Scaffold Morphing To Identify Novel DprE1 Inhibitors with Antimycobacterial Activity

Article abstract of DOI:10.1021/acsmedchemlett.9b00343

We report a novel benzimidazole (BI) based DprE1 inhibitor that resulted from scaffold morphing of a 1,4-azaindole series. The clinical progression of the 1,4-azaindole series from our previous work validates the potential of exploring newer chemical enti

Full text of DOI:10.1021/acsmedchemlett.9b00343

Letter
pubs.acs.org/acsmedchemlett
Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Scaffold Morphing To Identify Novel DprE1 Inhibitors with
Antimycobacterial Activity
Manjunatha M. R,† Radha Shandil,‡,∇ Manoranjan Panda,† Claire Sadler,§ Anisha Ambady,∥
Vijender Panduga,‡ Naveen Kumar,‡ Jyothi Mahadevaswamy,∥ M. Sreenivasaiah,† Ashwini Narayan,∥
Supreeth Guptha,∥ Sreevalli Sharma,∥ Vasan K. Sambandamurthy,∥ Vasanthi Ramachandran,∥
Meenakshi Mallya,† Christopher Cooper,⊥ Khisi Mdluli,⊥ Scott Butler,# Ruben Tommasi,#
Pravin S. Iyer,† Shridhar Narayanan,*,∥,∇ Monalisa Chatterji,*,∥ and Pravin S. Shirude*,†,○
†Department of Medicinal Chemistry, IMED Infection, AstraZeneca India, Bellary Road, Hebbal, Bangalore-560024, India
‡DMPK and Animal Sciences, IMED Infection, AstraZeneca, Bangalore-560024, India
§Safety Assessment, IMED, AstraZeneca, Alderly Park, Mereside, U.K.
∥Department of Biosciences, IMED Infection, AstraZeneca, Bangalore-560024, India
⊥Global Alliance TB, New York, New York 10005, United States
#Infection IMED, AstraZeneca, GHP, Waltham, Massachusetts 02451, United States
S
* Supporting Information
ABSTRACT: We report a novel benzimidazole (BI) based DprE1 inhibitor
that resulted from scaffold morphing of a 1,4-azaindole series. The clinical
progression of the 1,4-azaindole series from our previous work validates the
potential of exploring newer chemical entities with antimycobacterial activity
driven via a noncovalent inhibition of the decaprenylphosphoryl-β-D-ribose-2′-
epimerase (DprE1). The representative compounds from the new scaffold
reported in this study exhibited an improved solubility and higher free plasma
fraction, while retaining potent DprE1 inhibition and antimycobacterial activity.
A representative compound from the benzimidazole series demonstrated good
efficacy in a murine model of tuberculosis. Furthermore, molecular modeling of
the BI scaffold suggests plausible modes of binding in the active site of DprE1
enzyme from Mycobacterium tuberculosis that can be used for further exploration
of the series.
KEYWORDS: DprE1, Mycobacterium tuberculosis, azaindole, benzimidazole
uberculosis (TB) continues to be a global emergency
Twith the World Health Organization (WHO) reporting
an estimated 10 million new cases and 1.3 million deaths in
2017.1 The emergence of multidrug-resistant tuberculosis
(MDR-TB) and extremely drug-resistant tuberculosis (XDR-
TB) makes TB treatment challenging and highlighted an
urgent need to develop new TB drugs with a novel mechanism
of action.1 Several published reports from our group as well as
others have focused on targeting the decaprenylphosphoryl-β-
D-ribose-2′-epimerase (DprE1) of Mycobacterium tuberculosis
(Mtb), an essential enzyme involved in cell wall synthesis for
the identification of promising antitubercular agents.2−8 DprE1
is involved in the conversion of decaprenylphosphoryl-β-D-
ribose (DPR) to decaprenylphosphoryl-β-D-arabinofuranose
(DPA), a precursor of the mycobacterial cell wall arabinan.8
The identification of both covalent (e.g., BTZ043, PBTZ-
169) and noncovalent (e.g., TBA7371) inhibitors of DprE1
that are efficacious in various murine models of TB has
provided pharmacological validation of this important target in
the physiology of Mtb.2−10 Our earlier study reported 1,4
azaindolesa novel chemical series with an excellent in vivo
antimycobacterial activity achieved via noncovalent inhibition
of DprE1,4−6 which has advanced to first in human clinical
studies.7 This promising development mandates the need to
explore newer chemical entities toward populating the TB drug
pipeline.
Scaffold-morphing, a medicinal chemistry tool for molecular
backbone replacements, is a rational drug-design strategy that
has been used to build novel molecules with potentially
improved properties and generating, new intellectual property
(IP) space, while retaining the primary potency. Such drug-
design strategies are limited only by synthetic feasibility of new
scaffolds and are essentially chemistry-driven approaches. We
utilized a scaffold morphing approach with the objective of
identifying novel DprE1 inhibitors with diverse physicochem-
Received: July 29, 2019
Accepted: September 23, 2019
Published: September 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.9b00343
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ACS Medicinal Chemistry Letters
Letter
ical properties. Our scaffold morphing efforts led to the
identification of benzimidazole (BI) series, by the replacement
of the azaindole core with an alternative 5,6 fused bicyclic
heteroaromatics. This new scaffold retains potent DprE1
enzyme inhibition with potent antimycobacterial activity
coupled with improved properties including aqueous solubility,
similar logD, and increased free plasma fraction. A
representative benzimidazole compound assessed in a murine
model of TB demonstrated efficacy similar to the reported
azaindoles.5 In silico docking with DprE1 predicts different
binding interactions between the benzimidazole and the
azaindole scaffold. These new scaffolds have the potential to
be developed for the treatment of drug sensitive and drug
resistant tuberculosis therapy.
We designed several alternate scaffolds starting from the 1,4-
azaindole series (1). One of them was envisaged by moving the
N-4 nitrogen to the N-3 position, and subsequently trans-
posing the amide side chain from C-3 to the C-4 position
resulting in a new 5,6-fused bicyclic heteroaromatic core. The
resulting benzimidazole (2) compound was synthesized and
characterized for DprE1 enzyme inhibition and antimycobac-
terial activity (Figure 1). Although the azaindole core was
antimycobacterial activity (compounds 2−10). Based on the
knowledge gained from azaindole SAR, the optimal hydro-
phobic groups were retained in the exploration of SAR with the
BI series. Substitution at the C-6 position of the benzimidazole
core with methyl or methoxy groups also enhanced
antimycobacterial activity, as observed for azaindoles (com-
pound 2 vs compounds 3−10). All resulting BI compounds
exhibited potent DprE1 enzyme inhibition and potent Mtb
MIC (Table 1).
The synthesis of benzimidazole analogues is outlined in
Schemes 1−3. Synthesis was initiated with the commercially
available starting material, A. Benzimidazole was obtained
using formic acid and iron to yield B, which was further
alkylated with benzyl halide in the presence of cesium
carbonate to give compound C. Further hydrolysis of C to
acid D followed by amide coupling using HATU afforded
target molecule 2 (Scheme 1). The synthesis of the 6-methyl
group on the benzimidazole core involved the bromination of
A to afford E followed by Suzuki reaction to yield intermediate
F. Similar to Scheme 1, intermediate F was used to synthesize
compounds 3−6 (Scheme 2). To introduce 6-methoxy
functionality on benzimidazole core, the syntheses involved
the acetylation of 2-amino-5-methoxybenzoic acid (G) to give
intermediate H, which was subsequently hydrolyzed to yield
N-acetyl benzoic acid I. Nitration of I using nitronium
tetrafluoroborate yielded intermediate J, which was further
deprotected with 6 N HCl to obtain K. Reduction followed by
cyclization yielded benzimidazole core L, which on ester-
ification gave an intermediate M. Similar to Scheme 1,
intermediate M was used to obtain compounds 7−10 (Scheme
3).
The BI analogs and TBA7371 were docked (Glide6.1-
Schrodinger)11,12 to the Mtb DprE1 enzyme active site using
multiple published crystal structures.13−15 One of the potential
binding modes for BI (3) from unconstrained docking is
shown in Figure 2A (pdb ID 4KW5 binding site).15 The amide
carbonyl oxygen forms an H-bond contact with Ser228 and the
amide NH with the cofactor FAD carbonyl oxygen. The core
benzimidazole ring is engaged with Trp230 and Tyr314 via
CH−π contacts (Figure 2A). The terminal F atom is in close
proximity with Asn385 side chain. The substituted pyrimidine
is partly exposed to solvent. The hydrophobic contacts with
Trp230, Leu263, and val365 may be influencing its
conformation. An overlay with the binding mode of azaindole
(Figure 2B) revealed a similar binding mode for the amide
group. However, the relative disposition of the substituents
between the two chemotypes is reflected in the shift of the core
rings and conformational change in substituted pyrimidine
ring. The presence of multiple polar side chains, hydrophilic
centers, and a disordered loop (residues 316−322) in the
active site of DprE1 led to alternate possible binding modes for
these inhibitors (2, Supporting Information Figure S1). The
putative binding mode of BI suggests that wider structural
diversity can be accommodated for this target.
Figure 1. Scaffold morphing of azaindole to benzimidazole (BI).
altered, the hydrophobic group and the amide side chain were
retained in the BI scaffold. The presence of a 6-methoxy-5-
methylpyrimidine-4-yl group maintained the overall hydro-
phobic footprint and hydrogen bond acceptor nature, similar
to the 1,4-azaindoles, while the amide side chain maintained an
envisaged critical hydrogen bond donor−acceptor interaction
with the DprE1 enzyme. The benzimidazole compound 2
retained antimycobacterial activity with potent enzymatic
inhibition of the Mtb DprE1 enzyme, suggesting a similar
mode of action. Thus, our scaffold-morphing medicinal
chemistry design strategy has resulted in the successful
identification of BI ring system as a potent DprE1 inhibitors.
Analogous to the azaindoles,4,5 we have also established a
minimal inhibitory concentration (MIC)-based structure−
activity relationship (SAR) against Mtb for BI. Three
diversification points were maintained, namely, the amide
side chain, hydrophobic group, and core ring substitutions
(Table 1). The secondary amide of the amide side chain is
critical for maintaining a potent MIC and is hypothesized to be
involved in hydrogen bonding with the DprE1 enzyme
(compounds 2−10, Table 1). Small hydrophobic amides
such as fluoro-ethyl and difluoro ethyl amides are preferred for
From the scaffold morphing output, we decided to test a
representative compound for efficacy in a murine model of TB.
The microbiological profiling of compound 2 demonstrated a
profound bactericidal activity with >3 log10 CFU reduction in
10 days at 1−2× MIC concentration (Figure 3). In an
intracellular THP1 macrophage model, ∼1 log10 CFU
reduction was observed following treatment with compound
2 in 7 days at MIC concentration (Figure 3). In addition, 2
was active against other mycobacteria like Mycobacterium
B
DOI: 10.1021/acsmedchemlett.9b00343
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ACS Medicinal Chemistry Letters
Letter
Table 1. Structure−Activity Relationship of BI Analogues
C
DOI: 10.1021/acsmedchemlett.9b00343
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ACS Medicinal Chemistry Letters
Letter
a
Scheme 1. Synthesis of BI Analogues
Figure 3. (A) Bactericidality of 2. (B) Intracellular efficacy of 2 in
THP1 model.
a
Reagents/conditions: (a) HCOOH, Fe, iPrOH, 80%; (b) 4-
(chloromethyl)-6-methoxy-5-methylpyrimidine, CsCO3, DMF, 60%;
(c) LiOH, MeOH, 80%; (d) HATU, 2-fluoroethanamine, NMP, 60%.
expressing DprE1; BTZ043 resistant strains: DprE1 with a
C387G/S mutation; 1,4-azaindole resistant strain: DprE1 with
Y314H mutation. There was a ∼20-fold shift in MIC observed
for H37Rv overexpressing DprE1 compared to wild-type Mtb.
Also, a similar MIC shift was observed for an Mtb H37Rv
strain harboring a DprE1 Y314H mutation, whereas the MIC
was retained for H37Rv with DprE1 C387C/S strains (Table
2). Resistant mutants to compound 2 arose at the frequency of
10−7 and 10−8 CFU/mL at 8- and 16-fold MIC concentration,
respectively. A ∼10-fold shift in MIC was observed for
resistant mutants compared to the wild-type. The dprE1 gene
sequenced from clones resistant to compound 2 showed a
tyrosine to serine substitution at amino acid position 314.
The representative compounds from the BI series were
profiled for in vitro drug metabolism and pharmacokinetic
(DMPK) and in vitro safety properties, as described in Table 4.
The measured log D for the BI series ranges between 1.9 and
2.1 (compounds 2 and 9). Measurement of aqueous solubility
from DMSO-dried solids for BI compounds (9) was
significantly improved compared to the azaindole scaffold
(1) (Table 3). The improved solubility could be attributed to
the combination of the BI scaffold and 6-(dimethylamino)-5-
methylpyrimidine-4-yl group. Moreover, the human plasma
protein binding (PPB, % free) for BI compounds 2 and 9
overall shows an improved trend compared to azaindole
(Table 3). Based upon in vitro intrinsic clearance (Clint) using
human microsomes and rat hepatocytes, the predicted in vivo
clearance (CL) for compounds 2 and 9 ranged between 25 and
61% of liver blood flow (% LBF). In contrast, the in vitro
intrinsic clearance was higher in the presence of mouse liver
microsomes similar to azaindoles (data not shown), suggesting
species specific clearance mechanisms. Both series exhibit high
permeability with no significant efflux activity as measured in a
Caco2 assay and did not show inhibition of cytochrome P450
(CYP) enzymes (Table 3), suggesting a low probability for
drug−drug interactions. In vitro safety profiling of representa-
tive compound (2) from BI series against a panel of ∼28 high
severity human targets and the hERG channel indicated no
major safety liabilities (Table 3).
a
Scheme 2. Synthesis of 6-Substituted BI Intermediate
a
Reagents/conditions: (a) AcOH, Br2 90%; (b) 2,4,6-trimethyl-
1,3,5,2,4,6-trioxatriborinane, Pd(PPh3)2Cl2, K2CO3, DME, 80%.
a
Scheme 3. Synthesis of 6-Substituted BI Analogues
a
Reagents/conditions: (a) Ac2O, 90%; (b) H2O, 90%; (c) NO2BF4,
CH3CN, 85%; (d) 6 N HCl, 100%; (e) HCOOH, Fe, iPrOH, 85%;
(f) H2SO4, MeOH, 90%.
A representative compound from BI series (2) was evaluated
for its pharmacokinetic properties in mice and rats. Good oral
bioavailability and moderate clearance was observed for
compound 2 in rats (Table 3). The exposure in mice was
measured in the presence of 1-aminobenzotriazole (ABT), a
pan-inhibitor of CYP isoforms used to block mouse specific
clearance mechanism (Figure 4A). Significant exposure with
plasma levels above MIC for 6−10 h was observed. The
bactericidality of compound 2 was assessed in a BALB/c
model of “chronic” TB infection, wherein treatment was
Figure 2. (A) Proposed binding mode of BI (3) in the DprE1 active
site. (B) Overlay of docked poses of 1,4-azaindole (1, magenta) and
BI (3, green).
smegmatis (MIC 0.78−1.56 μM). However, 2 was inactive
against a panel of Gram positive and negative bacteria (>200
μM) thereby highlighting their specificity to mycobacterial
species. Since compound 2 retained activity against the DprE1
enzyme, the compound was tested for antibacterial activity on
available DprE1 related Mtb strains namelyH37Rv over-
D
DOI: 10.1021/acsmedchemlett.9b00343
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ACS Medicinal Chemistry Letters
Letter
Table 2. Microbiological Properties of Key Compounds
MIC (μM)
DprE1 C387G
#
H37Rv
DprE1 OE
DprE1 C387S
DprE1 Y314H
DprE1 Y314S
2
1.56−3.12
0.003−0.006
0.44
25−50
12.5
0.22
0.78
25
0.44
0.005
0.78
25
0.44
0.005
25−50
0.003
0.44
25
BTZ043
isoniazid
rifampicin
0.006
0.22
0.01
0.01
0.005
0.01
enzyme inhibition. This novel scaffold exhibited improved
solubility and higher free plasma fraction with a representative
benzimidazole compound demonstrating efficacy in a chronic
model of murine TB.
Table 3. DMPK and Safety Properties of BI Compounds
properties
1
2
9
log D
1.8
1.9
2
solubility (μM)
human CLpred microsomes (%
LBF)
170
19
152
25
>1000
61
ASSOCIATED CONTENT
* Supporting Information
■
S
rat CLpred hepatocytes (% LBF)
human PPB (% free)
14
22
11/30
>50
>33
25
32
37/14
>50
>33
52
31
26/22
>50
>33
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.9b00343.
Caco-2 A-B/B-A (1 × 10−6 cm/s)
b
CYP inhibition (μM)
Experimental details and H and 13C NMR spectra for
1
hERG (μM)
secondary pharmacology hits
c
a
new synthetic intermediates and products; assay
information (PDF)
no significant hits
ND
rat PK
CL (mL/min/kg)
F (%)
27
100
48
114
ND
ND
a
b
AUTHOR INFORMATION
Corresponding Authors
*E-mail: psshirude@gmail.com (P.S.S.).
*E-mail: monalisa.chaterji@gmail.com (M.C.).
*E-mail: shridhar.narayanan@fndr.in (S.N.).
ND: not determined. CYP1A2, CYP2C9, CYP2C19, CYP2D6,
■
c
CYP3A4. Panel of ∼28 high severity targets (binding and functional
data): IC50, >100 or >30 μM.
ORCID
Ruben Tommasi: 0000-0002-1573-7422
Pravin S. Shirude: 0000-0001-5950-6768
Present Addresses
○Biocon Bristol-Myers Squibb Research and Development
Centre, Bommasandra Jigani Link Rd, Bangalore-560099,
India. Tel: + 91 8698018138.
Figure 4. (A) Time vs conc. (mean
SD, n = 3) of 2 following
∇Foundation for Neglected Disease Research, 20A, KIADB
Industrial Area, Veerapura, Dodda-ballapur, Bengaluru-
561203, India.
multiple oral dose administration in Mtb infected male Balb/C mice
at 10 and 30 mg/kg. (B,C) Efficacy of 2 in chronic TB infection
model in BALB/c mice.
Author Contributions
started 28 days postinfection via the aerosol route.16,17 After 4
weeks of treatment the bacterial burden was reduced by ∼1.5
and ∼1 log10 CFU in lungs and spleen at 30 mg/kg dose,
respectively (Figure 4B). The oral exposure of compound 2
assessed from infected animals showed an AUC of 14−79 μM·
h (Table 4). No adverse events in the form of body weight
loss, organ weight loss or gross pathology were observed
following 4 weeks of repeated dosing in the efficacy study.
We have successfully demonstrated a scaffold morphing
approach to discover a novel series of benzimidazoles with
potent antimycobacterial activity while retaining DprE1
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Funding
This research was supported by the Global Alliance for TB
Drug Development (GATB).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Sudha R. for her contributions in DprE1
overexpression strain. Our sincere thanks to the Global
DMPK, Safety, Biosciences (AZ Boston, USA) and Discovery
Sciences (AZ, Alderly Park, UK) for technical support in
various assays.
Table 4. Pharmacokinetic Parameters (Mean SD, n = 3)
of 2 Following Multiple Oral Dose Administration in Mtb
Infected Male Balb/C Mice at 10 and 30 mg/kg
dose group (mg/kg)
ABBREVIATIONS
■
PK parameter
10
30
TB, tuberculosis; Mtb, Mycobacterium tuberculosis; DprE1,
decaprenylphosphoryl-β-D-ribose2′-epimerase 1; MDR-TB,
multidrug-resistant tuberculosis; MIC, minimum inhibitory
concentration; SAR, structure−activity relationship; Msm,
Mycobacterium smegmatis; DMPK, drug metabolism and
Cmax (μM)
Tmax (h)
AUCinf (μM.h)
T1/2 (h)
5.1 1.7
2.0 0.9
13.5 1.7
4.5 0.2
18.3 6.7
3.0 0.0
78.6 18.9
5.9 2.6
E
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Greenwood, J. R.; Halgren, T. A.; Sanschagrin, P. C.; Mainz, D. T.
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pharmacokinetic; Clint, intrinsic clearance; PPB, plasma protein
binding; CL, clearance; LBF, liver blood flow; CYP,
cytochrome P450 enzyme
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