J. Wu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5293–5296
5295
Table 1
2-Oxaisocephems 16a–g and 17a–g
Compd
R1
16a
16b
16c
16d
16e
16f
16g
N
N
S
CH3
R2
H2C
Compd
17a
17b
17c
17d
17e
17f
17g
N
N
N
R1
R2
N
HO
CH3
H2C
Table 2
In vitro antibacterial activity (MICa,
hydroxyethyl)-1H-tetrazol-5-yl)thiomethyl group in combination
with the [2-(5-amino-1,2,4-thiadizol-3-yl)-2-(Z)-alkoxyimino]-
acetamido moiety, which is often used as the side-chain at the 7-
position of fourth-generation cephalosporins, contributes more to
the enhancement of the activity against Gram-positive bacteria.
Compound 17a displayed the potency fourfold more than the
reference against S. aureus and 17b showed encouraging activity
l
g mLꢀ1) of the compounds 16a–g and 17a–g
Gram-positive bacteriab Gram-negative bacteriab
Compd
S. au.
S. ep.
E. c.
P. ae.
K. pn.
16a
16b
16c
16d
16e
16f
16g
17a
17b
17c
17d
17e
64
64
32
64
128
128
128
0.5
0.5
0.5
16
4
16
128
1
64
128
8
16
16
1
0.125
0.125
0.125
0.125
64
64
128
128
128
128
128
128
2
2
0.5
8
16
4
32
128
4
16
128
16
16
16
64
8
8
128
1
against S. epidermidis, with the MIC value 0.125 l
g mLꢀ1, which
32
128
4
16
32
64
32
32
64
8
was 128-fold lower than that of ceftazidime. Against the Gram-
negative bacteria strains, the antibacterial activity of 17c was
equal or superior to that of the reference, especially against
E. coli, 17c was the most potent agent in all the new 2-oxaisocep-
hems. Compounds 17c–f were 2- to 16-fold more potent than the
reference compound against P. aeruginosa. And compound 17f, the
most potent compound in series 2, was found to be fourfold more
potent than ceftazidime in its ability to inhibit K. pneumoniae.
In conclusion, introductions of the side-chains used of fourth-
generation cephalosporins into the 7-position of the 2-oxaisoc-
ephem nucleus and the alteration of the 3-subtituents into the side
chains which were often used at 3-position of oxacephems gave
new 2-oxaisocephems with good activity and broad antibacterial
spectrum. Among them, particularly 17c and 17f had well-bal-
anced potency and were found to have excellent antibacterial
activities against Gram-positive organism while maintaining good
Gram-negative activities. Encouraged by these findings, we are
continuing to conduct the evaluation of extensive antibacterial
activity and search more effective 2-oxaisocephem antibiotics,
while the results will be reported in due course.
4
8
2
17f
17g
1
2
32
4
64
16
128
32
Ceftazidime
2
16
a
Minimum inhibitory concentrations (106 cells/mL).
Definitions of organism abbreviations: S. au. = S. aureus ATCC25923, S. ep. = S.
b
epidermidis, E. c. = E. coli ATCC25922, P. ae. = P. aeruginosa ATCC27853, K. pn. = K.
pneumoniae.
Generally speaking, compounds in the series 1 with the C-30
(1,3,4-thiadiazol-2-yl)thiomethyl group, 2-oxaisocephem deriva-
tives (16a–g), most of which was less active against the micro-
organisms including the Gram-positive and Gram-negative bacte-
rial strains, especially against the Gram-positive bacteria, than
the ones in series 2 (17a–g) possessing a (1-(2-hydroxyethyl)-
1H-tetrazol-5-yl)thiomethyl group at C-3. Among those com-
pounds in series 1, there was generally no compound more potent
against S. aureus and E. coli than the reference. The activity of 16a
against S. epidermidis was equal to that of the reference, but against
K. pneumoniae, it was fourfold more potent than that of ceftazi-
dime. Compound 16d displayed about the same activity against
P. aeruginosa and K. pneumoniae as reference compound. Com-
pounds 16b and 16e showed poor activity against all the tested
strains, whereas 16c showed significantly enhanced activity
against S. epidermidis, P. aeruginosa and K. pneumoniae as compared
with the reference. In particular, against K. pneumoniae, it was the
most potent compound in all the synthetic 2-oxaisocephems with
Supplementary data
Supplementary data associated with this article can be found,
2012.06.040. These data include MOL files and InChiKeys of the
most important compounds described in this article.
References and notes
1. Barbosa, T. M.; Levy, S. B. Drug Resist. Updat. 2000, 3, 303.
2. Chopra, I.; Hodgson, J.; Metcalf, B.; Poste, G. Antimicrob. Agents Chemother. 1997,
41, 497.
3. Doyle, T. W.; Douglas, J. L.; Belleau, B.; Conway, T. T.; Ferrari, C. F.; Horning, D.
E.; Lim, G.; Luh, B.-Y.; Martel, A.; Menard, M.; Morris, L. R. Can. J. Chem. 1980, 58,
2508.
4. Conway, T. T.; Lim, G.; Douglas, J. L.; Menard, M.; Doyle, T. W.; Rivest, P.;
Horning, D. E.; Morris, L. R.; Cimmon, D. Can. J. Chem. 1978, 56, 1335.
5. Douglas, J. L.; Horning, D. E.; Conway, T. T. Can. J. Chem. 1978, 56, 2879.
6. Doyle, T. W.; Belleau, B.; Luh, B.-Y.; Ferrari, C. F.; Cunningham, M. P. Can. J.
Chem. 1977, 55, 468.
the MIC value 1 l
g mLꢀ1, which was 32-fold lower than that of
ceftazidime. While against the three bacterial strains, the activity
of compounds 16f and 16g was not apparently enhanced as 16c,
only 16f showed an MIC value eightfold lower than the reference
against K. pneumoniae.
Compounds in series 2 except 17g showed much more activity
against Gram-positive bacteria, on the other hand, the (1-(2-