Pyrazole-Thiazole Core-Containing Analogs Exhibit Adjunctive Activity with Meropenem against Carbapenem-Resistant Enterobacteriaceae (CRE)

Article abstract of DOI:10.1002/cmdc.202100321

Pyrazole-thiazole core-containing compound KP-40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed adjunctive activity with meropenem against Gram-negative bacteria evidenced by a range of fractional inhibitory concentration (FIC=0.5–0.25) and minimum adjunctive concentration (MAC=128–32 μM) values. Of this series of molecules, four compounds displayed notable adjunctive potential, with FIC and MAC values of 0.25 and 32 μM, respectively. Moreover, the solubility of these compounds was improved to an acceptable range. Further analysis using our “in house” permeation and efflux multi parameter optimization (PEMPO) algorithm revealed key physicochemical properties that may be critical for the development of active Gram-negative antibacterials. Taking PEMPO scores into consideration prior to executing synthesis of analogs may be a simple, yet rapid and effective strategy that can be used in conjunction with traditional SAR approaches to aid in the design of potent Gram-negative antibacterials.

Full text of DOI:10.1002/cmdc.202100321

Accepted Article
Title: Pyrazole-Thiazole Core-Containing Analogs Exhibit Adjunctive
Activity with Meropenem against Carbapenem-Resistant
Enterobacteriaceae (CRE)
Authors: Chungsik Kim, Mintesinot Kassu, Kenneth P. Smith, James E.
Kirby, and Roman Manetsch
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: ChemMedChem 10.1002/cmdc.202100321
Link to VoR: https://doi.org/10.1002/cmdc.202100321
01/2020

10.1002/cmdc.202100321
ChemMedChem
COMMUNICATION
Pyrazole-Thiazole Core-Containing Analogs Exhibit Adjunctive
Activity with Meropenem against Carbapenem-Resistant
Enterobacteriaceae (CRE)
Chungsik Kim,[a] Mintesinot Kassu,[a] Kenneth P. Smith,[c] James E. Kirby,[c] and Roman Manetsch*[a,b]
[a]
[b]
[c]
Dr. C. Kim, M. Kassu, Prof. R. Manetsch
Department of Chemistry and Chemical Biology
Northeastern University
360 Huntington Ave. Boston, MA 02115
E-mail: r.manetsch@northeastern.edu
Prof. R. Manetsch
Department of Pharmaceutical Science
Northeastern University
360 Huntington Ave. Boston, MA 02115
E-mail: r.manetsch@northeastern.edu
Dr. K. P. Smith, Prof. J. Kirby
Department of Pathology, Beth Israel Deaconess Medical Center
Harvard Medical School, Boston, MA, USA 02115
E-mail: jekirby@bidmc.harvard.edu
Abstract: Pyrazole-thiazole core-containing compound KP-40 and 20
novel derivatives were designed and synthesized through traditional
SAR analysis. These molecules displayed adjunctive activity with
meropenem against Gram-negative bacteria evidenced by a range of
fractional inhibitory concentration (FIC = 0.5 – 0.25) and minimum
adjunctive concentration (MAC = 128 – 32 μM) values. Of this series
of molecules, four compounds displayed notable adjunctive potential,
with FIC and MAC values of 0.25 and 32 μM, respectively. Moreover,
the solubility of these compounds was improved to an acceptable
range. Further analysis using our “in house” permeation and efflux
multi parameter optimization (PEMPO) algorithm revealed key
physicochemical properties that may be critical for the development
of active Gram-negative antibacterials. Taking PEMPO scores into
consideration prior to executing synthesis of analogs may be a simple,
yet rapid and effective strategy that can be used in conjunction with
traditional SAR approaches to aid in the design of potent Gram-
negative antibacterials.
United States alone, CREs were estimated to cause 13,000
infections in hospitalized patients and 1,100 deaths in 2017.[5]
A
major challenge in developing efficacious antibiotics against
certain MDR pathogens is overcoming particular enzymatic and
structural features that undermine antibiotic activity in Gram-
negative bacteria. Unlike their Gram-positive counterparts, Gram-
negative bacteria contain an outer lipopolysaccharide membrane
which impedes the entrance of many otherwise active
antimicrobials into the bacterial cell. This added barrier, coupled
Multidrug-resistant (MDR) bacterial infections are an emerging
global public health concern that has escalated at an alarming
rate over the last decade.[1] These emerging pathogens are a
grave threat in healthcare settings and are responsible for a
variety of infections such as urinary tract infections, bloodstream
infections, and pneumonia.[2] Carbapenem antimicrobials are a
last-line defense against MDR pathogens and, until recently, have
demonstrated to be reliable broad-spectrum treatments for
Figure 1. Representative growth curves of MDR pathogens in the presence
of an adjunctive (blue), an antimicrobial (green), or
a combination of
antimicrobial and adjunctive (red). The combinatorial administration of the two
compounds is more effective than the administration of either compound on
its own.
numerous
bacterial
infections.[3]
Carbapenem-resistant
with ubiquitous expression of efflux pumps, prevents most
antibiotics from reaching their biomolecular target and exhibiting
their antibacterial activity.
Enterobacteriaceae (CRE) encompass a group of MDR bacteria
that has emerged over the last few decades.[4] CREs exhibit
resistance to all currently available -lactam antibiotics including,
by definition, carbapenems and are often resistant to
aminoglycosides, fluoroquinolones, and tetracyclines.[4] In the
1
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10.1002/cmdc.202100321
ChemMedChem
COMMUNICATION
Carbapenems overcome both of these challenges and retain
compounds with eukaryotic cell cytotoxicity, 658 adjunctive hits
were obtained. Of these hits, 274 compounds were selected
based on primary screening potency for confirmatory analysis
using cherry picks from commercial library plates in a manner
identical to the primary screening assay. A 25% inhibition cut off
was used for this secondary analysis which yielded 127 adjunctive
hits. A cheminformatics filtering process was then applied,
removing nonspecific pan-assay interference compounds
(PAINS), leading to the removal of 20 hits. The remaining 107
adjunctive hits were clustered using two-dimensional fingerprint-
based structural similarity, generating 15 clusters and 17
singletons. Finally, compounds within each cluster were ranked
using a previously reported multi-parameter optimization (MPO)
algorithm.[14] Originally developed for CNS drugs, MPO scores
take six physicochemical properties into account in order to
predict the potential of drug molecules to permeate the blood-
brain barrier. Higher MPO scores have also shown to correlate
with more desirable physicochemical attributes, leading to greater
bioavailability. Furthermore, an “in-house” MPO algorithm, termed
permeation and efflux MPO (PEMPO), was designed to predict
[6]
[7]
detectable in vitro
and in vivo
activity in Gram-negative
bacteria. In CREs, however, with the expression of lactam
hydrolyzing carbapenemases, resistance to this class of β-lactam
antibiotics emerged.[8] Carbapenemases pose a new challenge
that warrants new strategies for addressing these resistant
pathogens. Developing new drug candidates with unique
mechanisms of action is a time-intensive endeavor which may
involve understanding the target and development of robust
assays for validating biological activity. Alternatively, it may be
more attractive to identify small molecules that block mechanisms
of resistance and thereby potentiate and restore clinically
meaningful activity of existing antibiotics (Figure 1). A synergistic
combination of small molecule potentiators and carbapenems, for
example, may restore antibacterial activity of carbapenems
against otherwise resistant CREs. This approach would enable
the continued use of these efficacious antibiotics which have an
excellent safety record. Recently the Martin group reported a
synergistic effect between two thiol-containing small molecules,
serving as metallo-β-lactamase (MBL) inhibitors, and the broad-
spectrum antibiotic, meropenem.[9] The ability of the two MBL
inhibitors to potentiate the activity of meropenem correlated with
their zinc-binding ability, with measured Kd values of 9.8 and 20.0
μM. The several FDA-approved diazabicyclooctane, serine -
lactamase inhibitors are also examples of use of direct adjunctive
inhibitors of prevalent carbapenemases to restore carbapenem
activity.[10] We also recently considered the identification of anti-
plasmid agents as adjunctives to eliminate plasmid-borne
antibiotic resistance elements and thereby restore antibiotic
susceptibility.[11] With the goal of identifying additional compounds
with adjunctive potential, agnostic of mechanism of action, our
the ability of
a
compound to permeate the outer
lipopolysaccharide membrane of Gram-negative bacteria and
avoid efflux – two essential characteristics of effective Gram-
negative
antimicrobial
compounds.[13]
42
compounds,
representing 15 clusters, and 6 singletons were identified for
Scheme 1. Synthetic route for the preparation of KP-40: a) tBuOK, THF,
0 ºC, 30 min., BnBr, reflux, 12 h; b) N2H4, EtOH, reflux; c) NBS, p-TsOH,
DCM, 0 ºC to r.t. 2 h; d) i. NaOH (2.5 M), ethanol, reflux; ii. SOCl2, m-
chloroaniline, DCM, pyridine, reflux; iii. thiourea, ethanol, reflux; iv. CuBr2,
tBuONO, CH3CN; e) microwave, CuBr, Cs2CO3, DMF.
secondary analysis through this process. In order to ascertain the
degree to which compounds exhibit a synergistic effect with
meropenem, fractional inhibitory concentration (FIC) values,[15]
defined as the minimum inhibitory concentration (MIC) of
meropenem in the presence of the adjunctive compound over the
MIC of meropenem alone, were measured. Select compounds
were then identified for resynthesis and confirmatory testing
based on FICs, potency, and desirable physicochemical
properties. For adjunctive antimicrobials, the minimum adjunctive
concentration (MAC, i.e., minimal concentration needed to reduce
the MIC of meropenem 4-fold) were determined. Of these
resynthesized compounds, 2-(4-benzyl-5-hydroxy-3-methyl-1H-
pyrazol-1-yl)-N-(3-chlorophenyl)-4-methylthiazole-5-carboxamid
KP-40 (Figure 2) was selected as a favored adjunctive partner of
meropenem for follow-up structure-activity relationship (SAR)
studies based on consistent FIC values observed between the
library sample (FIC = 0.31) and the “in-house” synthesized
sample (FIC = 0.42). By designing structural diversity in KP-40
derivatives, we aim to reduce FIC and MAC values, thus
Figure 2. Compounds selected for resynthesis from screening and
cheminformatics filtering results. A library of 182,427 commercially available
compounds were screened for adjunctive activity with meropenem against
representative carbapenem-resistant Enterobacteriaceae (CRE) strains.
After a series of confirmatory screens, the narrowed hit list underwent a
layer cheminformatics processing – leading to the removal of pan-assay
interference compounds (PAINS) and construction of structural similarity
clusters. KP-9, KP-56, KP-19, and KP-40 were selected for resynthesis
based on their potency, spectrum of activity and predicted physicochemical
properties.
previous work employed our validated screening/counter-
screening method[12] to probe the ability of a large collection of
small molecules to potentiate meropenem against a Klebsiella
pneumoniae CRE strain[13]. As previously described, we screened
a
182,427 compound library with and without previously
characterized biological activity in duplicate using this two-tiered
assay. We initially identified 604 (0.332 %), 599 (0.328 %) and 43
(0.02 %) weak, medium, and strong adjunctive hits, respectively.
After applying a primary filter which removed compounds
exhibiting <50% inhibition and a secondary filter removing
2
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10.1002/cmdc.202100321
ChemMedChem
COMMUNICATION
Our initial SAR investigation began with retention of the methyl
group on the R1 position and modification of the R2 and R3 groups
in order to determine potential functional group dependence and
activity at these sites. First, an unfunctionalized phenyl group was
introduced at R3 (entry 1), allowing us to examine the influence of
the chloro substituent in KP-40. FIC and MAC values of 0.50 and
64 μM, respectively were observed indicating that chlorine
substitution may not be essential for synergistic activity. The
introduction of more flexible and longer aryl groups at the R3
improving the synergistic potential of the compounds identified in
our original work. The chemical structure of KP-40 consists of a
hybrid heterocyclic pyrazole-thiazole core. Individually, these
heterocyclic moieties have previously been reported for their
antimicrobial activity against Gram-positive and Gram-negative
pathogens.[16] In addition, the synthesis of KP-40 has some
advantages in terms of facile synthesis and easily accessible
functional group modifications. To prepare the pyrazole (II)
fragment, α-benzylation of ethyl acetoacetate was performed by
condensation. The benzylated intermediate (I)[17] with hydrazine
hydrate afforded heterocyclic hydroxyl-pyrazole fragment (II) via
a condensation-intramolecular cyclization-aromatization cascade
reaction.[18] The synthesis of thiazole fragment (IV) commenced
with construction of the α-bromo ethyl acetoacetate intermediate
(III) [19] using NBS as a bromine source in a polar solvent, which
readily reacts with thiourea under reflux conditions to afford
heterocyclic 2-aminethiazole in a high yield.[20] This was followed
by the Sandmeyer reaction via a diazonium salt intermediate, 2-
aminethiazole, using CuBr2 which successfully yielded the target
heterocyclic 2-bromothiazole framework.[20] The ester group of 2-
bromothiazole was hydrolyzed at the C5 position under basic
conditions using NaOH (2.5 M) in good yield. Finally, 2-
bromothiazole acid was transformed into 2-bromothiazole (IV) via
acylation using thionyl chloride. With the two main heterocyclic
fragments in hand, a final coupling reaction was carried out
Table 2. Activity and solubility data of the most potent KP-40 derivatives.
FIC
0.25
0.25
0.25
MAC[a]
32
cLog D7.4
cLog P
no
17
18
19
Sol.
< 1
5.22
5.96
5.06
6.67
7.42
6.51
Table 1. MAC and FIC values of KP-40 derivatives from initial SAR study.
32
< 1
32
27.6 uM
R1
N
N
S
N
H
R2
0.25
32
2.84
N
20
4.32
26.9 uM
R3
OH
O
[a] MAC unit is μM.
[a]
[b]
R1
R2
R3
Ph
FIC
0.5
no
MAC
position (entry 2 and 3) delightfully led to a 2-fold decrease in the
FIC value. Next, we examined the R2 position with a mix of
electron-withdrawing and electron-donating groups (entry 4) and
the analog exhibited a 0.25 FIC value and 64 μM MAC. The
removal of the meta-chloro substituent at the R3 position (entry 5)
led to retention of FIC and MAC values when compared to analog
4. Afterwards, analogs with electron-withdrawing (entry 6) and
electron-donating (entry 7) moieties were prepared in order to
examine the influence of electron density at the R3 position.
However, both designs displayed the same results despite the
difference in electron density. Following the investigation of R2
and R3 modifications, we altered the functionality at R1 by first
1
2
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
64
64
64
64
64
64
64
64
Ph-4OPh
Ph-4Ph
m-ClPh
Ph
0.25
0.25
0.25
0.25
0.25
0.25
0.25
3
3-OMe-6-nitroPh
3-OMe-6-nitroPh
m-CF3Ph
4
5
Ph
6
Ph
3,5-diOMePh
Ph
7
tBu
Ph
Ph
Ph
m-ClPh
8
Ph
9
m-CF3Ph
64
0.5
introducing
a bulky tert-butyl group (entry 8). Adjunctive
10
11
12
13
14
15
16
Ph
128
128
0.25
0.25
3,5-diOMePh
Ph
antimicrobial activities of this analog resembled that of KP-40. We
further examined the effects of R1 substitution by incorporating a
less bulky, aromatic group. Simultaneous incorporation of a CF3
group at R2 (entry 9) was conducted based on the well-known
advantageous steric and electronic properties that this bioisostere
exhibits. Unfortunately, analog 9 exhibited a worse FIC value (0.5)
than the previous few entries. Interestingly, the presence of the
electron-donating group, 3,5-dimethoxyphenyl (entry 10), showed
a reverse result indicated by an increased FIC but a 2-fold
decrease in MAC (128 μM) compared to compound 10. Entries
11 and 12 have longer aromatic substituents at the R3 position
and both display 128 μM MAC values. Even heterocycle-
containing compound 13 showed the same activity as entries 11
and 12. Compounds 14 and 15 were prepared in order to examine
Ph-4OPh
Ph-4Ph
Ph
Ph
Ph
Ph
128
128
0.25
0.25
4,5-diMethiazole
p-OMePh
p-OMePh
p-CF3Ph
m-ClPh
Ph
0.25
0.25
0.25
128
64
Ph
Ph
Ph
Ph
64
[a] Calculated from quadruplicate testing against Klebsiella pneumoniae
BIDMC12A. [b] MAC unit is μM.
between hydroxy-pyrazole (II) and 2-bromothiazole (IV) under
microwave irradiation using Cu(I) as the coupling catalyst.[21] The
convergent synthesis of KP-40 was successfully completed in 8
total steps (Scheme 1).
3
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10.1002/cmdc.202100321
ChemMedChem
COMMUNICATION
Figure 3. Comparison of physicochemical property
values between a set of 100 known antibacterials
(blue) and synthesized KP-40 derivatives (orange).
The molecular weight (M.W.) of each compound
was plotted against (A) permeation and efflux
multiple parameter optimization (PEMPO) score,
(B) the sum of hydrogen bond donors (HBD) and
hydrogen bond acceptors (HBA), (C) polar surface
area (PSA), (D) calculated partition coefficient
(cLogP), (E) calculated partition coefficient at pH
7.4 (cLogD7.4).
the adjunctive activity change when the electron density of the R1
group is modulated. The electron-donating group, p-
methoxyphenyl, was added in entry 14 and displayed the same
FIC but a higher MAC value. The MAC value improved 2-fold
when the chlorine substituent in the aromatic R3 group was
removed. Our attempts to increase activity by adding a CF3 group
at the R1 position was unsuccessful, demonstrated by similar FIC
and MAC values as the previous analogs. After our initial SAR
studies, we identified several patterns that would guide our
following synthetic pursuits - 1) R1 group does not play a critical
role in providing a synergistic effect 2) electron-withdrawing
groups decrease FIC values 3) elongated aromatic groups have
no influence on the activity and solubility. Based on our synthetic
strategy, we designed and prepared diverse analogs with some
compounds displaying 2- to 4-fold improvements in MACs while
retaining FIC values. Entries 17 and 18 consist of aromatic rings
at R1, R2, and R3 positions and, consequently, their solubility was
hampered due to the high density of phenyl groups. To enhance
the solubility, a heteroaromatic group was introduced (entry 19) at
the R3 position and its solubility appropriately increased to 27.6
μM, while retaining its synergistic activity. Finally, removal of the
methylene unit at R2 generated analog 20 which, gratifyingly,
retained the activity and solubility of entry 19. While some
improvements in FIC and MAC values were observed, the
analogs generated during this SAR study did not exhibit
satisfactory synergism in combination with meropenem. A
potential reason for these disappointing results may be that the
physicochemical attributes of our analogs are not appropriate for
targeting Gram-negative bacteria. Previous examinations of
approved antibacterial versus non-antibacterial libraries have
highlighted a striking difference in physicochemical properties
between the two.[22] More specifically, antibacterial compounds
tend to be larger and more polar – demonstrated by higher M.W,
HBD, HBA, PSA values and lower cLogP and cLogD7.4 values
when compared to non-antibacterials. Additionally, antibacterials
typically possess one or more ionizable groups at pH 7.4 which
presumably assists in the molecule’s ability to permeate the
bacterial membrane. Therefore, when designing antibacterial
compounds, employment of traditional medicinal chemistry
optimization strategies may not be suitable. We previously
reported the use of our “in-house” MPO algorithm (PEMPO) to
compare our screened hits with known antibacterials.[13] This
score differs from the classical MPO algorithm in that it places
priority on key physicochemical properties, and their optimal
ranges, that are believed to be important for penetration and
avoidance of efflux in Gram-negative bacteria. PEMPO scores
range from 0 to 6, with 6 indicating optimal permeation and
minimal efflux potential while 0 indicates a lack of such potential.
In order to examine whether our synthesized analogs possess the
properties essential for Gram-negative antibacterial activity, we
calculated PEMPO scores for each of the compounds. We
reported that the average PEMPO score for 100 known
antibacterials was determined to be 5.08. In comparison, our
synthesized analogs exhibit an average PEMPO score of 2.43,
with entry 5 displaying the highest value of 3.22. Further
inspection of the 6 physicochemical properties used to construct
these scores revealed the reason for the drastic difference
observed between the two data sets. To summarize, our
compounds are too lipophilic, indicated by average HBD, HBA,
PSA, cLogD7.4, and cLogP values of 2.0, 4.7, 88 Å, 4.93, and 6.36,
respectively. By contrast, the set of 100 known antibacterials
exhibit average HBD, HBA, PSA, cLogD7.4, and cLogP values of
2.9, 7.0, 127 Å, -2.28, and -0.86, respectively.[22] The divergence
in values is visually represented in Figure 3 and underscores the
vast disparity between compounds designed with “drug-likeness”
in mind and those that are designed with emphasis on optimizing
the properties critical to bacterial membrane penetrance and
avoidance of efflux. Synthetic tractability is likely to contribute to
this disparity, as compounds with a greater PSA and higher
number of HBDs and HBAs are generally harder to synthesize.
As a result, the chemical space of potential drug molecules is
narrowed, thereby limiting the degree to which efficacious
antibacterials are discovered. By utilizing PEMPO scores as a
primary criterion for the selection of designed analogs, we might
capture features most relevant to antibacterial activity and
improved our results.
Overall, we conclude that KP-40 and its SAR-designed analogs
were adjunctive partners with meropenem. We successfully
synthesized 20 novel analogs of compound 1 with pyrazole-
thiazole core moieties. Within this new series of compounds,
4
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10.1002/cmdc.202100321
ChemMedChem
COMMUNICATION
several showed potent activity across a range of FIC and MAC
values. However, satisfactory synergistic activity with meropenem
was not observed among any of the analogs. Our previous report
suggested that these findings may reflect the limited potential of
our screening compound libraries due to significant enrichment
for molecules with “drug-likeness” properties, which generally do
not align with biologically active antibacterials. Results presented
here and our prior analysis suggests that PEMPO scores may
provide a pivotal guideline for antimicrobial screening library
optimization and rational design for future screening efforts based
on consideration of physicochemical properties deemed to be
important for penetration of the outer membrane and avoidance
of efflux mechanisms.
[8]
[9]
D. M. Taylor, J. Anglin, S. Park, M. N. Ucisik, J. C. Faver, N. Simmons,
Z. Jin, M. Palaniappan, P. Nyshadham, F. Li, J. Cambell, L. Hu, B.
Sankaran, B. V. V. Prasad, H. Huang, M. M. Matzuk, T. Palzkill, ACS.
Infect. Dis. 2020, ahead of print. b) G. L. Daikos, S. Tsaousi, L. S.
Tzouvelekis, Antimicrob. Agents Chemother. 2014, 58, 2322–2328.
K. H. M. E. Tehrani, N. I. Martin, ACS Infect. Dis. 2017, 3, 711-717.
[10] T. B. Krohn, R. Manetsch, G. A. O’Doherty, J. E. Kirby, Transl. Res. 2020,
220, 14-32.
[11] K.E. Zulauf, J.E. Kirby, Proc Natl Acad Sci USA, 2020, 117(47), 29839 –
29850.
[12] K. P. Smith, J. E. Kirby, Assay Drug Dev. Technol. 2016, 14, 194–206.
[13] K. P. Smith, M. Dowgiallo, L. Chiaraviglio, P. Prakash, C. Kim, R.
Manetsch, J. E. Kirby, SLAS Discovery. 2019, 24(8), 842-853.
[14] T. Wager, X. Hou, P. R. Verhoest, A. Villalobos, ACS Chemical
Neuroscience. 2010, 1(6), 435–449.
[15] a) R. L. White, D. S. Burgess, M. Manduru, J. A. Bosso, Antimicrob.
Agents Chemother. 1996, 40, 1914-1918. b) A. Serri, A. Mahboubi, A.
Zarghi, H. R. Moghimi, J. Pharm. Pharm. Sci. 2019, 22, 10-21. c) P. Goni,
P. Lopez, C. Sanchez, R. Gomez-Lus, R. Becerril, C. Nerin, Food Chem.
2009, 116, 982-989.
Acknowledgements
KPS and JEK were supported in part by the National Institute of
Allergy and Infectious Diseases of the National Institutes of Health
under award numbers F32 AI124590 and R33 AI119114,
respectively. The content is solely the responsibility of the authors
and does not necessarily represent the official views of the
National Institutes of Health. The HP D300 digital dispenser and
TECAN M1000 used in the MIC and FIC analysis were provided
by TECAN (Morrisville, NC). Tecan had no role in study design,
data collection/interpretation, manuscript preparation, or decision
to publish.
[16] a) O. Ebenezer, A. Singh-Pillay, N. A. Koorbanally, P. Singh, Mol. Divers.
2020, 25, in print. b) R. Gondru, K. Sirisha, S. Raj, S. K. Gunda, C. G.
Kumar, M. Pasupuleti, R. Bavantula, ChemistrySelect. 2018, 3, 8270-
8276. c) B. F. Abdel-Wahab, A. Sediek, H. A. Mohamed, G. E. A. Awad,
Eur. Lett. Drug. Des. Discov. 2013, 10, 111-118. d) S. Bondock, W.
Khalifa, A. A. Fadda, Eur. J. Med. Chem. 2007, 42, 948-954. e) K. Cheng,
J. Xue, H. Zhu, Bioorg. Med. Chem. Lett. 2013, 23, 4235-4238. f) P. K.
Sharma, N. Chandak, P. Kumar, C. Sharma, K. R. Aneja, Eur. J. Med.
Chem. 2011, 46, 1425-1432. g) L. L. Xu, C. J. Zheng, L. P. Sun, J. Miao,
H. R. Piao, Eur. J. Med. Chem. 2011, 48, 174-178. h) P. Khloya, P.
Kumar, A. Mittal, N. K. Aggarwal, P. K. Sharma, Eur. J. Med. Chem. 2013,
3, 9-16.
[17] J. E. Beddow, S. G. Davies, K. B. Ling, P. M. Roberts, A. J. Russel, A. D.
Smith, J. E. Thomson, Org. Biomol. Chem., 2007, 5, 2812-2825.
[18] a) L. A. Emert-Sedlak, H. M. Loughran, H. Shi, J. L. Kulp III, S. T. Shu, J.
Zhao, B. W. Day, J. E. Wrobel, A. B. Reitz, T. E. Smithgall, Bioorg. Med.
Chem. Lett. 2016, 26, 1480-1484. b) S. Nakao, M. Mabuchi, T. Shimizu,
Y. Itoh, Y. Takeuchi, M. Ueda, H. Mizuno, N. Shigi, I. Ohshio, K. Jinguji,
Y. Ueda, M. Yamamoto, T. Furukawa, S. Aoki, K. Tsujikawa, A. Tanaka,
Bioorg. Med. Chem. Lett, 2014, 24, 1071-1074.
Keywords: antibacterial activity • Carbapenem-Resistant
Enterobacteriaceae • adjunctive activity • meropenem
[1]
a) Y. Briers, M. Walmagh, V. V. Puyenbroeck, A. Cornelissen, W.
Cenens, A. Aertsen, H. Oliveira, J. Azeredo, G. Verween, J. Prinay, S.
Miller, G. Volckaert, R. Lavignea, mBio, 2014, 59, e01379-14. b) M. H.
Kollef, Y. Golan, S. T. Micek, A. F. Shorr, M. I. Restrepo, Clin. Infect. Dis.
2011, 53, 33-55. c) C. Yilmaz, G. Ozcengiz, Biochemical Pharmacology,
2017, 133, 43-62. d) A. K. Konreddy, G. U. Rani, K. Lee, Y. Choi, Cur.
Med. Chem. 2019, 26, 5363-5388.
[19] a) M. Kirihara, S. Ogawa, T. Noguchi, K. Okubo, Y. Monma, I. Shimizu,
R. Shimosaki, A. Htano, Y. Hirai, Synlett. 2006, 14, 2287-2289. b) A.
Srivastava, N. Jain, Tetrahedron 2013, 69, 5092-5097.
[20] R. Moldovan, R. Teodoro, Y. Gao, W. Deuther-Conrad, M. Kranz, Y. R.
Wang, H. Kuwabara, M. Nakano, H. Valentine, S. Fischer, M. G. Pomper,
D. F. Wong, R. F. Dannals, P. Brust, A. G. Horti, J. Med. Chem., 2016,
59, 7840-7855.
[2]
a) R. K. Flamm, D. J. Farrell, H. S. Sader, R. N. Jones, J. Antimicrob.
Chemother. 2014, 69, 1589-1598. b) D. M. Sievert, P. Ricks, J. R.
Edwards, A. Schneider, J. Patel, A. Srinivasan, A. Kallen, B. Limbago, S.
Fridkin, Infect. Control Hosp. Epidemiol, 2013, 34, 1-14. c) R. Gaynes, J.
R. Edwards, Clin. Infect. Dis. 2005, 41, 848-854. d) K. J. Popovich, B.
Hota, R. Hayes, R. A. Weinstein, M. K. Hayden, Infect. Control Hosp.
Epidemiol, 2009, 30, 959-963.
[21] J. Suh, H. Kang, J. Kim, E. Yum, Bull. Korean Chem. Soc, 2012, 33,
2067-2070.
[22] R. O’Shea, H. E. Moser, J. Med. Chem. 2008, 51, 2871-2878.
[3]
[4]
a) G. G. Zhanel, R. Wiebe, L. Dilay, K. Thomson, E. Rubinstein, D. J.
Hoban, A. M. Noreddin, J. A. Karlowsky, Drug. 2007, 67, 1027-1052. b)
R. D. Pryka, G. M. Haig, Ann. Pharmacother, 1994, 28, 1045-1054. c) J.
J. Schafer, D. A. Goff, J. E. Mangino, Clin. Infect. Dis. 2009, 4, 18-28.
a) N. Gupta, B. M. Limbago, J. B. Patel, A. J. Kallen, Clin. Infect. Dis.
2011, 53, 60-67. b) L. K. Logan, R. A. Weinstein, J. Infect. Dis, 2017, 215,
28-36. c) D. V. Duin, K. S. Kaye, E. A. Neuner, R. A. Bonomo, Diagn.
Micr. Infec. Dis. 2013, 75, 115-1204. d) H. J. Morrill, J. M. Pogue, K. S.
Kaye, K. L. LaPlante, Open Forum Infect. Dis. 2015, 2, 1-15. e) R. F.
Potter, A. W. D’Souzaa, G. Dantas, Drug. Resist. Updat. 2016, 29, 30-
46. f) H. M. Zowawi, B. M. Forde, M. Alfaresi, B. Alzarouni, Y. Farahat,
T. Chong, W. Yin, K. Chan, J. Li, M. A., Schembri, S. A. Beatson, D. L.
Paterson, Sci. Rep. 2015, 5. 15082-15090.
[5]
[6]
[7]
L. M. Weiner, A. K. Webb, B. Limbago, Infect. Control. Hosp. Epidemiol.
2016, 37, 1288–1301.
Centers for Disease Control and Prevention. Antibiotic Resistance
Threats in the United States, 2019 Report.
R. Fattouh, N. Tijet, A. McGeer, Antimicrob. Agent Chemother. 2015, 60,
1556-1559.
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10.1002/cmdc.202100321
ChemMedChem
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20 analogs of the antimicrobial adjunctive, KP-40, were synthesized. Analogs 17-20 displayed superior adjunctive activity (FIC =0.25,
MAC = 32 µM) to KP-40 when co-administered with meropenem. A comparison of physicochemical properties between our analogs
and 100 known antibacterials revealed a notable distinction between the two sets. PEMPO scores may be used to better align
properties of future analogs with that of known antibacterials.
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This article is protected by copyright. All rights reserved.