J. H. Lee et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4399–4403
4403
with the exception of 1a. In our series, the simple
Acknowledgements
hydroxyimino compound 1a (R1=R2=H) exhibited
potent and broad spectrum of antibacterial activity
including P. aeruginosa and similar stability to DHP-I
to meropenem. As to the oxyiminoalkyl substituents,
hydroxyimino compounds 1a,c showed better activities
against Gram-negative bacteria than methoxyimino
compounds 1b,d. There was no significant difference
among the activities of hydroxyimino derivatives 1a, 1c,
and 1e. 4-Aminomethyl compound 1c had comparable
antibacterial activity to meropenem against P. aerugi-
nosa, whereas it did not possess good stability to DHP-
I. Compared to the parent acid 1e, the ester 1f displayed
2-fold inferior activity against Gram-positive bacteria
and very poor activity against P. aeruginosa. Among the
compounds prepared, based on its balanced in vitro
antibacterial activity and stability to DHP-I, 1a was
selected for further evaluation.
We are grateful to the Ministry of Science and Tech-
nology (MOST) of Korea for financial support.
References and Notes
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Comparative in vitro activities of 1a, meropenem, and
ertapenem against clinical isolates of Gram-negative 40
bacterial species including MDR and ESBL-producing
strains were summarized in Table 2.
8. Ohtake, N.; Okamoto, O.; Kato, S.; Ushijima, R.; Fukatsu,
H.; Nakagawa, S. J. Antibiot. 1997, 50, 586.
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erocycles 1984, 21, 29.
The selected carbapenem 1a possessed excellent in vitro
activity against 40 target pathogens except for MDR P.
aeruginosa, and was almost equal to that of mero-
penem. Among Gram-negatives, ertapenem had excel-
lent activity against E. coli and K. pneumoniae (MICs,
ꢁ0.008–1 mg/mL) including MDR and ESBL-produ-
cing strains, but did not have good in vitro activity
against P. aeruginosa. Antibacterial activity of 1a
against clinical isolates of P. aeruginosa was similar to
that of meropenem, and superior to that of ertapenem.
Against MDR K. pneumoniae, 1a was 2–4 times more
active than the compared ertapenem. As a whole 1a was
comparable in potency to meropenem against Gram-
negative species including MDR and ESBL-producing
strains.
10. Selected spectral data: 1a: 1H NMR (300 MHz, D2O) d
1.09 (d, 3H, J=7.2 Hz), 1.17 (d, 3H, J=6.3 Hz), 1.78–1.84 (m,
1H), 2.69–2.76 (m, 2H), 2.79–2.86 (m, 1H), 3.25–3.29 (m, 2H),
3.33–3.36 (m, 1H), 3.48–3.52 (m, 1H), 3.57–3.80 (m, 2H),
3.82–3.90 (m, 1H), 4.09–4.17 (m, 3H), 4.29–4.35 (m, 1H),
4.43–4.49 (m, 1H); FABHRMS m/z calcd for C19H27N4O6S
(M+H)+ 439.1651, Found 439.1649. 1b: 1H NMR (300 MHz,
D2O) d 1.10 (d, 3H, J=7.2 Hz), 1.18 (d, 3H, J=6.3 Hz), 1.78–
1.84 (m, 1H), 2.69–2.76 (m, 2H), 2.79–2.86 (m, 1H), 3.25–3.29
(m, 2H), 3.33–3.36 (m, 1H), 3.48–3.52 (m, 1H), 3.57–3.80 (m,
2H), 3.77 (s, 3H), 3.82–3.90 (m, 1H), 4.09–4.17 (m, 3H), 4.29–
4.35 (m, 1H), 4.43–4.49 (m, 1H); FABHRMS m/z calcd for
C20H29N4O6S (M+H)+ 453.1808, found 453.1799.