 exhibited the strongest inhibition against L1
with a Ki value of 73 nm. Presumably, these compounds exhibit
greater inhibition of CcrA, NDM-1, and L1 than ImiS, because
the former three enzymes contain two ZnII ions as opposed to
a single ZnII ion, as in ImiS. Compound 10 was found to be
a very potent inhibitor (Ki values <2 mm) of all tested enzymes
except CcrA, which is clinically not very important.
To assess the inhibition mode of these compounds, steady-
state kinetic studies were conducted with CcrA, NDM-1, ImiS,
and L1. Azolylthioacetamides 1–18 yielded Lineweaver–Burk
plots that indicate mixed inhibition of the binuclear MbLs
CcrA, NDM-1, and L1. For the mononuclear MbL ImiS, com-
pounds 4, 7, 8, and 10 exhibited mixed inhibition, whereas 2
and 3 showed noncompetitive and uncompetitive inhibition,
respectively. Inhibitor 4 was taken as an example to show its
inhibition mode against NDM-1 and L1 as representative MbLs
(Figure 2).
All azolylthioacetamides 1–18 showed significant inhibitory
activity against L1, with Ki values <2 mm. We tested the inter-
mediates arylthiazolyl-, aryloxazolyl-, and aryltriazolylthiols as
inhibitors of L1, but these compounds exhibited no inhibitory
activity. It is possible that the thiol groups on the compounds
For docking calculations we focused on triazole 4, which in-
hibited all tested enzymes, and 10, which inhibited all enzymes
but CcrA (computational details along with more detailed re-
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pounds as flexible ligands. Fifty conformations were generated
for each enzyme–inhibitor complex and analyzed under con-
sideration of clustering and binding energies. We assume that
inhibition is indeed due to compounds binding to the active
site rather than depriving them of ZnII ions, because these en-
zymes bind ZnII tightly, and ZnII was provided in excess (50 mm)
in the assay buffer. In the mononuclear CphA–4 and CphA–10
complexes, the triazole coordinated Zn2, just like the nitrogen
atom derived from b-lactam hydrolysis[25] (Figure S1). In addi-
tion, the 2-phenolyl hydroxy group in 4 interacted with Lys224
(BBL standard numbering[26] is used throughout), and the
amide carbonyl in 10 interacted with Asn233 (Figures S1A and
S1B). The former interaction is usually made by the C3/C4 car-
boxylate in penicillins and carbapenems/cephalosporins (Fig-
ure 3c and Figure S1C),[21d,24] while the latter is reminiscent of
the interaction between the b-lactam carbonyl group and
Asn233.[27,28] In the binuclear complexes of CcrA, NDM-1, and
L1 with deprotonated triazoles (see Supporting Information for
rationale and details), the triazole coordinated the two ZnII
ions, and the N-phenylthioacetamide moiety of 4 and 10
either bound to the R1 or R2 binding site with the 2-phenolyl
(4) or 4-pyridyl (10) moiety binding to the other site, respec-
tively (Figure 3a,b). The interaction of the triazole with the ZnII
ions resembles the binding mode of a biphenyl tetrazole inhib-
itor of CcrA.[29] Conformations in which the N-phenylthioaceta-
mide bound to the R1 binding pocket (Figure 3a) closely re-
semble hydrolyzed benzylpenicillin found in a crystal structure
of NDM-1[22d] (Figure 3c), with the 2-phenolyl hydroxy group of
4 adopting the role of the C3 carboxylate to interact with
Lys244 in CcrA (Figure S1D) and NDM-1[22d] (Figure 3a) and
Ser221 in L1[30] (Figures S1E and S1F). The presence of the hy-
droxy group in 4 could explain why it inhibits CcrA if it inter-
acts with Lys224, but 10 does not. However, both 4 and 10 ef-
ficiently bind to NDM-1 and L1, and we can currently not ex-
plain this difference in binding.
Figure 2. Lineweaver–Burk plots of inhibition of a) NDM-1- and b) L1-cata-
lyzed hydrolysis activity by N-phenyl-5-(2-phenolyl-1,3,4-triazolyl)thioaceta-
mide 4. Cefazolin was used as substrate of NDM-1 and L1. Data points show
!
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inhibitor 4 concentrations of 0 ( ), 0.625 ( ), 1.25 ( ), and 2.50 mm ( ).
sults and discussion are available in the Supporting Informa-
tion). In summary, docking calculations were carried out as pre-
viously described[23] using the program AutoDock 4.2,[24] treat-
ing the enzyme as a rigid receptor and the synthesized com-
Figure 3. a),b) Two different low-energy conformations of 4 docked into NDM-1 (PDB code: 4EYL) with binding energies of À8.8 and À9.2 kcalmolÀ1, respec-
tively. c) Crystal structure of a complex between NDM-1 and hydrolyzed benzylpenicillin (PDB code: 4EYF). The backbone of the enzyme is depicted as
a green ribbon. Compound 4, hydrolyzed benzylpenicillin, and key protein residues are shown as sticks (H, white; C, gray; N, blue; O, red; S, yellow). The
backbone of Gln123 (BBL numbering Gln119, the side chain points to the left, away from the active site) and the side chain of Lys211 (BBL numbering Lys224)
are shown. Zinc ions are shown as magenta spheres; the lower (front) one is Zn1 and the upper (back) one is Zn2.
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Experimental Section
1
Synthetic procedures, H and 13C NMR data and physical properties
of inhibitors, biochemical procedures, inhibition studies. and dock-
ing calculations are provided in the Supporting Information.
Acknowledgements
This work was supported by grants 21272186 and 81361138018
(to K.W.Y.) from the National Natural Science Fund of China and
grant G02191 (to M.W.C) from the Natural Science Fund. Docking
calculations were carried out at the Center for Macromolecular
Modeling and Materials Design at California State Polytechnic
University, Pomona, which is supported by the W. M. Keck Foun-
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Published online on && &&, 0000
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COMMUNICATIONS
Y.-L. Zhang, K.-W. Yang,* Y.-J. Zhou,
A. E. LaCuran, P. Oelschlaeger,
M. W. Crowder
&& – &&
Diaryl-Substituted
Azolylthioacetamides: Inhibitor
Discovery of New Delhi Metallo-b-
Lactamase-1 (NDM-1)
New inhibitors for NDM-1: Azolylthio-
acetamides 1–18 were obtained and all
of them were found to be inhibitors of
metallo-b-lactamases (MbLs) L1 (Ki <2
mm). Compounds 1–7, 9–13, and 16 are
mixed inhibitors of NDM-1 (Ki <7 mm),
and 2, 4, 5, and 7 are broad-spectrum
inhibitors of all four tested MbLs: CcrA,
NDM-1, ImiS, and L1 (Ki <52 mm). Dock-
ing studies revealed that 4 and 10 coor-
dinate to the ZnII ion(s) via the triazole
moiety, while other moieties interact
with the conserved active site residues
Lys224 or Ser221.
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 0000, 00, 1 – 4
&
5
&
ÞÞ
These are not the final page numbers!