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5513
and resistance profiles that are markedly improved.
Compound 5j is a direct analogue of rifalazil and exhib-
its an MIC versus wild-type S. aureus that is identical to
that of rifalazil. However, MICs against the intermedi-
ate- and high-level rifamycin-resistant strains are 4-fold
improved over rifalazil, possibly indicating a better
resistance development profile. The compound 5k with
an isopropyl group attached to the distal nitrogen of
piperazine is even more potent than the compound 5j,
with MICs 8-fold and 4-fold lower against the wild-type
and CB372 strains, respectively. However, despite its
improved activity against wild-type and intermediate rif-
amycin-resistant strains, the activity of compound 5k
against high-level resistant strain CB370 is similar to
that of 5j, indicating an apparent limitation of this series
of 11-deoxy-11-hydroxyimino-benzoxazino-rifamycins.
agents that circumvent the rapid resistance development
liability. However, clinical agents of the rifamycin class
of antibiotics exhibit unique efficacy in the treatment
of persistent infections mediated by Mycobacterium
tuberculosis and in hard-to-treat settings like biofilm-
associated infections of indwelling medical devices
mediated by S. aureus.2 Therefore, development of a
rifamycin agent without the resistance development
liability and that could be employed in monotherapy
would be expected to be highly valued as a new addition
to the antimicrobial armamentarium.
References and notes
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et al. J. Am. Med. Assoc 1995, 274, 1706.
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In summary, we have prepared
a novel series
of 11-deoxy-11-hydroxyimino-rifamycins. 11-Deoxy-
11-hydroxyimino-rifamycin S (3) exhibited enhanced
antibacterial activity and an improved resistance devel-
opment profile when compared to rifampin. This
enhancement of activity may be due to an additional
binding interaction(s) of the C-11 oxime functionality
with the RNA polymerase enzyme. In an attempt to
further improve the resistance profile of C11-oxime
derivatives of rifamycin class compounds, we prepared
11-deoxy-11-hydroxyimino-benzoxino-rifamycins. Some
of the latter compounds have both improved activity
and resistance development profiles when compared to
rifalazil. The MIC of the best compound of the series
(compound 5k) against an intermediate rifamycin-resis-
tant strain of S. aureus (CB372) is more than 10-fold
lower than that of rifalazil. However, the MIC of the
same compound against a high-level rifamycin-resistant
strain of S. aureus (CB370) is still as high as 8 lg/mL.
This level of activity provides little comfort for the
future development of a rifamycin agent that will cir-
cumvent resistance development. Indeed, suppression
of the development of resistance may not be adequately
addressed by exploration of novel binding interactions
with the RNA polymerase enzyme as mediated through
small variations or substitutions of the core rifamycin
scaffold due of the existence and prevalence of single-
step mutations in the rpoB gene that confer high level
resistance. Hence other medicinal chemistry strategies,
like incorporation of other antibacterial pharmaco-
phores, may be necessary to develop novel rifamycin
8. Rothstein, D. M.; Farquhar, R. S.; Sirokman, K.; Son-
dergaard, K. L.; Hazlett, C.; Doye, A. A.; Gwathmey, J.
K.; Mullen, S.; van Duzer, J.; Murphy, C. K. Antimicrob.
Agents Chemother. 2006, 50, 3658; Murphy, C. K.; Mullen,
S.; Osburne, M. S.; van Duzer, J.; Siedlecki, J.; Yu, X.;
Kerstein, K.; Cynamon, M.; Rothstein, D. M. Antimicrob.
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C.; Murphy, C. K.; Steinlicht, A.; Campbell, L. A. Expert
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