Scaffold-switching: An exploration of 5,6-fused bicyclic heteroaromatics systems to afford antituberculosis activity akin to the imidazo[1,2-a]pyridine- 3-carboxylates

Article abstract of DOI:10.1016/j.bmcl.2014.05.062

A set of 5,6-fused bicyclic heteroaromatic scaffolds were investigated for their in vitro anti-tubercular activity versus replicating and non-replicating strains of Mycobacterium tuberculosis (Mtb) in an attempt to find an alternative scaffold to the imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidines that were previously shown to have potent activity against replicating and drug resistant Mtb. The five new bicyclic heteroaromatic scaffolds explored in this study include a 2,6-dimethylimidazo[1,2-b]pyridazine-3-carboxamide (7), a 2,6-dimethyl-1H-indole-3-carboxamide (8), a 6-methyl-1H-indazole-3-carboxamide (9), a 7-methyl-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide (10), and a 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxamide (11). Additionally, imidazo[1,2-a]pyridines isomers (2 and 12) and a homologous imidazo[1,2-a] pyrimidine isomer (6) were prepared and compared. Compounds 2 and 6 were found to be the most potent against H₃₇Rv Mtb (MIC's of 0.1 μM and 1.3 μM) and were inactive (MIC >128 μM) against Staphylococcus aureus, Escherichia coli and Candida albicans. Against other non-tubercular mycobacteria strains, compounds 2 and 6 had activity against Mycobacterium avium (16 and 122 μM, respectively), Mycobacterium kansasii (4 and 19 μM, respectively), Mycobacterium bovis BCG (1 and 8 μM, respectively) while all the other scaffolds were inactive (>128 μM).

Full text of DOI:10.1016/j.bmcl.2014.05.062

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Scaffold-switching: An exploration of 5,6-fused bicyclic
heteroaromatics systems to afford antituberculosis activity
akin to the imidazo[1,2-a]pyridine-3-carboxylates
Garrett C. Moraski a,c, Allen G. Oliver a, Lowell D. Markley a, Sanghyun Cho b, Scott G. Franzblau b,
Marvin J. Miller a,
⇑
a Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
b Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA
c Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A set of 5,6-fused bicyclic heteroaromatic scaffolds were investigated for their in vitro anti-tubercular
activity versus replicating and non-replicating strains of Mycobacterium tuberculosis (Mtb) in an attempt
to find an alternative scaffold to the imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidines that were
previously shown to have potent activity against replicating and drug resistant Mtb. The five new bicyclic
Received 24 April 2014
Revised 15 May 2014
Accepted 16 May 2014
Available online xxxx
heteroaromatic scaffolds explored in this study include
a 2,6-dimethylimidazo[1,2-b]pyridazine-
3-carboxamide (7), a 2,6-dimethyl-1H-indole-3-carboxamide (8), a 6-methyl-1H-indazole-3-carboxamide
(9), a 7-methyl-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide (10), and a 5,7-dimethyl-[1,2,4]triazolo
[1,5-a]pyrimidine-2-carboxamide (11). Additionally, imidazo[1,2-a]pyridines isomers (2 and 12) and a
homologous imidazo[1,2-a]pyrimidine isomer (6) were prepared and compared. Compounds 2 and 6 were
Keywords:
Antituberculosis
Imidazo[1,2-a]pyridine
Imidazo[1,2-a]pyrimidine
5,6-Fused bicyclic system
Scaffold hopping
found to be the most potent against H37Rv Mtb (MIC’s of 0.1
>128 M) against Staphylococcus aureus, Escherichia coli and Candida albicans. Against other non-tubercular
mycobacteria strains, compounds 2 and 6 had activity against Mycobacterium avium (16 and 122
respectively), Mycobacterium kansasii (4 and 19 M, respectively), Mycobacterium bovis BCG (1 and 8
respectively) while all the other scaffolds were inactive (>128 M).
Ó 2014 Elsevier Ltd. All rights reserved.
lM and 1.3 lM) and were inactive (MIC
l
l
l
M,
M,
l
l
Tuberculosis (TB) is a serious global health disease caused by
the contagious air borne pathogen Mycobacterium tuberculosis
(Mtb). In 2012, 1.3 million people died of TB and 8.6 million people
fell ill of the disease.1 For the first time in 40 years, a new TB treat-
ment (bedaquiline) was approved in 20122 giving new treatment
options particularly with the estimated 450,000 patients infected
with multidrug resistant Mtb.1 Our laboratories have had an inter-
est in inhibiting Mtb with small molecule heterocyclic compounds
since the serendipitous discovery of a simple synthetically attrac-
tive oxazoline scaffold3 derived from fragment screening of an iron
chelating class of compounds called the mycobactins.4 Through an
intensive structure activity relationship (SAR) campaign we
improved the Mtb potency of the oxazolines to sub-micromolar
MIC’s and expanded the chemical space to include various other
heterocyclic scaffolds (oxazole, thiazole, imidazole, and pyridine).5
Further SAR effort complimented by a screening agreement with
Dow AgroSciences (DAS) iteratively led to the exploration of fused
heterocyclic scaffolds which resulted in the discovery of a ‘hit’
5,6-fused bicyclic imidazo[1,2-a]pyridine.6–8 We have since
reported on the advent and advancement of various
imidazo[1,2-a]pyridine-3-carboxamides
(1–3),
imidazo[1,2-
a]pyrimidine-3-carboxamide (5 and 6) and a benzyl 2,5,7-trime-
thylimidazo[1,2-c]pyrimidine-3-carboxylate (7) with excellent
in vitro potency against replicating (H37Rv), as well as
multi- (MDR) and extensively drug (XDR) resistant Mtb strains
9–14
(Fig. 1).6–8 Herein, we report our efforts on ‘scaffold hopping’
to identify new heterocyclic scaffolds that will potentially retain
potency against H37Rv Mtb and subsequently have improved ADME
properties while also exploring new chemical space.
The scaffold switching that was performed in this study
involved moving, incorporating or removing nitrogen(s) within
the 5,6-fused bicyclic framework to give a set of analogs for screen-
ing (Fig. 2). Specifically, incorporating a nitrogen at the 5-position
gave the imidazo[1,2-b]pyridazine-3-carboxamide (7), removing a
nitrogen from the 4-position gave the 1H-indole-3-carboxamide
⇑
Corresponding author.
E-mail address: mmiller1@nd.edu (M.J. Miller).
http://dx.doi.org/10.1016/j.bmcl.2014.05.062
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Moraski, G. C.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.05.062

2
G. C. Moraski et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Scheme 1. Synthesis of imidazo[1,2-a]pyridine (2), imidazo[1,2-a]pyrimidine (6),
and imidazo[1,2-b]pyridazine (7). Reagents and conditions: (a) (1) ethyl 2-
chloroacetoacetate (for 13) or ethyl 2-bromoacetoacetate (for 15 and 17), DME,
reflux, 48 h; (b) (1) LiOH, EtOH; (2) HCl, 56 h; (c) EDC, DMAP, benzyl amine, ACN,
16 h.
2-amino-heteroaromatic (13 or 15) with either ethyl 2-bromoace-
toacetate (for 13) or ethyl 2-bromoacetoacetate (for 15) followed
by saponification and acidification gave the desired imidazo[1,2-
a]pyridine-3-carboxylic acid (14) or imidazo[1,2-a]pyrimidine-3-
carboxylic acid (15) (Scheme 1). Both carboxylic acids were
coupled with benzyl amine with EDC to give compounds 2 and 6.
In an efficient one step process, compounds 4 and 5 were prepared
through condensation of the appropriate 2-amino-heteroaromatic
precursor with benzyl 2-bromoacetoacetate.5 The N-benzyl-
2,6-dimethylimidazo[1,2-b]pyridazine-3-carboxamide (7) was
synthesized in an similar method by first condensation of the
3-amino-6-methylpyridazine (17) with ethyl 2-bromoacetoace-
tate, saponification of the ethyl ester followed by acidification then
coupling to the benzyl amine with EDC. By design, all of the other
5,6-fused bicyclic heteroaromatic scaffolds investigated for ‘scaf-
fold switching’ were commercially available. As such, the free acids
(19–22) were rapidly elaborated by EDC-mediated couplings with
benzyl amine to give the desired analogs (8, 9, 11 and 12) for
screening (Scheme 2). However, the N-benzyl-7-methyl-
[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide (10) was prepared
by amidation of the corresponding ethyl ester (23) with benzyl
amine in a sealed tube at 90 °C (Scheme 2).
Figure 1. Previously reported imidazo[1,2-a]pyridines (1–3) and imidazo[1,2-
a]pyrimidine (5) and two new analogs prepared for this SAR study the benzyl
2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate (4) and the N-benzyl-2,6-dime-
thylimidazo[1,2-a]pyrimidine-3-carboxamide (6). The imidazo[1,2-a]pyrimidine
nitrogen is denoted in red.
(8), moving a nitrogen from the 4-position to the 2-position gave
the 1H-indazole-3-carboxamide (9), incorporating a nitrogen to
the 2-position gave the triazolo[4,3-a]pyridine-3-carboxamide
(10), and incorporating nitrogen at the 3 and 8-positions then mov-
ing the 3-carboxamide to the 2-position gave the triazolo[1,5-
a]pyrimidine-2-carboxamide (11). We also made an isomer of
compound 1 wherein we switched the adjacent 3-carboxamide
with the 2-methyl group to give the imidazo[1,2-a]pyridine-2-car-
boxamide analog (12) (Fig. 2). These various 5,6-fused bicyclic
heterocyclic scaffolds (7–12) were all searched within literature
but to the best of our knowledge none of these scaffolds were
found to have been screened against Mtb H37Rv.
Syntheses of the imidazo[1,2-a]pyridines (1–4) and
imidazo[1,2-a]pyrimidines (5 and 6) are straightforward and have
been described in our previous publications5,6,8 as well as within
the Supplementary data. In brief, condensation of the appropriate
Table 1 summarizes the in vitro anti-TB activity of these six
‘scaffold switched’ 5,6-fused bicyclic heteroaromatic analogs
(6–12) in two different media the glycerol–alanine–salts ‘GAS’15
Figure 2. New 5,6-fused bicyclic heteroaromatic scaffold analogs (7–12) prepared to evaluate the effects of scaffold switching on anti-TB activity. The moving, incorporating
or removing nitrogen(s) within the 5,6-fused bicyclic framework from that of the imidazo[1,2-a]pyridine are denoted in red.
Please cite this article in press as: Moraski, G. C.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.05.062

G. C. Moraski et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
and the Middlebrook 7H1216 and their potency against non-repli-
cating ‘latent’ Mtb (LORA17) and an assessment of their toxicity
by the VERO18 assay. The most potent 5,6-fused heteroaromatics
were still the imidazo[1,2-a]pyridine (3) and imidazo[1,2-a]pyrim-
idine (6) scaffolds with MIC’s of <0.2 and 1.3 lM in the GAS media,
respectively. However, it is not the imidazo[1,2-a]pyridine scaffold
alone which imparts the majority of anti-TB activity as its isomer
(12) was >700 times less active (MIC’s of 0.1 and 70
tively). N-Benzyl-2,6-dimethyl-1H-indole-3-carboxamide
N-benzyl-6-methyl-1H-indazole-3-carboxamide (9) and N-ben-
zyl-2,6-dimethylimidazo[1,2-b]pyridazine-3-carboxamide (7)
were found to be moderately active compounds with MIC’s of 44,
41 and 64 in the GAS media, respectively. N-Benzyl-7-
l
M, respec-
(8),
l
M
methyl-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide (10) and
N-benzyl-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbox-
amide (11) had the weakest activity with MIC’s of 101 and 126 lM
in the GAS media, respectively. Replacement of the 2-methyl group
in compound 2 with nitrogen in compound 10 had a very negative
effect (1000Â) on potency (MIC of 0.1 and 101
Due to the modest activity observed in most of these new scaffolds
we recalculated the MIC’s in terms of g/mL and saw MIC values
lM, respectively).
l
which are more encouraging in the GAS media and kept the same
overall trends observed above (Table 1). Part of the attraction of
scaffold switching is often the enhancement of ADME properties19
which sometimes results in greater drug free fraction20 in vivo
even if analogous compounds have a lower MIC. Such ADME prop-
erty enhancement was demonstrated with the imidazo[1,2-a]pyr-
idines of Ramachandran et al. at AstraZeneca.21 The SAR observed
Scheme 2. Synthesis of various 5,6-fused bicyclic heterocyclic scaffold analogs (8–
10) and isomeric N-benzyl-3,7-dimethylimidazo[1,2-a]pyridine-2-carboxamide
(12). Reagents and conditions: (a) EDC, DMAP, benzyl amine, ACN, 16 h. (b) Benzyl
amine, ACN, 90 °C, 56 h.
Table 1
In vitro evaluation of compounds 2, 6–12 against H37Rv Mtb in GAST media, 7H12 media and LORA as well as toxicity to VERO cells (IC50 in lM)
Compound
Mol Wt
Calcd ClogPa
MIC mean against replicating Mtb in medium
GAS ( M) GAS ( g/mL) 7H12 ( M)
LORA (lM)
VERO IC50 (lM)
l
l
l
279.34
3.60
0.11 0.008
1.27 0.22
63.8 1.9
43.8 1.2
40.8 3.3
0.031 0.002
0.36 0.06
17.9 0.5
0.49 0.004
6.95 0.15
>128
>128
>128
280.32
280.32
278.35
265.31
2.60
2.26
3.73
4.02
>128
>128
>128
>128
>128
24.7
12.2 0.3
>128
>128
>128
10.8 0.9
>128
(continued on next page)
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G. C. Moraski et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Table 1 (continued)
Compound
Mol Wt
Calcd ClogPa
MIC mean against replicating Mtb in medium
LORA (lM)
VERO IC50 (lM)
GAS (lM)
GAS (l
g/mL)
7H12 (lM)
267.31
281.31
279.34
2.85
101 6.0
126 2.9
70 8.9
27 1.6
>128
>128
>128
2.20
3.61
35.4 0.8
>128
>128
>128
>128
>128
>128
19.6 2.5
822.95
6.04
0.11
0.09
0.06
2.6
113
359.26
2.62
0.12
0.04
0.09
4.9
>128
SD, standard deviation; MIC, minimum concentration required to inhibit growth by >90%; GAS, glycerol–alanine–salts media; 7H12, Middlebrook 7H9 broth base media with
BSA, casein hydrolysate, catalase, palmitic acid; LORA, low oxygen recovery assay using the H37Rv luxAB Mtb luminescence strain; VERO, African green monkey kidney cell
line to evaluate toxicity. Values reported are the average of three individual measurements.
a
Calculated ClogP by ChemDraw version 12.0
from screening in 7H12 medium again indicated that the most
potent compounds were 2 and 6 while all other compounds were
inactive (MIC >128 lM). This suggests that the potency of these
other 5,6-fused bicyclic heteroaromatics may be carbon source
dependant, an issue that was discovered in the pyrimidine–imida-
zoles reported by Pethe et al.22 or due to other medium effects.23
The GAS medium uses glycerol–alanine–salts as the carbon source
while the 7H12 medium uses palmitic acid. No activity was
detected in the ‘latent’ Mtb assay (LORA, MIC >128 lM) even with
compounds 2 and 6 suggesting that these compounds are only
effective on replicating Mtb. The VERO toxicity assay also showed
these compounds to be non-toxic with the exception of the N-ben-
zyl-2,6-dimethylimidazo[1,2-b]pyridazine-3-carboxamide
which had an IC50 of 25 M.
(7)
l
Despite varying degrees of activity observed against Mtb
compounds 2, 6–12 were all found to have a similar selectivity pro-
file since they were inactive against representative Gram positive
strains including Staphylococcus aureus (MIC >128
negative strains including Escherichia coli (MIC >128
fungus, Candida albicans (MIC >128 M), see Supplementary data.
Additionally, when screened against various other non-tubercular
mycobacteria strains only the imidazo[1,2-a]pyridine (2) and
imidazo[1,2-a]pyrimidine (6) analogs had any activity and that
l
M), Gram
lM), and the
Figure 3. Overlay of the 5,6-fused bicyclic heteroaromatic scaffolds (7–12) crystal
structures with potent N-benzyl-2,7-dimethyl-imidazo[1,2-a]pyridine-3-carbox-
amide (1). Legend: 1a—red, 1b—light pink, 7—green, 8—yellow, 9a—light orange,
9b—orange, 10—blue, 11—turquoise, 12—magenta. Hydrogen atoms omitted for
clarity. The nine atoms of 5,6-fused bicycle were used as template mapping atoms.
l
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G. C. Moraski et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
5
Figure 4. Positional variation of heterocyclic nitrogen.
was only against selective strains (see Supplementary data). In par-
ticular, compounds 2 and 6 inhibited Mycobacterium avium (MIC’s
compounds 3 and 4 are significantly lower than that of 24, 25 or
26 (see Supplementary data).
of 16 and 122
and 19 M, respectively), Mycobacterium bovis BCG (MIC’s of 1 and
M, respectively) while all the other analogs (7–12) were
inactive (>128 M) to Mycobacterium smegmatis, Mycobacterium
chelonae, Mycobacterium marinum, Mycobacterium avium, Mycobac-
terium kansasii and Mycobacterium bovis BCG (see Supplementary
data).
It is possible that a key to understanding the varying degree of
potency against Mtb may lie in the subtle structural or electronic
effects of these various 5,6-fused heteroaromatic analogs. As such,
compounds 1, 7–10 were crystallized and X-ray structural studies
undertaken. The resulting structures were subsequently compared
with our initial imidazo[1,2-a]pyridine ‘hit’ compound 1 (Fig. 3).
This information will be particularly useful once the target(s) of
these compounds (presumably the QcrB gene24) are ultimately
crystallized and these structures docked.
l
M, respectively), Mycobacterium kansasii (MIC’s of 4
In conclusion, various 5,6-fused heteroaromatic compounds
were explored as potential surrogates to our previously reported
imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine anti-TB
scaffolds, but none of these closely related heterocycles had
sub-micromolar potency. Additionally, there appears to be a great
preference for imidazo[1,2-a]pyridine-3-carboxamide, as the imi-
dazo[1,2-a]pyridine-2-carboxamides were found to be much less
active. Therefore, while scaffold switching can often lead to great
improvements in either potency or pharmacokinetic properties,
in this study the first scaffold we discovered and reported (the imi-
dazo[1,2-a]pyridine-3-carboxamides) remains the optimal scaffold
for synthesis of potent 5,6-fused heteroaromatic small molecule
anti-TB agents as this scaffold is the most potent and has drug-like
ADME properties.8,24,25
l
8
l
l
Acknowledgments
The overlay of the imidazo[1,2-a]pyridine-3-carboxamide (1)
crystal structure with its isomeric 2-carboxamide (12) shows that
these moieties lie in very different regions of space and this impor-
tant structural difference is also reflected in their different MIC’s as
compound 1 is 350 times more potent than 12 (MIC’s of 0.2 and
This work was supported by Grant R01AI054193 from the
National Institutes of Health (NIH) and in part by intermediates
provided from Dow AgroSciences. We would like to thank the Uni-
versity of Notre Dame, especially the Mass Spectrometry & Proteo-
mics Facility (Bill Boggess and Michelle Joyce), which is supported
by the grant CHE-0741793 from the NIH. We thank Professors Jen-
nifer DuBois and Jed Fisher for meaningful scientific discussion.
The excellent technical assistance of Baojie Wan and Yuehong
Wang with anti-TB assays at UIC is greatly appreciated.
70 lM, respectively). Finally, an additional nitrogen in the
5,6-fused system did not improve activity in any scaffold other
than the imidazo[1,2-a]pyrimidine (6) as the imidazo[1,2-b]pyrid-
azine (7), triazolo[4,3-a]pyridine-3-carboxamide (10) and triazol-
o[1,5-a]pyrimidine-2-carboxamide (11) had the weakest activity.
Curiously, in the solid state there is little correlation between the
orientations of the pendant groups as can be seen in Figure 3
whereas in solution we expect them to dynamic and fluxional. It
should be noted that in the solid state, compounds 2 and 9 have
two crystallographically independent molecules present in the
asymmetric unit. Though they are crystallographically indepen-
dent, they are chemically identical. Compound 7 displays an unu-
sual intra-molecular hydrogen-bond from the amide nitrogen to
the imidazopyridine bridge nitrogen (position 4, Fig. 1). This
hydrogen bond may be strong enough to persist in solution which
may explain the decreased activity of this compound.
Intrigued that the imidazo[1,2-a]pyrimidine (6), which has an
additional nitrogen at position 8, had retained good potency but
the imidazo[1,2-b]pyrazine (7), where the additional nitrogen is
at the 5 position, had poor potency, we prepared an additional
compound set (24–26) to explore the effects of placing the
nitrogen at the 6-(imidazo[1,2-c]pyrimidine) and 7-positions (imi-
dazo[1,2-a]pyrazine) (Fig. 4 and expanded Fig. 8, Supplementary
data). Interestingly, the MIC’s of the imidazo[1,2-c]pyrimidine
and imidazo[1,2-a]pyrazine compounds (25 and 26) were very
similar to that of the analogous imidazo[1,2-a]pyrimidine (24) in
Supplementary data
CCDC 987940-987946 contains the supplementary crystallo-
graphic data for compounds (1, 7–12). These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data (experimental procedures, analytical data
for compounds (1–12) and X-ray crystallization data for com-
pounds (1, 7–12) can be found as well as additional, SAR and
description of the assays used) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.bmcl.2014.05.062.
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l
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Please cite this article in press as: Moraski, G. C.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.05.062