N-Leucinyl Benzenesulfonamides as Structurally Simplified Leucyl-tRNA Synthetase Inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.7b00374

N-Leucinyl benzenesulfonamides have been discovered as a novel class of potent inhibitors of E. coli leucyl-tRNA synthetase. The binding of inhibitors to the enzyme was measured by using isothermal titration calorimetry. This provided information on enthalpy and entropy contributions to binding, which, together with docking studies, were used for structure-activity relationship analysis. Enzymatic assays revealed that N-leucinyl benzenesulfonamides display remarkable selectivity for E. coli leucyl-tRNA synthetase compared to S. aureus and human orthologues. The simplest analogue of the series, N-leucinyl benzenesulfonamide (R = H), showed the highest affinity against E. coli leucyl-tRNA synthetase and also exhibited antibacterial activity against Gram-negative pathogens (the best MIC = 8 μg/mL, E. coli ATCC 25922), which renders it as a promising template for antibacterial drug discovery.

Full text of DOI:10.1021/acsmedchemlett.7b00374

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Letter
N-Leucinyl benzenesulfonamides as structurally
simplified leucyl-tRNA synthetase inhibitors
Michael H. Charlton, Rihards Aleksis, Adelaide Saint-Leger, Arya Gupta, Einars
Loza, Lluis Ribas de Pouplana, Ilze Kaula, Daina Gusti#a, Marina Madre, Daina
Lola, Kristaps Jaudzems, Grace Edmund, Christopher P. Randall, Louise Kime,
Alex J O'Neill, Wil H.F. Goessens, Aigars Jirgensons, and Paul William Finn
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00374 • Publication Date (Web): 18 Jan 2018
Downloaded from http://pubs.acs.org on January 19, 2018
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N-Leucinyl benzenesulfonamides as structurally simplified leucyl-
tRNA synthetase inhibitors
a
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Michael H. Charlton, Rihards Aleksis, Adélaïde SaintꢀLeger, Arya Gupta,
†
Einars Loza, Lluís
c,d
b
b
b
b
b
Ribas de Pouplana, Ilze Kaula, Daina Gustina, Marina Madre, Daina Lola, Kristaps Jaudzems,
a
e
e
e
f
Grace Edmund, Christopher P. Randall, Louise Kime, Alex J. O’Neill, Wil Goessens, Aigars
b
a,g
Jirgensons, * Paul W. Finn *
Oxford Drug Design Ltd., Oxford Centre for Innovation, New Road, Oxford. OX1 1BY. UK.
a
b
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LVꢀ1006, Latvia.
c
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac,
1
0, 08028 Barcelona, Catalonia, Spain.
d
ICREA, Pg. Lluís Company 23, 08010 Barcelona, Catalonia, Spain.
e
Antimicrobial Research Centre and School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of
Leeds, Leeds LS2 9JT, UK.
f
Erasmus University Medical Center Rotterdam, Dept. of Medical Microbiology and Infectious Diseases, Wytemaweg 80,
3
015 CN Rotterdam, The Netherlands.
g
Department of Applied Computing, University of Buckingham, Hunter Street, Buckingham, MK18 1EG, UK
Keywords: leucyl-tRNA synthetase, inhibitors, antibacterial, sulfonamides, isothermal titration calorimetry
ABSTRACT: NꢀLeucinyl benzenesulfonamides have been discovered as a novel class of potent inhibitors of E. coli leucylꢀtRNA
synthetase. The binding of inhibitors to the enzyme was measured by using ITC. This provided information on enthalpy and entroꢀ
py contributions to binding, which, together with docking studies, were used for SAR analysis. Enzymatic assays revealed that Nꢀ
leucinyl benzenesulfonamides display remarkable selectivity for E. coli leucylꢀtRNA synthetase compared to S. aureus and human
_
orthologs. The simplest analog of the series Nꢀleucinyl benzenesulfonamide (R = H) showed the highest affinity against E. coli
leucylꢀtRNA synthetase and also exhibited antibacterial activity against gramꢀnegative pathogens (the best MIC = 8 ug/mL, E. coli
ATCC
25922)
which
renders
it
as
a
promising
template
for
antibacterial
drug
discovery.
AminoacylꢀtRNA synthetase (aaRS) enzymes are conserved
across bacteria and at the same time exhibit considerable evoꢀ
lutionary divergence with respect to the human enzymes.
They have therefore attracted attention as therapeutic targets
pseudomonic acid 1 (Figure 1), which is used to treat topical
8
skin
infections.
1
ꢀ4
for the discovery of broadꢀspectrum antibacterials. The aaRS
enzymes covalently link the cognate amino acid to its transfer
RNA (tRNA) as part of protein biosynthesis. Aminoacylation
of tRNA is a twoꢀstep process in which the enzymes initially
form an aminoacyl adenylate intermediate from the amino acid
and ATP. The amino acid is then transferred to the terminal
adenosine residue of the tRNA. The enzymes are classified
into two groups, depending upon whether the amino acid is
transferred to the 2’ꢀ (Class I) or the 3’ꢀhydroxyl group (Class
II) of adenosine. Clinical validation of class I aaRS enzymes
as druggable targets has been provided by the isoleucylꢀtRNA
5
ꢀ7
Figure 1. Representative class I aaRS inhibitors
synthetase (IleRS) inhibitor, mupirocin,
also known as
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A boronꢀcontaining molecule 2 (AN3365, GSK2251052, Figꢀ
ure 1) that inhibits leucyltRNA synthetase (LeuRS) by bindꢀ
the benzenesulfonamide derivatives into a protein model based
on an Xꢀray structure of E. coli LeuRS. These studies suggestꢀ
ed that this could be achieved via amino pyridine or amino
pyrimidine substituents at the meta position of of the benzeneꢀ
sulfonamide (Figure 3, compound 7c shown as an example).
Based on these considerations, several analogues 7a-c were
prepared and were found to exhibit binding affinity at nanoꢀ
molar concentrations against E. coli LeuRS in ITC experiꢀ
ments. Notably, potent inhibition of E. coli LeuRS with high
selectivity versus S. aureus and human LeuRS were also obꢀ
served (Table 1, Entries 1ꢀ3). Interestingly, the installation of a
methyl group in the pyrimidine ring (compound 7c) led to an
increased enthalpic contribution compared to analogues 7a,b.
However, this improvement is accompanied by a balancing
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ing at the enzyme’s editing site has also been evaluated cliniꢀ
cally, although its development is encumbered due to the rapid
1
0,11
emergence of resistance.
Nevertheless, to date, no catalytic
site LeuRS inhibitor has been advanced to clinical investigaꢀ
tion.
Most of the precedent work to develop LeuRS catalytic site
inhibitors has focused on nonꢀhydrolyzable aminoacylꢀAMP
12ꢀ14
intermediate analogues such as LeuAMS 3 (Figure 1).
Potent inhibitors have been discovered, but in general these
compounds lack selectivity for bacterial compared to human
aaRSs and also lack antibacterial activity, the latter owing to
0
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3,14
poor intracellular accumulation.
decrease in entropic contribution to leave K practically unalꢀ
D
Selectivity issues of bacterial LeuRS inhibition were overꢀ
come by researchers at Cubist who have developed acylꢀ
sulphonamideꢀbased LeuRS inhibitors 4 (Figure 1) in which
tered. Replacement of the methyl with a phenyl group (comꢀ
pound 7d, Table 1, entry 4) had a negative impact on binding
due to reduced enthalpy compared to compound 7c, which to
some extent was counterbalanced with increased entropy. The
net binding constant was unexpectedly strong given that comꢀ
pound 7d does not fit into the crystallographicallyꢀobserved
structures of E. coli LeuRS. This suggests further (as yet unꢀ
observed) conformational changes in the LeuRS structure on
ligand binding which will require crystallography studies in
the future to understand.
15
the adenine ring is replaced with a substituted thiazole.
Moreover, selective inhibitors of the homologous IleRS enꢀ
zyme, with activity against Gramꢀpositive organisms have
been achieved by replacing the adenine ring with substituted
phenyltetrazoles linked to the sugar ring by a short alkyl
16
group.
A drawback of adenosine analogues is their relatively comꢀ
plex structures. This limits rapid chemical modifications to
obtain crucial requirements such as selectivity and antibacteriꢀ
al activity. There are some examples in the recent literature
showing that the adenylate can be substituted with a benzeneꢀ
sulfonamide motif. Teng et al. have developed selective naꢀ
nomolar benzenesulfonamide based inhibitors 5 (Figure 2) of
Amino pyridine 7e (Table 1, entry 5) showed similar ITC
results to amino pyrimidine 7c which indicates no contribution
of pyrimidine N1 to the binding. On the other hand, analogue
7f (Table 1, entry 6) without amino group showed decreased
enthalpy of binding compared to inhibitor 7c, indicating that
amino group provides additional Hꢀbonding. However, comꢀ
1
7
bacterial ThrRS, including the enzyme from E. coli. In these
inhibitors, the metaꢀsubstituent at the benzenesulfonamide
(such as indazole) was designed to pick up the Hꢀbond interacꢀ
tions seen in the adenine of the native substrate. Zhang et al.
have developed low micromolar benzenesulfonamide 6 (Figꢀ
pound 7f has comparable K which is again due to counterbalꢀ
D
ancing with decreased binding entropy for this compound.
1
8
ure 2) based T. brucei LeuRS inhibitors. According to modꢀ
eling studies, the acylꢀthiourea group in these inhibitors proꢀ
vides additional Hꢀbonding interactions with the enzyme. Theꢀ
se findings motivated us to explore N-leucinyl benzenesulfonꢀ
amides 7 as simplified bacterial LeuRS inhibitors (Table 1, see
Supporting Information for the synthesis). The affinity of the
inhibitors 7 for Escherichia coli LeuRS was determined using
ITC. Enzymatic inhibition of compounds 7 against E. coli, S.
1
9
aureus and human LeuRS was also determined.
H
N
O
O
O
OH
O
O
H
O
N
S
N
S
S
N
N
H
H
NH
2
HN
O
NH2
O
5
, E.Coli ThrRS K = 0.18 uM
6, TbLeuRS IC50= 1.1 uM
Figure 3. Docked poses of 7c (purple), 7h (orange) and 7j
(cyan) in active site of E. coli LeuRS (3zgz)
i
Cl
Human K
i
>50 uM
Human IC50 = 4.5 uM
Br
The favourable decrease of binding entropy for compound
7f suggested the preparation and testing of more lipophilic
compounds 7gꢀi (Table 1, entries 7ꢀ9). Pyridine and phenyl
Figure 2. Known benzenesulfonamideꢀbased aaRS inhibitors
Our initial hypothesis, guided by the known aaRS acylꢀ
sulfonamide inhibitors and by analogy to inhibitor interactions
at other ATP binding sites, for example in kinases, was that
hydrogen bond interactions with Val569 and Met620, to mimꢀ
ic the interaction with adenine in the native substrate, would
be beneficial. Inhibitor design was performed by docking of
substituted analogues 7g,h showed K comparable to inhibiꢀ
D
tors 7a-c,e,f. However, by increasing the aromatic ring size to
naphthyl (compound 7i), a considerable loss of binding enꢀ
thalpy was observed which indicated that this compound does
not adopt the optimal conformation in the active site of the
enzyme.
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Table 1. ITC binding constants of N-leucinyl benzenesulfonamides 7 to E. coli LeuRS and the enzymatic potency against E. coli,
S. aureus and human LeuRS.
R, compound
number
E.coli LeuRS
ITC,a ꢁH,
ITC,a ꢀTꢁS, E.coli LeuRS S. aureus LeuRS Human LeuRS
Entry
1
ꢀ1
ꢀ1
b
b
b
ITC,a K
, nM kcal·mol
D
kcal·mol
IC , nM
IC , nM
50
IC , nM
50
5
0
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
14.5±0.3
12.8±1.2
ꢀ9.5±0.5
ꢀ1.2±0.5
54
14
9.2 x 10
650
3.9 x 10
490
7
7
a
2
3
ꢀ9.0±0.3
ꢀ1.7±0.3
1.6±1.0
b
3
10±3
ꢀ12.5±1.2
41
4.4 x 10
160
7
c
3
3
3
4
5
6
7
56±17
13.9±1.9
22±4
ꢀ7.6±0.3
ꢀ2.3±0.4
224
23
3.6 x 10
1.7 x 10
2.7 x 10
33
7
d
ꢀ9.10±0.11
ꢀ7.05±0.05
ꢀ8.27±0.11
ꢀ1.62±0.07
ꢀ3.40±0.13
850
7
e
3
47
2.0 x 10
7
f
3
3
10.9±1.5
10.2±1.4
ꢀ2.6±0.18
ꢀ2.8±0.5
13
32
920
640
1.2 x 10
3.4 x 10
7
7
g
8
9
ꢀ8.1±0.5
ꢀ6.5±0.9
h
3
3
64±18
ꢀ3.3±0.8
1.1±0.2
65
35
1.0 x 10
5.4 x 10
220
7
i
3
1
0
1.3±0.14
ꢀ13.1±0.3
1.1 x 10
7
j
a
b
ITC data for binding to E. Coli LeuRS enzyme, IC were within 10% of the error range.
5
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At this point, our interpretation of the data indicated a limꢀ
* aigars@osi.lv; paul.finn@oxforddrugdesign.com
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ited contribution to K from polar interactions and a variable
D
Present Addresses
contribution from more lipophilic compounds. Therefore, we
decided to simplify the scaffold further. The simplest member
of N-leucinyl benzenesulfonamide class, inhibitor 7j was preꢀ
pared and it was found to exhibit the best binding affinity
†
Institute for Infection and Immunity St George’s, University of
London, Cranmer Terrace, London, SW17 0RE, UK.
Author Contributions
against E. coli LeuRS with a K of 1.4 nM. The ITC data imꢀ
D
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manuꢀ
script.
ply that binding of compound 7j with LeuRS is enthalpy drivꢀ
en and that entropy does not provide a favorable contribution
to the Gibbs free energy of binding.
Funding Sources
Antibacterial susceptibility testing against a standard laboraꢀ
tory strain of E. coli (BW25113) was performed for all inhibiꢀ
tors 7a-j. Only inhibitor 7j showed detectable activity (Table
0
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3
4
5
6
7
8
9
0
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2
3
4
5
6
7
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0
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This work was supported by a grant from the European Union
Framework
7 (FP7) 294 program ꢀ Health.2013.2.31ꢀ1ꢀ
NABARSI, Grant agreement no: 601725.
2
, entry 1) and was screened against wider panel of strains.
The best antibacterial activity was observed against E. coli
(ATCC 25922) strains while it was weaker for other gramꢀ
negative pathogens such as K. pneumoniae, P. aeruginosa and
E. cloacae. No activity was detected against S. aureus as a
representative Gramꢀpositive pathogen. For comparison, comꢀ
pound 7c was also tested against the strains listed in Table 2,
however it showed no detectable activity against any of the
strains.
ACKNOWLEDGEMENT
We thank coordinator of NABARSI J.P Hays for the excellent
management of the consortium. We thank Dr. J. Popelis and prof.
E Liepins for assistance with NMR spectra. We thank E. Sarule
for performing elemental analysis.
ABBREVIATIONS
ITC, isothermal titration calorimetry; aaRS, aminoacylꢀtRNA
synthetase; LeuRS, leucinylꢀtRNA synthetase; IleRS, isoleucinylꢀ
tRNA synthetase; ThrRS, threoninylꢀtRNA synthetase; Tb, Trypꢀ
anosoma brucei; MIC, minimum inhibitory concentration.
Table 2. Activity of inhibitor 7j against a panel of selected
bacterial strains
Strains
Name
7j
MIC ug/mL
REFERENCES
E. coli
E. coli
BW25113
ATCC 25922
clinical isolate
PA01
ATCC 19606
clinical isolate
JE2
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64
64
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Hurdle, J. G.; O’Neill, A. J.; Chopra, I. Prospects for Amiꢀ
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(
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1
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(3)
Gadakh, B.; Van Aerschot, A. AminoacylꢀTRNA Synthetase
Inhibitors as Antimicrobial Agents: A Patent Review from
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2
1
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AcrAB. Nevertheless, neither tolC deletion strain nor AcrA
and AcrB deletion strains showed improved susceptibility to
compounds 7c,j. This indicates that the antibacterial activity
of N-leucinyl benzenesulfonamides 7 is limited by additional
mechanisms other than efflux.
Hughes, J.; Mellows, G. On the Mode of Action of Pseudoꢀ
monic Acid: Inhibition of Protein Synthesis in Staphylococꢀ
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Pope, A. J.; Moore, K. J.; McVey, M.; Mensah, L.; Benson,
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Characterization of IsoleucylꢀTRNA Synthetase from Staphꢀ
ylococcus Aureus: II. Mechanism of Inhibition by Reaction
Intermediate and Pseudomonic Acid Analogues Studied Usꢀ
ing Transient and SteadyꢀState Kinetics. J. Biol. Chem.
1999, 273 (48), 31691–31701.
(
6)
In summary, we have identified N-leucinylbenzene sulfonꢀ
amides as a novel class of E. coli LeuRS inhibitors. The simꢀ
plicity and potency of this class offers significant potential for
the development of much needed novel antibacterial agents.
ASSOCIATED CONTENT
(7)
Silvian, L. F.; Wang, J.; Steitz, T. A. Insights into Editing
Ile
from an IleꢀTRNA Synthetase Structure with TRNA and
Mupirocin. Science 1999, 285 (5430), 1074.
Supporting Information
(
(
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9)
Williamson, D. A.; Carter, G. P.; Howden, B. P. Current and
Emerging Topical Antibacterials and Antiseptics: Agents,
Action, and Resistance Patterns. Clin. Microbiol. Rev. 2017,
Synthesis and characterization of compounds 7; description of
molecular modeling; ITC titration curves; description of enzymatꢀ
ic assay and antimicrobial susceptibility.
3
0 (3), 827–860.
Hernandez, V.; Crépin, T.; Palencia, A.; Cusack, S.; Akama,
T.; Baker, S. J.; Bu, W.; Feng, L.; Freund, Y. R.; Liu, L.;
Meewan, M.; Mohan, M.; Mao, W.; Rock, F. L.; Sexton, H.;
Sheoran, A.; Zhang, Y.; Zhang, Y.ꢀK.; Zhou, Y.; Nieman, J.
A.; Anugula, M. R.; Keramane, E. M.; Savariraj, K.; Shekꢀ
har Reddy, D.; Sharma, R.; Subedi, R.; Singh, R.; O’Leary,
AUTHOR INFORMATION
Corresponding Author
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