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
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
References and notes
1. Global Tuberculosis Control WHO Report, 2013, WHO/HTM/TB/2013.
that the MIC’s all ranged from as low as 1–2
lM to as high as
5–9 M when screened in either the GAS and 7H12 media for all
l
three compounds. This suggests that placement of the nitrogen at
either the 6, 7, or 8 positions retains potency much better than at
the 5 position of the 5,6-fused bicyclic system, but the most potent
compounds remain the imidazo[1,2-a]pyridines lacking any
additional nitrogen as the MIC’s of imidazo[1,2-a]pyridine
Moraski, Garrett C.
