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AbstractA novel series of oxazolidinones containing a pyrroloaryl substituent was synthesized and screened against a representative panel of susceptible and resistant Gram-positive bacteria. Several members of this series were found to have antibacterial
activity comparable to or better than linezolid.
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properties make this compound an eective antibacterial agent: broad spectrum potency against resistant and susceptible Gram-positive bacteria; high
bioavailability, which allows for a facile transition from
parenteral to oral dosage forms; and an acceptable
therapeutic index.3 Of note is the activity of linezolid
against vancomycin-resistant S. aureus clinical isolates.2
Nevertheless, clinical failures of linezolid due to resistance in VRE,4 as well as documented safety concerns
following long term dosing,5 argue in favor of the continued development of new agents to treat multi-drug
resistant Gram-positive infections.
We have implemented a research program to develop
second-generation oxazolidinones with a primary goal
of identifying compounds with increased potency
against resistant Gram-positive bacteria compared to
linezolid. To this end we have explored replacing the
morpholine ring of linezolid with a pyrroloaryl substituent (Fig. 1).611 Several pyrroloaryl-substituted
oxazolidinones (8b, 8c, 10, 11a, 11b, and 12) were identied with superior or comparable in vitro antibacterial
activity to linezolid against a representative panel of
4174
Scheme 1. Reagents and conditions: (a) BH3THF, THF; (b) undecane, 180 C; (c) concd aq HCl, reux.
Scheme 6. Reagents and conditions: (q) 2- or 3-pyridinecarboxaldehyde, NaBH4, MeOH; (r) acetic acid, NaBH4.
provided the oxo-heterocycles 14 and 15. The pyrrolidinone ring forms via cyclic imine formation and subsequent 1,3-hydride shift.19 The dioxo-heterocycles (16)
were synthesized under standard conditions,20 via reaction of aniline 13 with the corresponding anhydrides.
Access to acyclic analogues was achieved by sequential
reductive aminations (Scheme 6). Reaction of aniline
intermediate 13 with 2- or 3-pyridinecarboxaldehyde
in the presence of sodium borohydride followed by
treatment with acetic acid and sodium borohydride21
aorded 17.
Minimum inhibitory concentrations (MIC) were measured against a group of antibiotic susceptible and
resistant strains of Gram-positive bacteria with linezolid
as a standard. A set of four strains was used as the
screening panel: S. aureus OC 4172 (Smith strain) is
methicillin-susceptible; S. aureus OC 2878 is methicillin-
4175
Compd
E. faecalis
VRE
MRSA
S. aureus broth
Linezolid
8a
16
8b
0.5
8c
0.5
0.5
0.25
0.5
10
11a
0.5
0.5
0.5
11b
0.5
12
0.5
14a
16
14b
16
16
15
32
16a
64
32
16
32
128
16b
>128
>128
>128
>128
>128
16c
>128
>128
>128
>128
>128
17a
16
16
16
32
17b
>128
>128
>128
>128
>128
The variance in the determination of MIC values is 2-fold such that an MIC dierence of at least 4-fold is signicant.
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4177
17. Ogawa, H.; Aoyama, T.; Shioiri, T. Heterocycles 1996, 42, 75.
18. Hutchinson, D. K. WO 96/23788, 1996, CAN 125:24827.
19. DoMinh, T.; Johnson, A. L.; Jones, J. E.; Senise, P. P., Jr.
J. Org. Chem. 1977, 42, 4217.
20. Harrington, P. M. Heterocycles 1993, 35, 683.
21. Marchini, P.; Liso, G.; Reho, A.; Liberatore, F.; Moracci,
F. M. J. Org. Chem. 1975, 40, 3453.
22. National Committee for Clinical Laboratory Standards.
Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria that Grow Aerobically, 5th ed. Approved standard:
NCCLS Document M7-A5, 2000.
23. Isolates were received from the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA)
program, generously provided by National Institutes of
Health/National Institutes of Allergy and Infectious Diseases,
Bethesda, MD, USA.