898
S. P. East et al. / Bioorg. Med. Chem. Lett. 19 (2009) 894–899
Table 3
Head-to-head comparison of the triazolopyridine and benzimidazole scaffolds
a
a
Compound
R
GyrB IC50
(l
M)
ParE IC50
(l
M)
SA MIC (lg/ml)
23
24
31
33
36
2-Pyridyl
3-Pyridyl
1-Pyrazolyl
–CO2Me
0.89
0.61
0.054
1.3
nd
nd
25
nd
nd
>256
>256
2
>256
8
N
N
N
H
N
H
N
–CONHMe
0.64
N
O
R
39
40
41
2
2-Pyridyl
3-Pyridyl
1-Pyrazolyl
–CO2Me
<0.004
0.006
<0.004
<0.004
0.005
0.014
1.3
0.046
0.035
0.15
0.031
4
0.063
0.063
16
N
N
H
N
H
42
–CONHMe
N
H
N
O
R
a
Ki data for compounds 39–42.
Table 4
In conclusion, we have identified an imidazopyridine and a triaz-
olopyridine scaffold which can be functionalized to provide com-
pounds that demonstrate antibacterial activity through inhibition
of GyrB/ParE. The triazolopyridine scaffold was selected for further
SAR evaluation and compounds with good antibacterial activity,
particularly against Gram-positive organisms, have been identified.
From our preliminary evaluation it appears that the GyrB IC50s need
to be ꢀ500 nM or lower in order to see single digit MICs in the anti-
microbial screen. The evaluation of the pharmacokinetics and effi-
cacies of these compounds will be presented in due course.
Antibacterial activities for compounds 27, 31 and 37
Strain
MIC (
l
g/ml)
27
31
37
E. coli ATCC 25922
>128
>128
0.5
>128
1
1
1
0.5
1
1
>128
16
1
>128
4
4
4
4
4
2
>128
16
2
>128
4
4
4
2
4
4
H. influenzae ATCC 49247
M. catarrhalis ATCC 25240
P. aeruginosa 101021
E. faecalis 1.5604 (VRE)
S. aureus 601055 (MSSA)
S. aureus 43300 (MRSA)
S. aureus ATCC 700698 (MRSA)
S. aureus Smith ATCC 19636 (MSSA)
S. pneumoniae ATCC 49619
Acknowledgments
The authors extend their thanks to Dr. Steve Ruston, Dr. Mark
Whittaker and Dr. Geoff Lawton for useful discussions during
course of this research programme. This work was funded by
investments from East Hill Management (Boston, USA). The Proly-
sis authors declare financial interests.
antibacterials should demonstrate low spontaneous resistance fre-
quencies. No bona fide resistant strains of S. aureus at 2Â, 4Â or 8Â
the MICs of the compounds were isolated despite multiple at-
tempts. The resistance frequency was estimated to be
<1.8 Â 10À9, consistent with a dual-targeting inhibitor series. The
three compounds demonstrate good activity against a range of
pathogenic bacteria including drug-resistant clinical isolates (Table
4) with MICs comparable with the oxazolidinone antibacterial
agent linezolid.22 It is interesting to note that all three compounds
were ineffective against the E. coli strain used in this study. This
data, coupled with the data on the efflux pump mutant (shown
in Table 2), suggests that compounds in the triazolopyridine series
may have reduced permeability as well as some susceptibility to
efflux, at least in E. coli, however, this has not been investigated
further. Overall, the microbiology suggests that this series of com-
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indication.
a Gram-positive clinical
The mammalian cytotoxicity of 27, 31 and 37 was evaluated in a
HepG223 cell assay to test the effect of the compounds on mito-
chondrial metabolism after 24 h exposure. The IC50s for the com-
pounds were all >64
selectivity for antimicrobial versus cytotoxic activity and indicates
that the compounds are not general ATPase inhibitors.
During the course of this work, a patent application describing
some of the triazolopyridines described here as antibacterial
agents was published.24 In this patent activity against a strain of
Neisseria gonorrhoeae was reported (e.g. compound 37 MIC of
1 lg/ml) but to our knowledge no additional data on the antimi-
crobial activity of these compounds has appeared in the literature
and the compounds 27 and 31 have not been reported previously.
l
g/ml providing a significant window of
10. Charifson, P. S.; Grillot, A.-L.; Grossman, T. H.; Parsons, J. D.; Badia, M.; Bellon,
S.; Deininger, D. D.; Drumm, J. E.; Gross, C. H.; LeTiran, A.; Liao, Y.; Mani, N.;
Nicolau, D. P.; Perola, E.; Ronkin, S.; Shannon, D.; Swenson, L. L.; Tang, Q.;
Tessier, P. R.; Tian, S. K.; Trudeau, M.; Wang, T.; Wei, Y.; Zhang, H.; Stamos, D. J.
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11. Meigh, J.-P.; Álvarez, M.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1 2001, 2012.
12. Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber, J.; Heinz, B. A.; Vance, L. J. Med.
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13. All compounds described in this manuscript were characterized by LC–MS and
1H NMR.
14. The yield for step (vi) of the reaction sequence illustrated in Scheme
represents the yield from one unoptimised reaction.
1
15. Nettekoven, M.; Püllmann, B.; Schmitt, S. Synthesis 2003, 1649.