Generation and exploration of new classes of antitubercular agents: The optimization of oxazolines, oxazoles, thiazolines, thiazoles to imidazo[1,2-a]pyridines and isomeric 5,6-fused scaffolds

Article abstract of DOI:10.1016/j.bmc.2012.02.025

Tuberculosis (TB) is a devastating disease resulting in a death every 20 s. Thus, new drugs are urgently needed. Herein we report ten classes of compounds - oxazoline, oxazole, thiazoline, thiazole, pyrazole, pyridine, isoxazole, imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine and imidazo[1,2-c]pyrimidine - which have good (micromolar) to excellent (sub-micromolar) antitubercular potency. The 5,6-fused heteroaromatic compounds were the most potent with MIC's as low as <0.195 μM (9 and 11). Overall, the imidazo[1,2-a]pyridine class was determined to be most promising, with potency similar to isoniazid and PA-824 against replicating Mtb H₃₇Rv, clinically relevant drug sensitive, multi- and extensively resistant Mtb strains as well as having good in vitro metabolic stability.

Full text of DOI:10.1016/j.bmc.2012.02.025

Bioorganic & Medicinal Chemistry 20 (2012) 2214–2220
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Bioorganic & Medicinal Chemistry
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Generation and exploration of new classes of antitubercular agents:
The optimization of oxazolines, oxazoles, thiazolines, thiazoles
to imidazo[1,2-a]pyridines and isomeric 5,6-fused scaffolds
Garrett C. Moraski a, Lowell D. Markley a, Mayland Chang a, Sanghyun Cho b, Scott G. Franzblau b,
Chang Hwa Hwang b, Helena Boshoff c, Marvin J. Miller a,
⇑
a Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46656, USA
b Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA
c Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Tuberculosis (TB) is a devastating disease resulting in a death every 20 s. Thus, new drugs are urgently
needed. Herein we report ten classes of compounds—oxazoline, oxazole, thiazoline, thiazole, pyrazole,
pyridine, isoxazole, imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine and imidazo[1,2-c]pyrimidine—
which have good (micromolar) to excellent (sub-micromolar) antitubercular potency. The 5,6-fused het-
Received 23 December 2011
Revised 3 February 2012
Accepted 8 February 2012
Available online 16 February 2012
eroaromatic compounds were the most potent with MIC’s as low as <0.195 lM (9 and 11). Overall, the
imidazo[1,2-a]pyridine class was determined to be most promising, with potency similar to isoniazid
and PA-824 against replicating Mtb H37Rv, clinically relevant drug sensitive, multi- and extensively resis-
tant Mtb strains as well as having good in vitro metabolic stability.
Keywords:
Mycobacterium tuberculosis
MDR-TB
Ó 2012 Elsevier Ltd. All rights reserved.
XDR-TB
5,6-Fused heteroaromatics
Imidazo[1,2-a]pyridine
1. Introduction
drugs to combat the spread of TB, particularly in its hard-to-kill
multidrug-resistant and latent forms where, most likely, only sus-
The battle against tuberculosis (TB, caused by the bacterium
Mycobacterium tuberculosis, Mtb) has raged for millennia.1
Throughout history, TB has claimed the lives of over one billion
people and currently infects one third of the world’s population.
With 1.4 million deaths in 2010, TB, as a single causative agent,
is the leading killer among infectious diseases.1 The spread of TB
was significantly affected with the advent of several chemotherapy
agents during the mid 1900s.2 However, since the 1980s TB has
been on the rise. Presently, 8.8 million new cases are added annu-
ally.1 The increase in cases of TB/HIV co-infection and the spread of
multiple-drug resistant TB (MDR-TB, strains that are resistant to
first line drugs isoniazid and rifampin) and extensively drug resis-
tant TB (XDR-TB, strains that are resistant to isoniazid and rifam-
pin, as well as any fluoroquinolone and at least one of three
injectable second-line drugs, such as amikacin, kanamycin, or cap-
reomycin) are making matters worse.3 The increase in TB infection
has become so alarming that the World Health Organization
(WHO) declared TB a global emergency as far back as 1993.4 More
than ever, there is an urgent need to develop new antitubercular
tained aggressive chemotherapy with a combination of drugs will
stop the disease.
Our laboratory serendipitously discovered a small molecule het-
erocyclic TB inhibitor based on an oxazoline scaffold through broad
screening of synthetic mycobactin siderophore fragments.5 This hit
was initially optimized by dehydration to an oxazole and hundreds
of analogs were prepared in an effort to increase potency against
Mtb and possibly refine ADME (absorption, distribution, metabo-
lism and excretion) properties.5,6 Not previously reported was that
many amides and hindered benzyl ester derivates were prepared in
an effort to improve the in vitro stability to rat microsomes and
simulated gastric fluid. However, very little improvement was
found and nearly all the amides prepared had substantially less
potency against Mtb relative to the corresponding ester (see Sup-
plementary data). Therefore, we were compelled to reprioritize
the risk of trying to find a new metabolically robust heterocyclic
class of antitubercular compounds over the optimization of oxazo-
line/oxazole class. Herein we report our structure activity relation-
ship (SAR) studies starting from the serendipitous oxazoline/
oxazole benzyl ester discovery7 and leading to the identification
of imidazo[1,2-a]pyridines as a new class of potent and metaboli-
cally robust antitubercular agents8,9 (see Fig. 1).
⇑
Corresponding author. Tel.: +1 574 631 7571; fax: +1 574 631 6652.
E-mail address: mmiller1@nd.edu (M.J. Miller).
0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2012.02.025

G. C. Moraski et al. / Bioorg. Med. Chem. 20 (2012) 2214–2220
2215
2. Results and discussion
The syntheses of the oxazoline and oxazole scaffolds started by
coupling of benzoyl chloride with -serine benzyl ester followed by
L
the dehydrative cyclization of the resulting b-hydroxy amide with
bis(2-methoxyethyl)amino-sulfur trifluoride (DAST) as reported by
Wipf et al.10 to form the oxazoline core (1) in 84% yield for the two
steps. This oxazoline (1) was converted in 91% yield to the corre-
sponding oxazole analog (2) by a mild BrCCl3/DBU oxidation proce-
dure11 (Scheme 1). Hydrogenolysis of compound 2 gave the
oxazole carboxylic acid intermediate which was converted to the
corresponding benzyl amide (3) by an EDC-mediated coupling with
benzyl amine (67% overall yield).
Scheme 1. Synthesis of oxazoline (1) and oxazoles (2, 3) analogs. Reagents and
conditions: (a) L-serine benzyl ester, DIPEA, CH2Cl2, 0 °C–50 °C, 14 h; (b) DAST,
Thiazoline (4) was prepared by esterification of the correspond-
ing carboxylic acid, which was obtained in 80% yield from conden-
K2CO3, À78 °C, CH2Cl2, 1 h; (c) DBU, BrCCl3, CH2Cl2, 0 °C to rt, 2 h; (d) H2, Pd–C, 14 h;
(e) benzyl amine, EDC, DMAP, CH3CN, rt, 14 h.
sation of benzonitrile and
L-cysteine in a buffered aqueous
methanol (pH 7.0) solution as reported Bergeron et al.12 (Scheme
2). Subsequent oxidation with BrCCl3/DBU gave the desired thiazole
(5) in 68% yield. The pyrazole, isoxazole, pyridine and benzyl
7-methyl-2-phenylimidazo[1,2-a]pyridine-3-carboxylate analogs
(6, 7, 8, and 9, respectively), as well as the N-benzyl-7-methyl-
2-phenylimidazo[1,2-a]pyridine-3-carboxamide (10) and N-ben-
zyl-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide (12) were
formed by separate EDC-mediated coupling reactions of the com-
mercially available carboxylic acids with benzyl alcohol or benzyl
amine, respectively (see Supplementary data) in yields ranging from
26% to 80%.
Previously, we reported facile three step syntheses of various
substituted N-benzyl imidazo[1,2-a]pyridine-3-carboxamides,
including compound 12 that had potent antitubercular
activity.8 Herein we report that similar heterocycles, 2,7-dimethy-
limidazo[1,2-a]pyridine-3-carboxylate (11), benzyl 2,6-dimethy-
Scheme 2. Syntheses of thiazoline (4) and thiazole (5) benzyl esters. Regents: (a) L-
cysteine, NaHCO3, MeOH / H2O (pH = 7), reflux, 14 h; (b) Benzyl alcohol, EDC, DMAP,
CH3CN, room temp, 14 h; (c) DBU
scaffold (1 and 2) by preparing nearly a thousand analogs and
screening them for activity against Mtb H37Rv (ATCC #27294) by
the microplate alamar blue assay (MABA).13 We anticipated that
various benzyl amides (like 3) would not only retain potency seen
with the benzyl esters but also improve the in vitro metabolic
properties of the oxazoline and oxazole scaffolds. However, such
modifications were not effective (see Supplementary data). Next,
we explored the closely related thiazoline/thiazole scaffolds
limidazo[1,a]pyrimidine-3-carboxylate
(13)
and
benzyl
2,5,7-trimethylimidazo[1,2-c]pyrimidine-3-carboxylate (14) can
each be prepared in just a single step by condensation of benzyl
2-bromo-3-oxobutanoate with the appropriate 2-amino-heteroar-
omatic precursor demonstrating that these 5,6-fused heteroaro-
matic antitubercular agents can be made efficiently and cost
effectively in respectable yields of 46–75% (Scheme 3). These com-
pounds also exhibit notable antitubercular activity against repli-
cating and non-replicating Mtb and no toxicity to VERO cells
(Table 1).
(4 and 5) and found that their MIC values (13 and 6
tively, in GAS13 media) were similar to those of the oxazoline/oxaz-
oles (5 and 6 M for 1 and 2, respectively, Table 1). The thiazoline/
thiazole scaffolds (4 and 5) were also found to be non-toxic to
VERO14 cells with IC50 values >128
M, but, unfortunately, they
lM, respec-
l
Previously, we spent considerable synthetic effort to develop an
understanding of the SAR of the oxazoline/oxazole benzyl ester
l
Figure 1. Various heterocyclic classes (1–14) explored for antitubercular activity.

2216
G. C. Moraski et al. / Bioorg. Med. Chem. 20 (2012) 2214–2220
showed no improved in vitro metabolic stability (see Supplemen-
tary data). The pyrazole scaffold (6) gave the most ambiguous
screening results showing good activity in GAS media (3.5 M,
average of three tests), but weak potency in 7H1213 media
(>38 M, average of three tests). It is possible that the potency of
l
l
the pyrazoles might be carbon source dependant, an issue experi-
enced and described by Pethe et al. at Novartis,15 more protein
bound in the 7H12 media than the GAS or just not very soluble.
Nonetheless, we purposely screened our compounds against Mtb
H
37Rv in at least two different types of assay media as GAS media
Scheme 3. One step syntheses of benzyl 2,7-dimethylimidazo[1,2-a]pyridine-3-
carboxylate (10), benzyl 2-methylimidazo[1,2-a]pyrimidine-3-carboxylate (13) and
benzyl 2,5,7-trimethylimidazo[1,2-c]pyrimidine-3-carboxylate (14). Reagents: (a)
Benzyl 2-bromo-3-oxobutanoate, NaHCO3, 1,2-dimethoxyethane, 110 °C, 24–36 h.
contains glycerol-alanine-salts while the 7H12 uses palmitic acid
as its carbon source. Additionally, we periodically performed
assays in GAST16 media to rule out possible iron dependence. Use
Table 1
Activity of various heterocyclic scaffolds (1–14) against replicating Mtb H37Rv in various media, against non-replicating Mtb ‘LORA’ and cytotoxicity in VERO cells
Compound
Mol
Wt
Calcd
MIC mean +/ÀSD (
l
M)[MIC range] against replicating Mtb LORA (
l
M)
VERO IC50
M)
ClogPa
in medium
(l
GAS
GAST
7H12
4.4 [5.7–
3.7]
16.6 11.1[3.8–
24.0]
281.31
279.29
278.31
297.37
2.76
3.47
3.70
2.94
4.9 1.7[2.9–6.2]
5.7 2.3[0.5–7.9]
>65[23.1–>128]
63
37
NT
>128
121
NT
0.49 [<1–
0.5]
3.9 1.0[3.0–5.0]
59
>40[19.5–>50]
12.9 4.8[9.1–18.3] 3.5
11.6 5.1[7.7–17.4] NT
>128
295.36
278.31
279.29
4.10
4.54
4.30
6.0 4.0[1.5 - 8.5]
3.5 1.4[1.8–4.3]
2.2 1.0[1.1–2.9]
6.2
>64
NT
7.2 3.0[4.0–9.8]
>38[15.0 - >50]
0.8 0.01[0.7–0.8]
NT
NT
>128
>128
>50
28.0 1.3 [26.9–
29.4]

G. C. Moraski et al. / Bioorg. Med. Chem. 20 (2012) 2214–2220
2217
Table 1 (continued)
Compound
Mol
Wt
Calcd
MIC mean +/ÀSD (
l
M)[MIC range] against replicating Mtb LORA (
lM)
VERO IC50
M)
ClogPa
in medium
(l
GAS
GAST
7H12
319.35
4.71
1.9 0.6[1.5–2.5]
NT
9.5 3.2[5.8–11.9]
NT
NT
21.7 0.8 [21.1–
22.6]
342.39
341.41
280.32
279.34
5.89
5.30
4.07
3.60
<0.195
NT
NT
NT
<0.195
>50
>50
>50
>128
>50
0.6 0.1[0.5–0.7]
2.9 0.1[2.8–3.0]
>50
34.8 3.4 [31.3–
38.2]
<0.195
<0.195
2.0 [<0.5–
3.4]
0.7 [0.4–1.1]
2.3[1.9–2.7]
54
267.28
295.34
2.40
3.40
2.3 0.5[1.7–2.7]
NT
4.7 1.1 [3.2–5.2]
NT
1.1 0.3 [0.9–1.4]
NT
NT
5.3 0.5 [5.0–5.9]
NT
>50
0.22 0.01[0.23–
0.22]
0.37 0.12[0.23–
0.46]
137.14 À0.67
>512
>128
0.09 0.01[0.08–
0.1]
0.04 0.01[0.03–
0.05]
822.94
6.04
0.2
2.6
113
SD, standard deviation; MIC, minimum inhibitory concentration required to inhibit the growth of 90% of organisms; NT, not tested; GAS, glycerol-alanine-salts media; GAST,
iron deficient glycerol-alanine-salts with Tween 80 media; 7H12, 7H9 broth base media with BSA, casein hydrolysate, catalase, palmitic acid; LORA, low oxygen recovery
assay using the Mtb H37Rv luxAB 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.

2218
G. C. Moraski et al. / Bioorg. Med. Chem. 20 (2012) 2214–2220
oxazoline (1) / oxazole (2, 3)
thiazoline (4) / thiazole (5)
pyrazole (6)
isoxazole (7)
pyridine (8)
imidazo[1,2-a]pyridine (9 - 12)
imidazo[1,2-a]pyrimidine (13)
imidazo[1,2-c]pyrimidine (14)
INH
RMP
0.001
0.01
0.1
1.0
10
100
MIC ( M)
µ
Figure 2. Comparison of the MIC range against Mtb H37Rv of the various heteroaromatic scaffolds prepared (MIC in lM).
of GAST, an iron deficient media containing glycerol-alanine-salts
with Tween 80, often causes a shift in antibacterial MIC values of
iron binding siderophores17 and hydroxamate-substituted cepha-
losporin derivatives.18 Though originally modeled after the oxazo-
line core of the mycobactin class of siderophores,17 all of the
heterocyclic classes screened appear to be non-iron dependant.
The isoxazole and pyridine scaffolds (7 and 8) showed good
compounds likely inhibited different targets, a notion that was
confirmed by microarray analysis of Mtb H37Rv treated with these
compounds which showed different transcriptional signatures
(Ref.8 and unpublished results). Imidazo[1,2-a]pyridine (12) had
excellent in vitro stability in rat liver microsomes with 90% of com-
pound remaining after a 15-min incubation and 100% remaining
after a 15-min incubation in simulated gastric fluid20 compared
to oxazole (2) where only 11% remained in microsomes and 0.6%
remained in the simulated gastric fluid after a 15-min incubation.
In 2009, various functionalized 2-aryl-3-amino-imidazo[1,2-a]pyr-
idines were reported21 as in vitro Mtb glutamine synthetase inhib-
itors, but this publication neglected to give an assessment of these
compounds versus whole cell Mtb H37Rv making it hard to com-
pare these scaffolds for potential similarities. Previous data8 sug-
potency against Mtb H37Rv (2.2 and 1.9 lM, respectively in the
GAS media) that was comparable to the activity of the analogous
oxazoline/oxazole and thiazoline/thiazole scaffolds, but concerns
about metabolic stability of the constituent benzyl ester lingered.
The isoxazole scaffold (7) also has been well documented as a
potent antitubercular scaffold by Kozikowski et al.19
At this juncture we were fortunate to have made an agreement
allowing for the access and screening of compounds from the Dow
AgroScience (DAS) chemical bank against Mtb. This allowed for a
deepening of our SAR studies around our oxazole and thiazole scaf-
folds, as well as exploration of other heterocyclic classes including
various ethyl imidazo[1,2-a]pyridine-3-carboxylates that showed
gested
a mechanism of action distinct from inhibition of
glutamine synthesis since transcriptional profiling experiments of
Mtb H37Rv treated with compound 12 had suggested an effect on
energy metabolism. Additionally, a set of polyfunctional imi-
dazo[1,2-a]pyridines was recently disclosed22 which displayed a
broader spectrum of antibacterial activity than that which was
published for our 2,7-dimethylimidazo[1,2-a]pyridine-3-carbox-
amide scaffold.8 In comparison, we reported our class to be active
against only select mycobacteria strains (Mycobacterium kansasii,
Mycobacterium bovis BCG, and Mycobacterium avium, MIC’s 1.3,
moderate activity with MIC values of 41–86 lM (see Supplemen-
tary data). These initial imidazo[1,2-a]pyridines screened from
DAS lacked the benzyl ester that was found to improve potency
in the oxazoline/oxazole scaffolds we previously explored.5 Grati-
fyingly, when the benzyl ester analog (11) was made, a dramatic
>2 orders of magnitude increase in potency was observed from
0.3, 1.3 lM, respectively) while no activity (MIC >50 lM) was seen
an MIC of ꢀ65
l
M as the ethyl ester (79, in Supplementary data)
against + the Gram positive (Streptococcus aureus) or Gram negative
(Escherichia coli) organisms whereas the reported polyfunctional
imidazo[1,2-a]pyridines did have potency against both the Gram
to MIC <0.195
lM as the corresponding benzyl ester (11). In
comparison, the benzyl ester oxazole (2), with an MIC range of
0.5–6 M, was within an order of magnitude as potent as the cor-
responding ethyl ester analog (81, in Supplementary data) with an
MIC of 8–20 M. Therefore, simple ethyl esters do not appear to
l
positive and Gram negative organisms (MIC’s of 0.5 and 1 lg/mL,
respectively). The potency of these compounds against M. avium
further suggested that the target was unlikely glutamine synthe-
tase since glutamine synthetase inhibitors were found to have con-
siderably poorer efficacy against M. avium due to the finding that
this organism secretes only small quantities of this protein.23
Comparison of the MIC ranges (taken from multiple screens) of
the various scaffold analogs to one another showed a positive
improvement in activity with the 5,6-fused heteroaromatics
(9–14), displaying potency closer to that of the first line antituber-
cular drug isoniazid (MIC = 0.2–0.5 lM) and significantly better
than the previous explored classes (1–8) that have low micromolar
potency (Fig. 2). The 5,6-fused heteroaromatics were non-toxic to
the VERO cells (IC50 >50 lM) and some had moderate activity in
l
impart the sub-micromolar potency seen with the benzyl esters
(see Supplementary data). Next, when the N-benzyl-2,7-dimethy-
limidazo[1,2-a]pyridine-3-carboxamide (12) was synthesized and
assessed (MIC of 0.7–2.3 lM), we confirmed that extended scaffold
SAR studies beyond esters had been appropriate. Indeed, the
2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide scaffold dis-
played both excellent antitubercular potency, greatly improved
in vitro metabolic stability and pharmacokinetic properties relative
to the oxazoline/oxazole scaffolds (as reported previously in sepa-
rate publications).5,8 The chemical dissimilarity between the oxa-
zole and imidazo[1,2-a]pyridine scaffolds suggested that these

G. C. Moraski et al. / Bioorg. Med. Chem. 20 (2012) 2214–2220
2219
Table 2
MDR- and XDR-Mtb activity of compounds 2, 5, 11 and control PA-824 lM (MICin lg/mL)
Compound MIC
lM (lg/mL)
2
5
11
PA-824
Drug sensitive Mtb clinical strain #1
Drug sensitive Mtb clinical strain #2
MDR-TB resistant to HREZSKP
MDR-TB resistant to HREKP
MDR-TB resistant to HRERb
XDR-TB resistant to HRESKO
XDR-TB resistant to HREKO
4.4–8.9 (1.25–2.5)
2.2–4.4 (0.6–1.25)
8.9 (2.5)
1.1 (0.3)
8.9 (2.5)
33.9 (10)
8.5 (2.5)
33.9 (10)
4.2 (1.25)
33.9 (10)
16.9 (5)
<0.04 (<0.01)
<0.04 (<0.01)
<0.04 (<0.01)
<0.04 (<0.01)
0.57 (0.16)
0.45–0.86 (0.16–0.31)
>13.9 (>5)
0.45–0.86 (0.16–0.31)
0.45–0.86 (0.16–0.31)
0.45–0.86 (0.16–0.31)
0.86 (0.31)
4.4 (1.25)
8.9 (2.5)
<0.04 (<0.01)
<0.04 (<0.01)
16.9 (5)
0.22 (0.08)
⁄Almost no growth though up to 0.07
lM (0.02 lg/mL). MIC, minimum inhibitory concentration required to inhibit the growth of 90% of organisms; MICs were done in 7H9/
glucose/glycerol/BSA/0.05% Tween 80 and the average of three individual measurements. Abbreviations: H, isoniazid; R, rifampin; E, ethambutol; Z, pyrazinamide; S,
streptomycin; K, kanamycin; P, para-aminosalicylic acid; Rb, rifabutin; O, ofloxacin.
the simulated latent TB assay (LORA16) with compound 9 having
Acknowledgments
the lowest MIC of 22 lM (isoniazid was >512 lM). Again, the
5,6-fused heteroaromatics were prepared in just a single synthetic
step with the exception of compounds 10 and 12.
This research was supported in part by the Intramural Research
Program of the NIH, NIAID and by Grant 2R01AI054193 from the
National Institutes of Health (NIH) and in part by intermediates
provided from DAS. We would like to thank the University of Notre
Dame, especially the Mass Spectrometry and Proteomics Facility
(Bill Boggess, Michelle Joyce, Nonka Sevova), which is supported
by the grant CHE-0741793 from the NIH. We thank Prof. Jennifer
DuBois for regular and lasting scientific discussions. The excellent
technical assistance of Baojie Wan and Yuehong Wang with antitu-
bercular assays at UIC is greatly appreciated.
Curious as to whether there would be potency against
multi-drug resistant (MDR) and extensively drug resistant (XDR)
Mtb strains, three compounds typical of their class—an oxazole
(2), a thiazole (5) and an imidazo[1,2-a]pyridine (11), as well as
the bactericidal nitroimidazole PA-82424 were screened against a
panel of clinical drug sensitive and drug resistant strains (Table
2). We were pleased to find that the potency determined in
replicating Mtb H37Rv (in the 7H9 media) was retained and at
times improved against the drug sensitive, MDR- and XDR-Mtb
strains screened for all three classes. Oxazole (2) had good potency
Supplementary data
in the lower micromolar range (MIC = 1–9 in
clinical strains, while the related thiazole (5) was significantly less
potent having MIC values from 4 to 34 M. The imidazo[1,2-a]pyr-
idine (11) had potency better than that of PA-824, a clinical
candidate, with MIC values of <0.04 M against all of the clinical
strains with the exception of one MDR strain (MIC = 0.6 M) that
lM) against these
Supplementary data (experimental procedures and analytical
data for compounds (1–14) can be found as well as additional
SAR, metabolism studies and a description of the assays used) asso-
ciated with this article can be found, in the online version, at
doi:10.1016/j.bmc.2012.02.025.
l
l
l
is resistant to isoniazid, rifampin, ethambutol and rifabutin.
Interestingly, there was a drug sensitive strain that showed
resistance to PA-824 (MIC >14 lM) but was nonetheless inhibited
References and notes
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Herein we report ten classes of compounds with good (micro-
molar) to excellent (sub-micromolar) antitubercular potency, sug-
gesting that there are new antitubercular compound classes yet to
be found. Three 5,6-fused heteroaromatic scaffolds (imidazo[1,2-
a]pyridine, imidazo[1,2-a]pyrimidine, and imidazo[1,2-c]pyrimi-
dine) were prepared in just one synthetic step and each is amena-
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isoniazid and PA-824 against replicating Mtb H37Rv, clinically rele-
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compound 11), as well as good in vitro metabolic stability (demon-
strated by compound 12). It is our hope that the introduction of
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industry to join in the fight to combat TB.
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