Discovery of Pyrazolopyridones as a Novel Class of Gyrase B Inhibitors Using Structure Guided Design

Article abstract of DOI:10.1021/acsmedchemlett.5b00368

The ATPase subunit of DNA gyrase B is an attractive antibacterial target due to high conservation across bacteria and the essential role it plays in DNA replication. A novel class of pyrazolopyridone inhibitors was discovered by optimizing a fragment screening hit scaffold using structure guided design. These inhibitors show potent Gram-positive antibacterial activity and low resistance incidence against clinically important pathogens.

Full text of DOI:10.1021/acsmedchemlett.5b00368

Letter
pubs.acs.org/acsmedchemlett
Discovery of Pyrazolopyridones as a Novel Class of Gyrase B
Inhibitors Using Structure Guided Design
Jason B. Cross,*,† Jing Zhang,† Qingyi Yang,† Michael F. Mesleh,† Jan Antoinette C. Romero,† Bin Wang,†
Doug Bevan,† Katherine M. Poutsiaka,† Felix Epie,† Terence Moy,† Anu Daniel,† Joseph Shotwell,†
Brian Chamberlain,† Nicole Carter,† Ole Andersen,‡ John Barker,‡ M. Dominic Ryan,†
Chester A. Metcalf, III,† Jared Silverman,† Kien Nguyen,† Blaise Lippa,† and Roland E. Dolle†
†Cubist Pharmaceuticals, Inc., 65 Hayden Avenue, Lexington, Massachusetts 02421, United States
‡Evotec U.K., Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom
S
* Supporting Information
ABSTRACT: The ATPase subunit of DNA gyrase B is an
attractive antibacterial target due to high conservation across
bacteria and the essential role it plays in DNA replication. A
novel class of pyrazolopyridone inhibitors was discovered by
optimizing a fragment screening hit scaffold using structure
guided design. These inhibitors show potent Gram-positive
antibacterial activity and low resistance incidence against
clinically important pathogens.
KEYWORDS: Antibacterials, DNA gyrase B, fragment-based drug design, structure-based drug design
acterial DNA gyrase is the molecular target for the
An X-ray crystallographic structure of 2a bound to a 24 kDa
Bclinically important fluoroquinolone drug class, making it a construct of S. aureus GyrB containing the ATPase domain
(PDB ID 5CTY)13 provided a reference for structure-based
optimization of this scaffold. Several key binding interactions
are highlighted in Figure 1b, with amino acid numbering based
on the Sa sequence. A hydrogen bond donor−acceptor motif
was clearly seen between the pyrazole of 2a, the carboxylate
side chain of Asp81 (Asp73 Ec numbering), and a conserved
water molecule stabilized by hydrogen bonds to Asp81, Gly85,
and Thr173 (Ec Asp73, Gly77, and Thr165, respectively).
Lipophilic contacts were evident between the central thiazole
and Ile86 (Ec Ile78). The pyridine ring stacked with Arg84 (Ec
Arg76), forming a π−cation interaction, and also participated in
a hydrogen bond with the cationic side chain of Arg144 (Ec
Arg136). There was also a hydrogen bond formed between the
pyridone carbonyl oxygen and the side chain of Asn54 (Ec
Asn46). Trius reported that interaction with Asn54 was a
critical feature of their tricyclic GyrB inhibitors, which greatly
improved enzymatic and antibacterial activities.14
In addition to the protein−ligand interactions observed in
the X-ray costructure with 2a, there was also clear electron
density for two water molecules deeply trapped in a small
hydrophobic pocket between Ile51 and Ile175 (Ec Val43 and
Val167). Water analysis using 3D-RISM (as implemented in
MOE15) was performed on this X-ray structure with compound
2a present and with compound 2a removed (mimicking the
apo protein). Analysis of the pseudoapo binding site (Figure
highly valuable target for antibacterial research.1 Functionally,
DNA gyrase exists as an A2B2 tetramer that binds dsDNA and
catalyzes strand breakage/reformation that leads to the
introduction of negative supercoils.2,3 Novel chemotypes that
bind to other regions of the protein complex would have the
advantage of avoiding on-target fluoroquinolone resistance
mechanisms. Inhibition of the ATPase activity of the GyrB
subunit is known to block bacterial DNA replication, resulting
in potent antibacterial activity.4−9 There is high sequence and
structural homology between GyrB and the ParE subunit of
topoisomerase IV, which presents the possibility of dual-
targeting that is expected to lead to improved bacterial
resistance. As a result, there has been considerable interest in
targeting both GyrB and ParE simultaneously.5,6,8,9
Identification of novel scaffolds with antibacterial activity
using synthetic library screening approaches, i.e., high-
throughput screening, has yielded few tractable lead com-
pounds, despite large-scale screening campaigns conducted by
pharmaceutical companies.10 An alternate strategy for hit
identification is fragment-based drug design (FBDD). This
technique has been used successfully to find novel hits in
several therapeutic areas, including antibacterials.9,11
A fragment-based screen using NMR as the detection
method was conducted to identify novel scaffolds that bind
to the GyrB ATPase site. One of the most promising hits was a
pyrazolopyridone, compound 1 (Figure 1a), chemically similar
to a primary hit from the screen. Structure guided design
techniques were used to improve the potency of the fragment
hit, leading to a novel compound 2a.12
Received: September 20, 2015
Accepted: February 6, 2016
© XXXX American Chemical Society
A
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Figure 1. (a) Pyrazolopyridone fragment hit was transformed into a lead using structure guided design. (b) Key interactions between GyrB and the
pyrazolopyridone scaffold (compound 2a, cyan), including hydrogen bonds to Asp81, Asn54, Arg144, and water molecules, as well as a π−cation
stacking interaction with Arg84 (Sa numbering). (c) 3D-RISM analysis of the GyrB ATPase site. Calculations were performed without a ligand
occupying the active site; compound 2a (cyan) was overlaid on the 3D-RISM results for clarity. Energetically favorable water molecules predicted
using 3D-RISM are green, and energetically disfavored water molecules are red. (d) 3D-RISM analysis of the GyrB ATPase site with compound 2a
(cyan) present. An energetically favored water site (green sphere) overlays a tightly bound water molecule bound to Asp81, Gly85, and Thr173,
while two poorly bound water sites (red/gray spheres) overlay water molecules in the hydrophobic binding site adjacent to Asn54. Graphics
generated using MOE.15
1c) suggested that highly bound water molecules (green)
should exist at the sites of the crystallographically conserved
water molecule and at the nitrogen of the pyridine ring
(calculated free energies of −19.8 and −6.1 kcal/mol,
respectively). These results indicate that displacement of
water from these positions is unlikely without very favorable
compensatory protein−ligand interactions.
In addition, there were several water sites in the pseudoapo
binding site that were predicted to have poorly bound water
molecules (Figure 1c, red, pink, and gray). These included sites
that overlapped the pyrazolopyridone (4.2 and 0.7 kcal/mol)
and were within the van der Waals radius of the thiazole sulfur
atom (1.0 kcal/mol), as well as the hydrophobic pocket (0.8
and 0.6 kcal/mol). Coverage of these regions of the active site,
as in compound 2a, resulted in nanomolar inhibition and a
promising starting point for optimization.
Table 1. Enzymatic and in Vitro Antibacterial Activities of
Pyrazolopyridone Analogues Containing Pyridone
Substitutions
Sa GyrB
ATPase IC50
(μM)
Sa42 MSSA
MIC
Cpd
Moxifloxacin
R1
R2
R3
(μg/mL)
0.06
>32
>32
2
2a
2b
2c
2d
2e
2f
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
0.270
0.051
0.020
0.006
0.004
0.564
0.035
0.202
3.349
3.248
1.315
Me
H
Et
H
n-Pr
H
0.06
0.25
>32
2
Allyl
H
CH2CH2OH
H
Solvent analysis of the bound structure of compound 2a
showed that the water molecules in the hydrophobic pocket
were still moderately or poorly bound in the presence of an
inhibitor (1.0 and −0.2 kcal/mol), as seen in Figure 1d. This
suggested an opportunity for improvement of binding affinity
by displacing these water molecules.
2g
2h
2i
Et
Et
Et
H
H
Me
CH2OH
>32
>32
ND
ND
CONHMe
2j
H
H
2k
Based on these analyses, structure-based optimization was
undertaken to explore the SAR of the pyridone ring (Table 1).
Scheme 1 outlines the synthesis of analogues with various
substituents on the pyrazolopyridone ring. At the R1 position,
improvements in IC50 and whole cell activity (as measured by
MICs against Sa42, a methicillin-susceptible S. aureus strain)
correlated with n-alkyl extension into the hydrophobic pocket,
consistent with the results of the 3D-RISM calculations.
B
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Scheme 1. Synthetic Route for Varying Substituents on the
a
Pyrazolopyridone Ring
Figure 2. X-ray structure of compound 2d bound to S. aureus GyrB
(1.70 Å resolution; PDB ID 5D7D). The lipophilic pocket is filled by
the n-propyl group attached to the pyridone. Graphics generated using
MOE.15
Table 2 outlines a series of substitutions that were made at
the 2-position of the pyridine group of compound 2d, in order
Table 2. Enzymatic and in Vitro Antibacterial Activities of
Pyrazolopyridone Analogues Containing Pyridine
Substitutions
Sa GyrB ATPase IC50
Sa42 MSSA MIC
(μg/mL)
Cpd
R
(uM)
3a NMe2
0.015
0.5
2
a
Reagents and conditions: (a) Pd(dppf)Cl2, dioxane, Na2CO3, 100 °C,
3b 4-methylpiperazine
3c Me
0.008
55%; (b) n-BuLi, CH3CN, −78 °C, THF, 35%; (c) t-BuNHNH2,
NEt3, iPrOH, 80 °C, 50%; (d) POCl3, DMF, 70 °C, 100%; (e) 40%
aq. NaOH, EtOH, 80 °C, 52%; (f) R1X, Cs2CO3, DMF, RT; (g) TFA,
70 °C; (h) diethylmalonate, piperidine, EtOH, 80 °C; (i) 40% HBr,
140 °C, mv; (j) LiOH, THF/MeOH; (k) CH3NH2, HATU, DMF,
20%; (l) NBS, 25 °C, 87%; (m) HOCH2Sn(Bu)3, Pd(PPh3)2Cl2,
dioxane, mv, 120 °C, 10%; (n) (MeBO)3, Pd(dppf)Cl2, dioxane,
Na2CO3, 110 °C, 12%; (o) 1. AcOH, 110 °C; 2. TFA, 70 °C; (p) 1.
OsO4, NMO, 53%; 2. NaIO4, MeOH, 66%; 3. NaBH4, MeOH, 33%.
<0.008
<0.008
0.023
0.25
0.25
1
3d CH2OH
3e i-Pr
3f
3g CH2-4-
methylpiperazine
3h CH2NEt2
CH2-morpholine
<0.008
0.010
0.5
4
0.009
0.015
0.008
<0.008
0.013
4
3i
3j
COOMe
CONMe2
0.5
2
3k CONHCH2CH2NEt2
1
Optimal enzymatic and whole cell potency for R1 substitutions
was achieved through incorporation of an n-propyl group
(compound 2d), resulting in complete displacement of water,
as seen in a high resolution X-ray structure (Figure 2, PDB ID
5D7D). Introduction of an allyl group (compound 2e)
maintained activity in the enzymatic assay relative to compound
2d, but resulted in poorer whole cell activity, while hydrophilic
groups, such as hydroxyethyl (compound 2f), were not
tolerated.
3l
CONHCH2CH2-
morpholine
2
to modulate the physicochemical properties of the series, while
Scheme 2 illustrates the route used for synthesis.
Consistent with the solvent exposed nature of pocket beyond
the arginine interaction region, along with the 3D-RISM water
analysis, the pyridine 2-position tolerated a variety of different
chemical substitutions while maintaining enzymatic potency.
However, whole cell activities were impacted by differences in
the composition of the substituent. Small substituents, such as
those of compounds 3a, 3c, and 3d, generally had the best
whole cell activity, but some larger substituents (compounds 3f
and 3i) did result in reasonable MICs, albeit inconsistently.
While substitutions in this region allowed exploration of
physicochemical properties, including features such as charge
state, hydrophobicity, and polar surface area, cheminformatics
analyses showed little correlation between these properties and
whole cell activity. This resulted in a design strategy that
favored physicochemical property diversity and the use of
The R2 position only tolerated substitution of small groups,
such as methyl (compound 2g), which was consistent with the
constricted binding pocket features observed in the S. aureus
GyrB X-ray structures. Larger substitutions, including those
with hydrophilic groups, had poor enzyme and whole cell
activity.
Hydrogen at the R3 position resulted in the best potency of
the substitutions explored, due to the need for a small dihedral
angle between the pyrazolopyridone and thiazole rings. Larger
dihedral angles, caused by larger substituents at the R3 position
(compounds 2j and 2k), resulted in unfavorable interactions
between the thiazole and lipophilic wall of the protein.12
C
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Letter
a
electronic structure of this linker. Generally, moderately sized
polar groups were tolerated in this position (e.g., compounds
4c and 4d), but this did not translate into robust whole cell
activity.
Scheme 2. Synthetic Route for Pyridine Analogues
Alternate linkers that replace the central thiazolyl ring were
also explored using in silico scaffold replacement techni-
ques.15,16 Although linear and saturated ring linkers were
somewhat tolerated, all compounds of this type suffered from
decreased enzymatic activity and MICs. Care also had to be
taken in the design of these compounds to ensure interactions
in the arginine region of the pocket were maintained as the
linker was varied. This often required simultaneous modifica-
tion of the linker and tail group, as evidenced by compound 4e.
Further characterization of compounds 2c and 2d was carried
out against Sa ParE ATPase (Table 4). These compounds were
a
Reagents and conditions: (a) n-PrNH2, 130 °C, 50%; (b) n-BuLi,
HCOOEt, THF, −78 °C; (c) NH2NH2, P2O5, EtOH, 80 °C, 25% over
2 steps; (d) NIS, DCE, 85 °C, 68%; (e) DDQ, dioxane, 110 °C, 99%;
(f) Dihydropyran, TFA, 95 °C, 80%; (g) Pd(PPh3)2Cl2, Me6Sn2,
dioxane, 110 °C, 37%; (h) 1. Pd(PPh3)2Cl2, P(furyl)3, 100 °C; 2. TFA;
(i) Pd(PPh3)2Cl2, P(furyl)3, 100 °C; (j) NBS, DMF.
Table 4. GyrB/ParE Activity and Resistance Profiles of
Compound 2c and 2d
Cpd
2c
20
2d
Sa GyrB ATPase IC50 (nM)
Sa ParE ATPase IC50 (nM)
RI @ 4× MIC vs Sa
6
746
<10−9
183
3 × 10−9
structure-based design to drive improvements in ATPase
inhibition.
The thiazolyl and pyridyl rings of compound 2d were also
varied to explore the SAR of this part of the scaffold (Table 3).
Removal of the pyridyl ring (compound 4a) resulted in a ∼50-
fold loss in IC50, underscoring the importance of the Arg84 and
Arg144 interactions in enzymatic potency.
MIC (μg/mL)
Sa1118 MRSA
2
4
4
4
0.06
0.06
0.125
0.25
Sa1721 MRSA CiproR
E. faecium (ATCC 6569)
S. pneumonia (ATCC 6303)
chosen because they were available early in the program and, at
the time, had the best MICs. Both compounds showed activity
against Sa ParE, though they were 30- to 40-fold weaker against
these enzyme subunits than Sa GyrB. Interaction with Ile86
(Ile78 in Ec GyrB), which is Met79 in Sa ParE, has been
suggested by Charifson et al.6 to contribute to dual activity.
Since our compounds did not extend as far along this
hydrophobic wall, ParE activity may have suffered. The weak
ParE activity could be a contributing factor to the lower than
expected RI observed for these compounds (∼10−9), if they are
considered single-target antibacterials; however, activity on
another, unknown target cannot be ruled out as a cause.
The MICs for compounds 2c and 2d remained unchanged
against a ciprofloxacin resistant MRSA strain (Sa1721 MRSA
CiproR, Table 4). In comparison, moxifloxacin has a sizable
MIC shift when tested against ciprofloxacin resistant MRSA
(Sa1118 MRSA MIC = 0.06 μg/mL vs Sa1721 MRSA MIC > 2
μg/mL). This strongly suggests the site of action of the
pyrazolopyridone compounds is not in the fluoroquinolone
binding site and that target-based fluoroquinolone resistance
mechanisms are not likely an issue for this class of inhibitor.
Both compounds also displayed potent whole cell activity
against other Gram-positive organisms, including E. faecium and
S. pneumoniae, suggesting broad coverage of Gram-positives.
In conclusion, NMR-based fragment screening and hit
follow-up identified pyrazolopyridone as a novel, active
chemical scaffold against Sa GyrB. Medicinal chemistry efforts,
guided by structure-based drug design, resulted in the discovery
of pyrazolopyridone analogues with potent dual GyrB/ParE
enzymatic activity, excellent resistance profiles, and broad
spectrum Gram-positive antibacterial activity. The most potent
analogue described herein, compound 2d, showed whole cell
activity against MRSA equivalent to that of moxifloxacin, while
retaining activity against a ciprofloxacin resistant S. aureus
A regioisomer of the thiazolyl moiety was used to explore
substitutions from this ring without significantly altering the
Table 3. Enzymatic and in Vitro Antibacterial Activities of
Pyrazolopyridone Analogs with Linker (L) and Tail (R)
Region Modifications
D
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.5b00368.
General procedure for GyrB and TopoIV IC50
determination, MIC protocol, X-ray structure determi-
nation, experimental procedure for synthesis of com-
pounds (PDF)
(10) Payne, D. J.; Gwynn, M. N.; Holmes, D. J.; Pompliano, D. L.
Drugs for Bad Bugs: Confronting the Challenges of Antibacterial
Discovery. Nat. Rev. Drug Discovery 2007, 6, 29−40.
(11) Rees, D. C.; Congreve, M.; Murray, C. W.; Carr, R. Fragment-
Based Lead Discovery. Nat. Rev. Drug Discovery 2004, 3, 660−672.
(12) Mesleh, M. F.; Cross, J. B.; Zhang, J.; Kahmann, J.; Andersen, O.
A.; Barker, J.; Moy, T. I.; Yang, Q.; Shotwell, J.; Nguyen, K.; Lippa, B.;
Dolle, R.; Ryan, M. D. Fragment-Based Discovery of Novel DNA
Gyrase Inhibitors Targeting the ATPase Subunit of GyrB. Bioorg. Med.
Chem. Lett. 2016, 26, 1314.
AUTHOR INFORMATION
Corresponding Author
*Tel: 1-713-745-7499. E-mail: jbcross@mdanderson.org.
Notes
■
The authors declare no competing financial interest.
(13) Zhang, J.; Yang, Q.; Romero, J. A. C.; Cross, J.; Wang, B.;
Poutsiaka, K. M.; Epie, F.; Bevan, D.; Wu, Y.; Moy, T.; Daniel, A.;
Chamberlain, B.; Carter, N.; Shotwell, J.; Arya, A.; Kumar, V.;
Silverman, J.; Nguyen, K.; Metcalf, C. A., III; Ryan, D.; Lippa, B.;
Dolle, R. E. Discovery of Indazole Derivatives as a Novel Class of
Bacterial Gyrase B Inhibitors. ACS Med. Chem. Lett. 2015, 6, 1080−
1085.
(14) Li, X.; Tari, L. W.; Bensen, D. C.; Trzoss, M.; Lam, T.; Zhang,
J.; Chen, Z.; Lee, S.-J.; Cunningham, M.; Kwan, B.; Nelson, K.;
Stidham, M.; Brown-Driver, V.; Hough, G.; Phillipson, D.; Nguyen, T.;
Lightstone, F.; Wong, S.; Shaw, K. J.; Finn J. Presented at the 52nd
Interscience Conference on Antimicrobial Agents and Chemotherapy
(ICCAC), 2012, Poster F-2017.
(15) Molecular Operating Environment (MOE), 2014.09; Chemical
Computing Group Inc.: Montreal, QC, 2014.
(16) Maass, P.; Schulz-Gasch, T.; Stahl, M.; Rarey, M. ReCore: A
Fast and Versatile Method for Scaffold Hopping Based on Small
Molecule Crystal Structure Conformations. J. Chem. Inf. Model. 2007,
47, 390−399.
ACKNOWLEDGMENTS
The authors thank the reviewers of this manuscript for their
insightful comments.
■
ABBREVIATIONS
■
Cipro, ciprofloxacin; Ec, Escherichia coli; MIC, minimum
inhibitory concentration; MRSA, methicillin-resistant Staph-
ylococcus aureus; MSSA, methicillin-sensitive Staphylococcus
aureus; RI, resistance incidence; Sa, Staphylococcus aureus
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