Lead optimization of 1,4-azaindoles as antimycobacterial agents

Article abstract of DOI:10.1021/jm500571f

In a previous report, we described the discovery of 1,4-azaindoles, a chemical series with excellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-β-d-ribose-2′- epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. Herein, we report lead optimization of this series, culminating in potent, metabolically stable compounds that have a robust pharmacokinetic profile without any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles in a rat chronic TB infection model. We believe that compounds from the 1,4-azaindole series are suitable for in vivo combination and safety studies.

Full text of DOI:10.1021/jm500571f

Article
pubs.acs.org/jmc
Lead Optimization of 1,4-Azaindoles as Antimycobacterial Agents
Pravin S. Shirude,*,†,∞ Radha K. Shandil,‡ M. R. Manjunatha,† Claire Sadler,§ Manoranjan Panda,†
Vijender Panduga,‡ Jitendar Reddy,‡ Ramanatha Saralaya,‡ Robert Nanduri,‡ Anisha Ambady,∥
Sudha Ravishankar,∥ Vasan K. Sambandamurthy,∥ Vaishali Humnabadkar,∥ Lalit K. Jena,†
Rudrapatna S. Suresh,† Abhishek Srivastava,‡ K. R. Prabhakar,‡ James Whiteaker,⊥
Robert E. McLaughlin,⊥ Sreevalli Sharma,∥ Christopher B. Cooper,# Khisi Mdluli,# Scott Butler,⊥
Pravin S. Iyer,† Shridhar Narayanan,∥ and Monalisa Chatterji*,∥
†Department of Medicinal Chemistry, iMED Infection, AstraZeneca, Bellary Road, Hebbal, Bangalore 560024, India
‡DMPK and Animal Sciences, iMED Infection, AstraZeneca, Hebbal, Bangalore 560024, India
§Safety Assessment, iMED, AstraZeneca, Alderly Park, Mereside SK10 4TG, United Kingdom
∥Department of Biosciences, iMED Infection, AstraZeneca, Hebbal, Bangalore 560024, India
⊥Infection iMED, AstraZeneca, GHP, Waltham, Massachusetts 02451, United States
#Global Alliance for TB Drug Development, New York, New York 10005, United States
S
* Supporting Information
ABSTRACT: In a previous report, we described the discovery
of 1,4-azaindoles, a chemical series with excellent in vitro and
in vivo antimycobacterial potency through noncovalent
inhibition of decaprenylphosphoryl-β-D-ribose-2′-epimerase
(DprE1). Nevertheless, high mouse metabolic turnover and
phosphodiesterase 6 (PDE6) off-target activity limited its
advancement. Herein, we report lead optimization of this
series, culminating in potent, metabolically stable compounds
that have a robust pharmacokinetic profile without any PDE6
liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles in a rat chronic TB infection model. We believe that
compounds from the 1,4-azaindole series are suitable for in vivo combination and safety studies.
INTRODUCTION
■
Tuberculosis (TB) remains a global health emergency, as the
WHO estimated 8.6 million TB cases and 1.3 million fatalities
in 2012.1 The current chemotherapy for the treatment of TB is
more than 40 years old and has significant compliance
challenges because of associated toxicities and the long duration
of therapy.2 The TB threat has acquired a new dimension with
Figure 1. Structure of BTZ043 (1).5
the appearance of multidrug-resistant TB (MDR-TB) and
extensively drug-resistant TB (XDR-TB).2 The treatment for
known covalent inhibitors of the DprE1 enzyme.5 Unlike
drug-resistant TB is prolonged and challenging, with limited
benzothiazinones, azaindoles are noncovalent inhibitors and do
not show cross-resistance to 1-resistant Mtb.3 In our previous
report,3 we described developing a robust understanding of the
cellular potency-based structure−activity relationship (SAR) for
this series. The potent antimycobacterial activity, drug-like
properties, lack of pre-existing resistance, and minimal in vitro
safety liabilities encouraged us to develop 1,4-azaindoles toward
a drug candidate shortlist.
treatment options. Therefore, there is a dire need for new
agents that work via novel mechanisms and that are effective in
curing drug-resistant TB.
In an earlier report, we described the discovery of a novel and
promising class of compounds, 1,4-azaindoles, that shows
activity against Mycobacterium tuberculosis (Mtb) in vitro, ex
vivo, and in mouse infection models of TB. Decaprenylphos-
phoryl-β-D-ribose-2′-epimerase (DprE1) of Mtb was identified
as the target for azaindoles.3 DprE1 catalyzes the conversion of
decaprenylphosphoryl-β-D-ribose (DPR) to decaprenylphos-
phoryl-β-D-arabinofuranose (DPA).4 DPA is an essential
precursor of mycobacterial cell wall arabinan.4 Benzothiazi-
nones, 1 (BTZ043)5 (Figure 1), and related compounds are
This series was one of the first examples of a potent,
noncovalent class of DprE1 inhibitors that demonstrated
Received: April 12, 2014
© XXXX American Chemical Society
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Table 1. Structure−Activity Relationship of 1,4-Azaindoles with Respect to PDE6 Activity
a
Scheme 1. Synthesis of 1,4-Azaindole Analogues
a
Reagents and conditions: (a) diethyl malonate, NaH, THF, 80 °C, 50−80%; (b) LiCl, DMSO/H2O, 80 °C, 70−80%; (c) DMF dimethylacetal,
DMF, 80 °C, 60−70%; (d) Fe, acetic acid, 60 °C, 25−30%; (e) aryl halide, K2CO3, 60−70%; (f) LiOH, CH3OH/H2O, 60 °C, 70−80%; (g) amine,
T3P, Et3N or HATU, NMP, Et3N, 70−80%.
efficacy in a rodent model of tuberculosis, making it promising
for further development. However, there were two significant
challenges associated with the series that still needed to be
optimized. The in vitro secondary pharmacology profiling (a
panel of 65 high- and medium-severity targets) of various
compounds in the series identified PDE6 inhibition as a
potential liability. PDE6 is expressed in rod and cone cells in
the human eye. PDE6 inhibition is expected to have effects on
visual acuity, which can have serious implications for a chronic
therapy regimen such as that of TB.
Another significant challenge associated with the 1,4-
azaindole series is low exposure in mice coupled with a poor
pharmacokinetic (PK) profile. This suboptimal PK behavior
could be correlated to rapid metabolism in the presence of
mouse liver microsomes. This posed a major challenge in
assessing efficacy in the mouse models of TB infection.
Ultimately, we co-dosed our compounds with 1-amino-
benzotriazole (ABT), a pan-inhibitor of CYP isoforms, in order
to achieve efficacious exposures by blocking mouse-specific
clearance. Interestingly, the intrinsic clearance in other species,
including humans, was predicted to be more favorable, as assessed
by a comparatively low compound turnover in the presence of
microsomes and hepatocytes from rat, dog, and human,
demonstrating that this was a mouse-specific challenge.3 To
mitigate high mouse clearance, during our lead optimization
program we attempted to identify analogues with improved oral
exposure in mice by blocking microsomal metabolism. Com-
pounds in the series had low clearance and significant oral
exposure in rats; therefore, a rat chronic infection model was used
in parallel to assess the bactericidal activity of these compounds.
Hence, our overall focus during the lead optimization phase was to
identify analogues with improved metabolic stability across species,
including mice, and to mitigate the PDE6 liability while
maintaining or improving DprE1 inhibition and cellular activity.
B
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a
Table 2. Structure−Activity Relationship of 1,4-Azaindole Analogues
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Table 2. continued
a
ND, not determined; ND*, precipitated under assay conditions.
In this article, we describe our strategy for identifying
improved DprE1 inhibitors that have potent cellular activity,
good oral exposure across species, and minimal in vitro safety
risks. We also demonstrate that 1,4-azaindoles are efficacious in
a rat chronic infection model. We believe that these optimized
compounds from the 1,4-azaindole series are suitable for in vivo
safety and combination studies with other antitubercular agents.
RESULTS AND DISCUSSION
■
To understand the SAR for PDE6 inhibition, structurally
diverse compounds from the 1,4-azaindole series were profiled
in an in vitro PDE6 assay (Table 1). The results revealed that
the N-1,6-methoxy-5-methylpyrimidine-4-yl substituent was the
primary cause of PDE6 activity (compounds 9−12 vs 13−16;
Table 1). With a goal to mitigate PDE6 activity, we initially
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Figure 2. Optimized SAR and SPR for 1,4-azaindoles.
Figure 3. (A) Binding mode of compound 11 in the DprE1 active site. (B) Two-dimensional ligand interaction plot.
sought to replace the 6-methoxy-5-methylpyrimidine-4-yl
substituent with groups that maintained the overall hydro-
phobic footprint and that act as a hydrogen-bond acceptor
(Table 2). The syntheses of these analogues were straightfor-
ward, as shown in Scheme 1. As described earlier, synthesis of
the azaindole core followed by alkylation with a variety of aryl
halides and subsequent hydrolysis and amide coupling provided
the desired analogues.3 The synthesis of some of the aryl halides
required an additional manipulation (Supporting Information).
The DprE1 inihibition (IC50) and Mtb cellular activities
(minimum inhibitory concentration, MIC) were evaluated
using biochemical and cellular assay, respectively. All
compounds in the series have potent DprE1 enzyme inhibition
and Mtb MIC’s. Three points of diversification, namely, the
amide side chain, a hydrophobic group, and core ring
substitutions, were explored, as shown in Figure 2. The SAR
and structure−property relationship (SPR) optimization is
shown in Figure 2 and Tables 2 and 4. The aqueous solubility,
microsomal stability, and PDE6 inhibition are influenced
primarily by the amide side chain and the hydrophobic group
(Figure 2). The hydrophilic amide side chain (hydroxyethyl)
influences the physicochemical properties, which is evident
from the high solubility values observed (Table 4). The
hydroxyethyl amide side chain also showed a significant
improvement in mouse liver microsome (MLM) stability
relative to that with hydrophobic amide side chains. The high
MLM instability is possibly due to the high lipophilicity
(measured logD) rather than any specific metabolic softspot.
Compounds with logD of 2 or less (18, 19, 22, 25, and 28)
showed a remarkable improvement in MLM stability. The
disubstituted heteroaryl-methyl group at the northern position
is critical to modulate MIC, physicochemical, and in vitro safety
properties. It was observed that the replacement of the 6-
methoxy-5-methylpyrimidine-4-yl substituent with a 6-(dime-
thylamino)-5-methylpyrimidine-4-yl or 6-(difluoromethoxy)-5-
methylpyrimidine-4-yl substituent helped to mitigate PDE6
activity (compounds 9−12 vs 13−16; Table 1). Thus, the
overall hydrophobic footprint and a hydrogen-bond acceptor
are required for enzymatic and cellular activity. The C-6
substitution was found to be most favorable for cellular potency
compared to that of C-5 and C-7 substitutions (compounds
17−30 vs 35−36; Table 1); however, the CF3 group at the C-6
position (33) was not tolerated. The methyl or methoxy group
at the C-6 position of the 1,4-azaindole helped to improve
cellular potency (compounds 17−30 vs 31−34; Table 1),
whereas bioisosteric replacement of the amide to a substituted
pyrazole helped to retain both enzymatic and cellular potency
(compound 37). Thus, the compounds from the 1,4-azaindole
series have nanomolar IC50’s, submicromolar MIC’s, and the
desired mouse microsomal stability, and they lack in vitro
PDE6 safety liability.
In order to understand the possible mode of binding for
azaindoles, we performed docking using Glide6.1.6,7 A series of
seminal studies on the structural biology of DprE1 over the last
2 years has culminated in a number of ligand-bound crystal
structures of Mycobacterium smegmatis (Msm) and Mtb.8−10
The crystal structure reported with one of the noncovalent
inhibitors, TCA1,6 was used (PDB ID: 4KW5) for modeling.
The docking without constraints suggested multiple binding
modes; one of the major binding modes is shown in Figure 3.
Tyr314, the residue that was mutated by azaindole, is involved
in a C−H−π van der Waals contact with the azaindole ring.
The N atom of the pyridyl ring in azaindole forms an H-bond
with Ser 228. The amide carbonyl oxygen is within H-bonding
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distance from the Ser 228 −OH group and thus can participate
in bifurcated H-bonding along with the N atom of the pyridyl
ring. The NH group of the amide is within H-bonding distance
from the FAD ring carbonyl oxygen. The terminal OH/F atom
makes a H-bonding contact with the amide NH of Asn385.
Thus, Tyr314, Ser228, and Asn385 are the key residues
involved in binding interactions with 1,4-azaindoles.
DprE1 C387G and C387S are sensitive to 1,4-azaindoles. Although
1 and 1,4-azaindoles share the same target, these studies indicate
that they have different patterns of interaction with the target
binding site.
In vitro drug metabolism and pharmacokinetic (DMPK) and
physicochemical properties of the representative compounds
are shown in Table 4. Measurement of aqueous solubility from
DMSO-dried solids for compounds 12, 18, 19, 22, and 25 was
greater than that for compounds 11 and 17; the improved
solubility can be attributed to the hydroxyethyl amide side
chain. On the basis of in vitro intrinsic clearance (Clint) using
human microsomes and rat hepatocytes, the predicted in vivo
clearance (CL) for compounds 11, 12, 17, 18, 19, 22, and 25
ranged between 8 and 30% of liver blood flow (% LBF),
indicating low metabolic turnover. In contrast, the in vitro
intrinsic clearance was higher from mouse microsomes for
compounds 11 and 17 than it was for compounds 18, 19, 22,
and 25 (Table 2), suggesting an influence of the hydroxyethyl
amide side chain on the possible species-specific clearance
mechanism. The compounds were found to be highly permeable
and did not inhibit cytochrome P450 (CYP) enzymes. No major
safety liabilities were indentified for the 1,4-azaindole series when
tested against a panel of mammalian targets and hERG channel.
However, compounds 11, 12, and 22 showed modest PDE6
inhibition.
In vivo PK measurements in rats showed good oral exposure,
low-to-moderate CL (12−48 mL/min/kg), and good (>60%)
oral bioavailability. Compounds 11 and 17 were assessed for in
vivo efficacy in Wistar rats in a chronic TB infection model.12
After 4 weeks of treatment with these compounds, the bacterial
burden in the lungs was reduced by ∼1 log CFU compare to
that of the untreated control group (Figure 4A). The observed
efficacy in the chronic TB infection model was supported by the
exposures measured in infected animals (AUCs: 23 to 98 μM·h)
and free plasma concentrations (above MIC for 10−24 h)
(Figure 4B). During the 4 weeks of repeated dosing in the efficacy
study, no adverse events were observed. Body weight, organ weight,
and gross pathology were found to be unaffected.
Spontaneous resistant mutants to compounds 11 and 12
arose at a frequency of 4−7 × 10−7 at 4−16 times MIC. Mutant
strains showed a >100-fold upward shift in MIC with respect to
that of the wild-type H37Rv strain. A single-nucleotide change
in dprE1 (Rv3790), resulting in an amino acid substitution
(Tyr → His) at position 314, was found by genome sequencing
of the resistant Mtb mutants. This was the same mutation that
was previously observed in all of the resistant strains raised
against two early 1,4-azaindole compounds.3 Although no
significant secondary targets were observed for earlier compounds,
resistant strains raised against compounds 11 and 12 had an
additional mutation in Rv1937 that resulted in an amino acid
substitution (Phe → Cys) at position 462. Rv1937, an oxygenase,
has been shown to be nonessential by TraSH transposon
mutagenesis.11 Also, the DprE1 Y314H strain imparts a similar
degree of resistance compared to that of strains with mutations in
two loci. Hence, the contribution of Rv1937 F426C toward
imparting resistance to 1,4-azaindoles is unclear. For these mutant
strains, as reported previously, compounds within the series were
cross-resistant; however, the strains were still susceptible to 1
(Table 3).3 On the other hand, benzothiazinone-resistant strains
Table 3. Cross-Resistance of 1,4-Azaindoles
Mtb MIC (μM)
DprE1 DprE1 DprE1
DprE1
DprE Y314H
compd H37Rv
OE
C387S C387G Y314H Rv1937 F426C
11
0.39
12.5
0.39
0.78
ND
0.39
0.78
ND
>100
>100
>100
>100
>100
>100
>100
0.0015
0.002
0.625
0.125
>100
>100
>100
>100
>100
>100
>100
0.003
0.004
0.625
0.125
12
0.78
>100
>100
>100
100
17
<0.39
0.39
18
0.39
0.78
1.56
0.39
12.5
0.004
0.625
0.125
0.39
0.78
1.56
0.39
25
As described above, compounds such as 11 and 17 were
rapidly metabolized in the presence of mouse liver microsomes,
leading to low exposures in mice along with a poor PK profile.
Our medicinal chemistry exploration identified compounds 12,
18, 22, and 25 as having low in vitro clearance in the presence
of mouse liver microsomes. Therefore, these compounds were
profiled for in vivo PK assessment in mice to help establish in
19
0.78
22
1.56
>100
>100
12.5
25
0.39
1
0.0015
0.004
0.312
0.125
RIF
INH
Moxi
0.004
0.156
0.125
0.004
0.312
0.125
a
Table 4. 1,4-Azaindoles: DMPK and Safety Properties
11
12
1.8
17
18
1.8
19
22
1.6
25
1.6
logD
2.6
2.95
3
2
solubility (μM)
4
170
19
464
30
68
315
16
129
29
human CLpred microsomes (% LBF)
rat CLpred hepatocytes (% LBF)
human PPB (% free)
15
16
20
12
14
9
16
16
8
16
7
22
5
30
30
17
30
Caco-2 A-B/B-A (1 × 10−6 cm/s)
33/18
11/30
>50
>33
24/9
>50
>33
>10
5/37
>50
>33
>100
13/23
>50
>33
>100
11/31
>50
>33
2
3/39
>50
>33
>100
b
CYP inhibition (μM)
>50
hERG (μM)
>33
PDE6 IC50 (μM)
1
4
c
secondary pharmacology hits IC50 (μM)
no significant hits
rat PK
CL (mL/min/kg)
14
80
27
ND
24
87
48
64
12
16
87
F (%)
100
100
a
b
c
ND, not determined. CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Panel of ∼65 high- and medium-severity targets (binding and
functional data); IC50 > 100 μM or > 30 μM
F
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Figure 4. (A) Summary of efficacy of 11 and 17 in a chronic TB infection model in Wistar Rats following 6 days/week PO dosing at 100 mg/kg for
4 weeks. The net log CFU reduction/left lobe of the lungs was obtained by subtracting lung bacterial counts from that of the vehicle treated controls.
Both compounds exhibited a statistically significant effect vs untreated controls (*p < 0.05). (B) Time vs concentration profiles of 11 and 17
following multiple oral administrations at 100 mg/kg in chronically Mtb infected rats.
visualized by UV light. Flash column chromatography was performed
using silica cartridges purchased from Grace Purification systems. All
compounds were analyzed for purity by HPLC and characterized by
1H NMR using Bruker 300 MHz NMR and/or Bruker 400 MHz NMR
vitro to in vivo correlations (IVIVE). All four compounds
exhibited good oral exposure in mice, thus confirming IVIVE
(Figure 5 and Table 5).
spectrometers. Chemical shifts are reported in ppm (δ) relative to the
residual solvent peak in the corresponding spectra: chloroform, δ 7.26;
methanol, δ 3.31; DMSO, δ 3.33. Coupling constants (J) are reported
in hertz (Hz), where s, singlet; br s, broad singlet; d, doublet; dd,
double doublet; bd, broad doublet; ddd, double doublet of doublets; t,
triplet; tt, triplet of triplets; q, quartet; and m, multiplet, and were
analyzed using ACD NMR data processing software. Mass spectra
values are reported as m/z. All final compounds for biological testing
were purified by reverse-phase HPLC with >95% purity [Shimadzu
HPLC instrument with a Hamilton reversed-phase column (HxSil,
C18, 3 μm, 2.1 mm × 50 mm (H2)). Eluent A: 5% CH3CN in H2O;
eluent B: 90% CH3CN in H2O. A flow rate of 0.2 mL/min was used
with UV detection at 254 and 214 nm].
N-(2-Fluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)-
methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (9). MS
1
(ES+) m/z: 344. H NMR (300 MHz, DMSO-d6): δ 2.24 (s, 3H),
Figure 5. Time vs concentration profiles of 11, 12, 18, 22, and 25
following single oral dose administrations in healthy BALB/c mice.
3.67 (d, J = 5.46 Hz, 1H), 3.76 (d, J = 5.46 Hz, 1H), 3.93 (s, 3H), 4.50
(t, J = 4.99 Hz, 1H), 4.66 (t, J = 4.99 Hz, 1H), 5.69 (s, 2H), 7.26 (dd,
J = 8.29, 4.71 Hz, 1H), 7.94 (d, J = 8.52 Hz, 1H), 8.28 (s, 1H), 8.41 (s,
1H), 8.49 (d, J = 4.57 Hz, 1H), 8.95 (s, J = 5.89, 5.89 Hz, 1H). HRMS
(M + H) calcd for C17H18FN5O2, 344.1517; found, 344.15242.
N-(Cyclopropylmethyl)-1-((6-methoxy-5-methylpyrimidin-4-
yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (10). MS
(ES+) m/z: 352. 1H NMR (300 MHz, DMSO-d6): δ 0.02 (q, J = 4.58
Hz, 2H), 0.18−0.31 (m, 2H), 0.83 (t, J = 6.88 Hz, 1H), 2.00 (s, 3H),
2.98−3.11 (m, 3H), 3.69 (s, 3H), 5.43 (s, 2H), 7.00 (dd, J = 8.29, 4.71
Hz, 1H), 7.68 (dd, J = 8.29, 1.13 Hz, 1H), 7.98 (s, 1H), 8.17 (s, 1H),
8.24 (dd, J = 4.71, 1.13 Hz, 1H), 8.55 (t, J = 5.75 Hz, 1H). HRMS (M
+ H) calcd for C19H21FN5O2, 352.17677; found, 352.17712.
Table 5. Pharmacokinetic Parameters of 11, 12, 18, 22, and
25 Following Single Oral Dose Administration in BALB/c
a
Mice
compd
PK parameter
11
30
12
18
100
70
0.4 0.9
106
0.9 0.2
22
100
25
100
23
0.3 0.2
dose (mg/kg)
Cmax (μM)
tmax (h)
50
73
5.24
0.25
2
2
4
3
105
0.5
8
5
0.25
62
0
0
AUCinf (μM·h)
t1/2 (h)
5
286 41
0.3
57
2
9
0.5
0.7 0.3
2
1
N-(2-Fluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)-
a
methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
Mean SD; n = 3.
1
(11). MS (ES+) m/z: 358. H NMR (300 MHz, DMSO-d6): δ 2.17−
2.30 (3, 3H), 2.40 (s, 3H), 3.59−3.73 (m, 1H), 3.73−3.83 (m, 1H),
3.94 (s, 3H), 4.50 (t, J = 4.99 Hz, 1H), 4.66 (t, J = 4.99 Hz, 1H), 5.64
(s, 2H), 7.76 (s, 1H), 8.15 (s, 1H), 8.35 (s, 1H), 8.42 (s, 1H), 8.87 (t,
J = 5.84 Hz, 1H). HRMS (M + H) calcd for C18H20FN5O2, 358.16735;
found, 358.16808.
N-(2-Hydroxyethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)-
methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
(12). MS (ES+) m/z: 356. 1H NMR (300 MHz, DMSO-d6): δ 2.23 (s,
3H), 2.39 (s, 3H), 3.39−3.65 (m, 4H), 3.93 (s, 3H), 4.84 (t, J = 5.09
Hz, 1H), 5.63 (s, 2H), 7.74 (s, 1H), 8.12 (s, 1H), 8.33 (s, 1H), 8.41 (s,
1H), 8.80 (t, J = 5.65 Hz, 1H). HRMS (M + H) calcd for
C18H21FN5O3, 356.17168; found, 356.17200.
In summary, we have successfully mitigated the challenge of
metabolic instability and PDE6 inhibition associated with 1,4-
azaindoles, while retaining potent DprE1 inhibition and cellular
activity. We believe that these optimized compounds have the
potential to deliver a candidate drug for TB.
EXPERIMENTAL SECTION
■
All chemicals, reagent grade solvents, and anhydrous solvents were
purchased from either Sigma-Aldrich Chemical Co. or Fisher
Scientific. All reactions were conducted under nitrogen unless
otherwise noted. Solvents were removed in vacuo on a rotary
evaporator. Thin-layer chromatography was performed to monitor
reactions using precoated Merck Silica Gel 60 F254 plates and
1-((6-(Dimethylamino)-5-methylpyrimidin-4-yl)methyl)-N-
(2-fluoroethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (13).
MS (ES+) m/z: 357. 1H NMR (400 MHz, DMSO-d6): δ 2.27 (s, 3H),
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3.32 (s, 6H), 3.68 (q, J = 5.1 Hz, 1H), 3.75 (q, J = 5.2 Hz, 1H), 4.52 (t,
J = 5.0 Hz, 1H), 4.64 (t, J = 5.0 Hz, 1H), 5.59 (s, 1H), 7.24 (dd, J =
4.7, 8.3 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 8.24 (s, 1H),
8.47 (d, J = 4.6 Hz, 1H), 8.94 (t, J = 5.6 Hz, 1H). HRMS (M + H)
calcd for C18H21FN6O, 357.18333; found, 357.18395.
(d, J = 2.45 Hz, 1H), 8.43 (s, 1H), 8.64−8.74 (m, 1H). HRMS (M +
H) calcd for C18H21F2N5O4, 372.1666; found, 372.16642.
1-((6-(Dimethylamino)-5-methylpyrimidin-4-yl)methyl)-N-
(2-fluoroethyl)-6-methoxy-1H-pyrrolo[3,2-b]pyridine-3-car-
1
boxamide (23). MS (ES+) m/z: 387. H NMR (400 MHz, DMSO-
d6): δ 2.28 (s, 3H), 2.96 (s, 6H), 3.67 (q, J = 5.2 Hz, 1H), 3.74 (q, J =
5.4 Hz, 1H), 3.83 (s, 3H), 4.51 (t, J = 5.0 Hz, 1H), 4.63 (t, J = 5.0 Hz,
1H), 5.55 (s, 2H), 7.62 (d, J = 2.4 Hz, 1H), 8.05 (s, 1H), 8.27−8.25
(m, 2H), 8.77 (t, J = 6.0 Hz, 1H). HRMS (M + H) calcd for
C19H23FN6O2, 387.19389; found, 387.19384.
N-(2,2-Difluoroethyl)-1-((6-(dimethylamino)-5-methylpyri-
midin-4-yl)methyl)-6-methoxy-1H-pyrrolo[3,2-b]pyridine-3-
carboxamide (24). MS (ES+) m/z: 405. 1H NMR (400 MHz,
DMSO-d6): δ 2.27 (s, 3H), 2.95 (s, 6H), 4.00−3.84 (m, 5H), 5.55 (s,
2H), 6.32−6.04 (m, 1H), 7.62 (d, J = 2.3 Hz, 1H), 8.08 (s, 1H), 8.27−
8.24 (m, 2H), 8.79 (t, J = 6.0 Hz, 1H). HRMS (M + H) calcd for
C19H22F2N6O2, 405.18447; found, 405.18516.
(S)-1-((5-Fluoro-2-methoxypyridin-3-yl)methyl)-N-(2-fluoro-
propyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
1
(14). MS (ES+) m/z: 375. H NMR (300 MHz, DMSO-d6): δ 1.24−
1.37 (m, 3H), 2.44 (s, 3H), 3.47 (s, 1H), 3.64 (br s, 1H), 3.75 (s, 1H),
3.90 (s, 3H), 4.76 (br s, 1H), 4.90 (br s, 1H), 5.42 (s, 2H), 7.38 (s,
1H), 7.93 (s, 1H), 8.12 (d, J = 3.01 Hz, 1H), 8.23 (s, 1H), 8.38 (s,
1H), 8.90 (s, 1H). HRMS (M + H) calcd for C19H20F2N4O2,
375.16267; found, 375.16286.
N-(2-Hydroxyethyl)-1-((2-methoxy-5-(trifluoromethyl)-
pyridin-3-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-
carboxamide (15). MS (ES+) m/z: 409. 1H NMR (300 MHz,
DMSO-d6): δ 2.43 (s, 3H), 3.40−3.48 (m, 2H), 3.49−3.59 (m, 2H),
3.98 (s, 3H), 4.79−4.89 (m, 1H), 5.47 (s, 2H), 7.75−7.81 (m, 1H),
7.94 (s, 1H), 8.22 (s, 1H), 8.36 (d, J = 1.32 Hz, 1H), 8.56 (d, J = 1.13
Hz, 1H), 8.75−8.85 (m, 1H). HRMS (M + H) calcd for
C19H19F3N4O3, 409.14817; found, 409.1489.
1-((6-(Dimethylamino)-5-methylpyrimidin-4-yl)methyl)-N-
(2-hydroxyethyl)-6-methoxy-1H-pyrrolo[3,2-b]pyridine-3-car-
1
boxamide (25). MS (ES+) m/z: 385. H NMR (400 MHz, DMSO-
d6): δ 2.28 (s, 3H), 2.96 (s, 6H), 3.46−3.43 (m, 2H), 3.55−3.54 (m,
2H), 3.82 (s, 3H), 4.82 (br s, 1H), 5.54 (s, 2H), 7.60 (d, J = 2.4 Hz,
1H), 8.01 (s, 1H), 8.37−8.17 (m, 2H), 8.69 (t, J = 5.7 Hz, 1H).
HRMS (M + H) calcd for C19H24N6O3, 385.19823; found, 385.19822.
1-((6-(Difluoromethoxy)-5-methylpyrimidin-4-yl)methyl)-N-
(2-fluoroethyl)-6-methoxy-1H-pyrrolo[3,2-b]pyridine-3-car-
N-(2-Fluoroethyl)-6-methyl-1-((3-methyl-4-(2,2,2-
trifluoroethoxy)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]-
1
pyridine-3-carboxamide (16). MS (ES+) m/z: 425. H NMR (300
MHz, DMSO-d6): δ 2.24 (s, 3H), 2.39 (s, 3H), 3.66 (q, J = 5.21 Hz,
1H), 3.75 (q, J = 5.15 Hz, 1H), 4.49 (t, J = 4.99 Hz, 1H), 4.65 (t, J =
4.99 Hz, 1H), 4.90 (q, J = 8.85 Hz, 2H), 5.63 (s, 2H), 7.07 (d, J = 5.65
Hz, 1H), 7.76 (s, 1H), 8.11 (s, 1H), 8.17 (d, J = 5.65 Hz, 1H), 8.34 (s,
1H), 8.88 (t, J = 5.84 Hz, 1H). HRMS (M + H) calcd for
C20H20F4N4O2, 425.15948; found, 425.16032.
1
boxamide (26). MS (ES+) m/z: 410. H NMR (400 MHz, DMSO-
d6): δ 2.31 (s, 3H), 3.68−3.67 (m, 1H), 3.77−3.71 (m, 1H), 3.82 (s,
3H), 4.52 (t, J = 4.9 Hz, 1H), 4.64 (t, J = 4.9 Hz, 1H), 5.75 (s, 2H),
7.99−7.63 (m, 2H), 8.09 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.54
(s, 1H), 8.78 (t, J = 5.7 Hz, 1H). HRMS (M + H) calcd for
C18H18F3N5O3, 410.14342; found, 410.14421.
N-(2,2-Difluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-
yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
N-(2,2-Difluoroethyl)-1-((6-(difluoromethoxy)-5-methylpyri-
midin-4-yl)methyl)-6-methoxy-1H-pyrrolo[3,2-b]pyridine-3-
carboxamide (27). MS (ES+) m/z: 428. 1H NMR (400 MHz,
DMSO-d6): δ 2.32 (s, 3H), 3.90−3.82 (m, 5H), 5.76 (s, 2H), 6.34−
6.05 (m, 1H), 7.99−7.63 (m, 2H), 8.13 (s, 1H), 8.29 (d, J = 2.4 Hz,
1H), 8.81 (t, J = 6.2 Hz, 1H), 8.54 (s, 1H), 8.81 (t, J = 6.2 Hz, 1H).
HRMS (M + H) calcd for C18H17F4N5O3, 428.134; found, 428.13468.
1-((6-(Difluoromethoxy)-5-methylpyrimidin-4-yl)methyl)-N-
(2-hydroxyethyl)-6-methoxy-1H-pyrrolo[3,2-b]pyridine-3-car-
1
(17). MS (ES+) m/z: 376. H NMR (300 MHz, DMSO-d6): δ 2.18−
2.31 (m, 3H), 2.40(s, 3H), 3.84−3.97 (m, 5H), 5.62−5.70 (m, 2H),
6.01- 6.22 (tt,1H), 7.78 (s, 1H), 8.20 (s, 1H), 8.38−8.41 (d, J = 14.51
Hz, 2H), 8.87−8.96 (m, 1H). HRMS (M + H) calcd for
C18H19F2N5O2, 376.15792; found, 376.1579.
1-((6-(Dimethylamino)-5-methylpyrimidin-4-yl)methyl)-N-
(2-hydroxyethyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-car-
1
boxamide (18). MS (ES+) m/z: 369. H NMR (300 MHz, DMSO-
1
boxamide (28). MS (ES+) m/z: 408. H NMR (400 MHz, DMSO-
d6): δ 2.27 (s, 3H), 2.40 (s, 3H), 2.95 (s, 6H), 3.41−3.58 (m, 4H),
4.84 (t, J = 4.99 Hz, 1H), 5.53 (s, 2H), 7.73 (s, 1H), 8.10 (s, 1H), 8.22
(s, 1H), 8.33 (s, 1H), 8.80 (t, J = 5.46 Hz, 1H). HRMS (M + H) calcd
for C19H24N6O2, 369.20331; found, 369.20369.
d6): δ 2.30 (s, 3H), 3.46−3.42 (m, 2H), 3.56−3.52 (m, 2H), 3.82 (s,
3H), 4.81 (t, J = 5.0 Hz, 1H), 5.73 (s, 2H), 7.97−7.61 (m, 2H), 8.04
(s, 1H), 8.25 (d, J = 2.3 Hz, 1H), 8.53 (s, 1H), 8.69 (t, J = 5.6 Hz,
1H). HRMS (M + H) calcd for C18H19F2N5O4, 408.14775; found,
408.14848.
1-((6-(Difluoromethoxy)-5-methylpyrimidin-4-yl)methyl)-N-
(2-hydroxyethyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-car-
1
boxamide (19). MS (ES+) m/z: 392. H NMR (400 MHz, DMSO-
1-((3,5-Dimethylpyrazin-2-yl)methyl)-N-(2-fluoroethyl)-6-
d6): δ 2.32 (s, 3H), 2.40 (s, 3H), 3.46 (d, J = 5.6 Hz, 2H), 3.56 (d, J =
5.1 Hz, 2H), 5.75 (s, 2H), 4.83 (brs, 1H), 8.02−7.53 (m, 2H), 8.21−
8.04 (m, 1H), 8.35 (s, 1H), 8.52 (s, 1H), 8.81 (br s, 1H). HRMS
(M + H) calcd for C18H19F2N5O3, 392.15284; found, 392.15328.
N-(2-Fluoroethyl)-6-methoxy-1-((6-methoxy-5-methylpyri-
midin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (29). MS
1
(ES+) m/z: 342. H NMR (300 MHz, DMSO-d6): δ 2.40 (d, J =
0.94 Hz, 6H), 2.58 (s, 4H), 3.63−3.70 (m, 1H), 3.75 (q, J = 5.53 Hz,
1H), 4.49 (t, J = 4.99 Hz, 1H), 4.65 (t, J = 5.18 Hz, 1H), 5.67 (s, 2H),
7.75−7.79 (m, 1H), 8.12−8.17 (m, 2H), 8.33−8.37 (m, 1H), 8.87 (t,
J = 5.93 Hz, 1H). HRMS (M + H) calcd for C18H20FN5O, 342.17243;
found, 342.17312.
1
(20). MS (ES+) m/z: 374. H NMR (300 MHz, DMSO-d6): δ 2.14−
2.32 (m, 3H), 3.64−3.86 (m, 5H), 3.94 (s, 3H), 4.49 (t, J = 4.99 Hz,
1H), 4.65 (t, J = 4.90 Hz, 1H), 5.64 (s, 2H), 7.63 (d, J = 2.45 Hz, 1H),
8.07 (s, 1H), 8.26 (d, J = 2.45 Hz, 1H), 8.43 (s, 1H), 8.76 (t, J = 5.93
Hz, 1H). HRMS (M + H) calcd for C18H20FN5O3, 374.16226; found,
374.16291.
N-(2,2-Difluoroethyl)-1-((3,5-dimethylpyrazin-2-yl)methyl)-
6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (30). MS
1
(ES+) m/z: 360. H NMR (300 MHz, DMSO-d6): δ 2.39 (s, 6H),
2.58 (s, 3H), 3.76−3.95 (m, 2H), 5.68 (s, 2H), 5.98−6.05 (m, 1H),
6.15−6.22 (m, 1H), 6.35−6.40 (m, 1H), 7.78 (s, 1H), 8.14 (s, 1H),
8.19 (s, 1H), 8.36 (s, 1H), 8.85−8.97 (m, 1H). HRMS (M + H) calcd
for C18H19F2N5O, 360.16301; found, 360.1629.
N-(2,2-Difluoroethyl)-6-methoxy-1-((6-methoxy-5-methyl-
pyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxa-
1
mide (21). MS (ES+) m/z: 392. H NMR (300 MHz, DMSO-d6): δ
6-Fluoro-N-(2-fluoroethyl)-1-((6-methoxy-5-methylpyrimi-
2.18−2.31 (m, 3H), 3.77−3.97 (m, 8H), 5.62−5.69 (m, 2H), 6.00−
6.38(tt, 1H), 7.64 (d, J = 2.45 Hz, 1H), 8.11 (s, 1H), 8.27 (d, J = 2.45
Hz, 1H), 8.43 (s, 1H), 8.74−8.84 (m, 1H). HRMS (M + H) calcd for
C18H19F2N5O3, 392.15284; found, 392.15328.
N-(2-Hydroxyethyl)-6-methoxy-1-((6-methoxy-5-methylpyr-
imidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
(22). MS (ES+) m/z: 372. 1H NMR (300 MHz, DMSO-d6): δ 2.23 (s,
3H), 3.31−3.43 (m, 4H), 3.81 (s, 3H), 3.94 (s, 3H), 4.83 (t, J = 4.99
Hz, 1H), 5.63 (s, 2H), 7.61 (d, J = 2.45 Hz, 1H), 8.03 (s, 1H), 8.25
din-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
1
(31). MS (ES+) m/z: 362. H NMR (300 MHz, DMSO-d6): δ 2.25
(s, 3H), 3.62−3.80 (m, 2H), 3.98 (s, 3H), 4.48−4.70 (m, 2H), 5.68
(s, 2H), 8.0−8.10 (m, 1H), 8.30 (s, 1H), 8.41 (s, 1H), 8.55 (s, 1H),
8.66−8.72 (t, 1H).
6-Bromo-N-(2-fluoroethyl)-1-((6-methoxy-5-methylpyrimi-
din-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
(32). MS (ES+) m/z: 423. 1H NMR (400 MHz, DMSO-d6): δ 2.24 (s,
3H), 3.68 (br s, 1H), 3.75 (br s, 1H), 4.51 (br s, 1H), 4.64 (br s, 1H),
H
dx.doi.org/10.1021/jm500571f | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
5.70 (s, 2H), 8.28 (s, 1H), 8.39 (d, 1H, J = 10.9 Hz), 8.58 (s, 1H), 8.64
(br s, 2H).
Discovery Sciences (AZ, Alderly Park, U.K.) for technical
support in various assays. We also thank Rajkumar and Subhash
for animal welfare support. Our sincere thanks to G. Riccardi
(University of Pavia) for providing the DprE1 expression
plasmid.
N-(2-Fluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)-
methyl)-6-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-3-car-
1
boxamide (33). MS (ES+) m/z: 412. H NMR (300 MHz, DMSO-
d6): δ 2.25 (s, 3H), 3.66−3.82 (m, 2H), 3.94 (s, 3H), 4.51 (s, 1H),
4.67 (s, 1H), 5.82 (s, 2H), 8.38 (s, 1H), 8.47−8.58 (m, 2H), 8.76 (br
s, 1H), 8.85 (s, 1H).
ABBREVIATIONS USED
■
6-Cyclopropyl-N-(2-fluoroethyl)-1-((6-methoxy-5-methyl-
TB, tuberculosis; Mtb, Mycobacterium tuberculosis; DprE1,
decaprenylphosphoryl-β-D-ribose-2′-epimerase 1; MDR-TB,
multidrug-resistant tuberculosis; BTZs, nitro-benzothiazinones;
DPR, decaprenylphosphoryl-β-D-ribose; DPA, decaprenylphos-
phoryl-β-D-arabinofuranose; DPX, decaprenylphosphoryl-2-
keto-β-D-erythro-pentofuranose; MBC, minimum bactericidal
concentration; MIC, minimum inhibitory concentration; SAR,
structure−activity relationship; Msm, Mycobacterium smegmatis;
DMPK, drug metabolism and pharmacokinetic; Clint, intrinsic
clearance; PPB, plasma protein binding; CL, clearance; LBF,
liver blood flow; CYP, cytochrome P450 enzymes; NMP, N-
methyl pyrrolidine; HCl, hydrochloric acid; DMF, N,N-
dimethylformamide; NaH, sodium hydride; EI, electrospray
ionization; HRMS, high-resolution mass spectrometry
pyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxa-
1
mide (34). MS (ES+) m/z: 384. H NMR (300 MHz, DMSO-d6): δ
0.71−0.74 (m, 2H), 0.98−1.01 (m, 2H), 1.90−2.20 (m, 1H), 2.23 (s,
3H), 3.65−3.76 (m, 2H), 3.94 (s, 3H), 4.47−4.65 (m, 2H), 5.64 (s,
2H), 7.62 (s, 1H), 8.13 (s, 1H), 8.34−8.35 (m, 1H), 8.42 (s, 1H), 8.87
(s, 1H).
N-(Cyclopropylmethyl)-1-(5-fluoro-2-methoxybenzyl)-7-
methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (35). MS
1
(ES+) m/z: 368. H NMR (300 MHz, DMSO-d6): δ 0.22−0.24 (m,
2H), 0.48−0.50 (m, 2H), 1.05−1.09 (m, 1H), 2.44 (s, 3H), 3.28 (t,
2H, J = 6.2 Hz), 3.86 (s, 3H), 5.63 (s, 2H), 5.97−6.00 (m, 1H), 7.03−
7.04 (m, 1H), 7.12−7.14 (m, 2H), 8.22 (s, 1H), 8.37 (d, 1H, J = 4.8
Hz), 9.01 (t, 1H, J = 5.6 Hz).
N-(Cyclopropylmethyl)-1-(2,4-dimethylbenzyl)-5-methoxy-
1H-pyrrolo[3,2-b]pyridine-3-carboxamide (36). MS (ES+) m/z:
364. 1H NMR (300 MHz, DMSO-d6): δ 0.23−0.30 (m, 2H),
0.49−0.52 (m, 2H), 1.04−1.10 (m, 1H), 2.19 (s, 3H), 2.23 (s, 3H),
3.23−3.26 (m, 2H), 3.97 (s, 3H), 5.44 (s, 2H), 6.67−6.72 (m, 2H),
6.92−6.95 (m, 1H), 7.04 (s, 1H), 7.87−7.89 (m, 2H), 8.60−8.61
(m, 1H).
REFERENCES
■
(1) Global Tuberculosis Report 2013; World Health Organization:
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3-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-1-((6-methoxy-5-
methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]-
pyridine (37). MS (ES+) m/z: 385. 1H NMR (300 MHz, DMSO-d6):
δ 2.24 (s, 3H), 2.41 (s, 3H), 3.94 (s, 3H), 5.55 (s, 2H), 7.69 (s, 1H),
7.94 (s, 1H), 8.29−8.35 (m, 2H), 8.46 (s, 1H), 8.75 (s, 1H). HRMS
(M + H) calcd for C19H18F2N6O, 385.15826; found, 385.15793.
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ASSOCIATED CONTENT
* Supporting Information
■
S
̌ ́
(4) Mikusova, K.; Huang, H.; Yagi, T.; Holsters, M.; Vereecke, D.;
Details of the synthesis of key intermediates and final
compounds (35−37, 39−42, 44b, 45−47, and 49−55). This
material is available free of charge via the Internet at http://
pubs.acs.org.
D’Haeze, W.; Scherman, M. S.; Brennan, P. J.; McNeil, M. R.; Crick,
D. C. Decaprenylphosphoryl arabinofuranose, the donor of the D-
arabinofuranosyl residues of mycobacterial arabinan, is formed via a
two step epimerization of decaprenylphosphoryl ribose. J. Bacteriol.
2005, 187, 8020−8025.
̌ ́
(5) Makarov, V.; Manina, G.; Mikusova, K.; Mollmann, U.; Ryabova,
̈
AUTHOR INFORMATION
Corresponding Authors
*(P.S.S.) E-mail: psshirude@gmail.com. Tel.: +91 080 23621212.
Fax: +91 080 23621214
■
O.; Saint-Joanis, B.; Dhar, N.; Pasca, M. R.; Buroni, S.; Lucarelli, A. P.;
Milano, A.; De Rossi, E.; Belanova, M.; Bobovska, A.; Dianiskova, P.;
Kordulakova, J.; Sala, C.; Fullam, E.; Schneider, P.; McKinney, J. D.;
Brodin, P.; Christophe, T.; Waddell, S.; Butcher, P.; Albrethsen, J.;
Rosenkrands, I.; Brosch, R.; Nandi, V.; Bharath, S.; Gaonkar, S.;
Shandil, R. K.; Balasubramanian, V.; Balganesh, T.; Tyagi, S.; Grosset,
J.; Riccardi, G.; Cole, S. T. Benzothiazinones kill Mycobacterium
tuberculosis by blocking arabinan synthesis. Science 2009, 324, 801−
804.
*(M.C.) E-mail: monalisa.chatterji@astrazeneca.com.
Present Address
∞Sai Life Sciences Ltd, Pune 411057, India.
Notes
The authors declare no competing financial interest.
(6) Glide6.1, small-molecule drug discovery suite 2013-3; Schro-
dinger, LLC: New York, 2013.
̈
(7) Friesner, R. A.; Murphy, R. B.; Repasky, M. P.; Frye, L. L.;
Greenwood, J. R.; Halgren, T. A.; Sanschagrin, P. C.; Mainz, D. T.
Extra precision glide: docking and scoring incorporating a model of
hydrophobic enclosure for protein−ligand complexes. J. Med. Chem.
2006, 49, 6177−6196.
ACKNOWLEDGMENTS
■
This research was supported by the Global Alliance for TB
Drug Development (GATB). We thank M. Jyothi for support
with the DprE1 assay. We also thank Sunita DeSousa for
coordinating this work with the TB alliance. Our sincere thanks
to Global DMPK, Safety, Biosciences (AZ Boston, U.S.) and
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