G. P. Nora et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3966–3970
3969
Table 1. Antimicrobial activity in the agar diffusion assay Growth inhibition zones in mm
Species
Strain
Relevant property 9a 9b
9c
Penicillin G Lorabid Cefotaxime Ciprofloxacin 5 lg/ml
Gram + bacteria
Staphylococcus aureus
Staphylococcus aureus
Enterococcus faecalis
Mycobacterium vaccae
SG 511
134/93
1528
Wild type
MRSA
VRE
0
0
0
0
NA NA NA
NA NA NA
NA NA NA
NA NA NA
28
0
26
0
29
0
0
22
0
24
38
IMET 10670 Wild type
0
Gram À bacteria
Escherichia coli
Escherichia coli
Enterobacter cloacae
DC0
IV-3-2
P99
Wild type
0
0
0
0
NA NA NA
NA NA NA
NA NA NA
NA NA NA
24
23
21
28
25
27
TEM1 b-lactamase
ampC b-lactamase
PSE1 b-lactamase
NA
0
0
30
35
Pseudomonas aeruginosa IV-3-13
X580
0
14p
NA
NA
NA
NA
Escherichia coli
26 25
20
0
54
23
37
12
NA
NA
NA
NA
NA
NA
NA
NA
Escherichia coli
Samonella enterica
Klebsiella pneumoniae
ATCC 33475 NA
ATCC 13311 NA
0
0
0
0
0
0
0
ATCC 8308
NA
0
Fungus
Candida albicans
BMSY 212
NA
0
NA NA NA
NA
NA
NA
NA, not acquired.
p: colonies within the inhibition zone.
Test organisms (106 CFU/ml) were suspended in melted Nutrient agar (Serva) and poured into Petri dishes. Holes of 9 mm in diameter were made in
the agar and filled with 50 ll of a 0.2 mM solution of the compounds. Inhibition zones for bacteria were read after incubation for 18 h at 37 °C, for
Candida albicans at 30 °C.
with oxamazins.5 A representative isoxazolidine, 9c,
was also tested for b-lactamase inhibitory activity
using penicillinase from Bacillus cereus (EC 3.5.2.6)
under standard conditions15 and was found not to
be an inhibitor.
Princeton, 1949; (b) Chemistry and Biology of b-Lactam
Antibiotics Penicillins and Cephalosporins; Morin, R. B.,
Gorman, M., Eds.; Academic Press: New York, 1982; Vol.
1, (c) Chemistry and Biology of b-Lactam Antibiotics
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If isoxazolidines 9a–c are acting through the same
pathway that b-lactam antibiotics use, then, as with
the previously studied oxamazins5 and other mono-
bactams,6,7 alteration of the phenylacetyl side chain
would be expected to improve broad spectrum activi-
ty. Efforts are continuing in our laboratory to increase
and broaden the activity of these and related
isoxazolidines.
´
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Andreotti, D.; Biondi, S.; Fabio, R. D.; Donati, D.; Piga,
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Acknowledgments
Special thanks go to Anna Riley, Doug Zeckner, and
Eli Lilly and Company for broad screen testing of our
compounds. We gratefully acknowledge the NIH
(GM068012) for partial support of this research.
Supplementary data
Supplementary data associated with this article can be
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dakou, N. H. Antimicrob. Agents Chemother. 1982, 21, 85;
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