Syntheses of New Cephalosporins as Potent Antibacterial Agents
Jih Ru Hwu,*,§,¶ Shwu-Chen Tsay,§
Shu-Mei Liao,§ and Shahram
§Organosilicon and Synthesis Laboratory, Institute of Chemistry,
Academia Sinica, Nankang, Taipei, Taiwan 11529, Republic of China, and ¶Department of
Chemistry, National Tsing Hua University, Hsinchu, Taiwan 30043, Republic of China
New isodethiaazacephems (±)-2, (±)-3, and
(±)-10 were synthesized and found to possess biological activity
against S. aureus FDA 209P in vitro. The mesylate and the
triflate functionalities in isodethiaazacephems (±)-2 and
(±)-3 acted as electron sinks and remarkably enhanced the
biological activity in comparison with the parent 3-hydroxy-isodethiaazacephem
b-Lactam antibiotics can acylate a serine residue of
transpeptidases,1 which is responsible for cross-linking of
peptidoglycans.2 For enhancement of the antibacterial activity
resulting from b-lactam cephalosporins (1), a nucleofuge may be attached
to their C-3' position.3 Upon reaction with bacterial enzymes, the
b-lactam ring therein is opened readily to result in liberation of the
nucleofuge as shown in Scheme 1.4-7 Accordingly, we designed and
synthesized isodethiaazacephems (±)-2 and (±)-3 . We
believe that the sulfone moieties at the O-3' position of 2 and 3
could act as nucleofuges and thus enhance the antibacterial activity in
comparison with that of the parent isodethiaazacephem (±)-10.
For the synthesis of isodethiaazacephem (±)-2, we treated racemic
b-lactam mesylate 58 with NaN3 in DMF to give
azido b-lactam 6 in 90% yield (Scheme 2). Subsequently, azido b-lactam
6 was chlorinated with CF3SO2Cl and
Et3N to give 7
in 90% yield.9 Reaction of 7 with H2S in
Et3N produced a mixture of isodethiaazapenam 8 (40%) and
isodethiaazacephem 9 (15%). Catalytic reduction of 7 by use of
Pd/C and H2 (30-35 psi) in EtOAc gave the desired compound 9
(87%) exclusively. On the other hand, catalytic hydrogenation of 6 by
use of Pd/C and H2 (30-35 psi) in EtOAc resulted in the reduction of
the azide moiety and spontaneous formation of isodethiaazacephem 9 in
94% yield. Debenzylation of 9 to 10 (50%) was accomplished by
use of H2 (60 psi) and PdCl2 in EtOH.
We attached the sulfonyl group to the cephem nucleus by mesylation of 9
with MeSO2Cl in pyridine. The resultant 3-mesyloxy b-lactam 11
was then hydrogenated with PdCl2 in EtOH at 60 psi of
H2 to give the desired isodethiaazacephem (±)-2 in 35%
Moreover, we treated b-lactam 9 with CF3SO2Cl in
pyridine to afford a 3:1 mixture of trifluoromethanesulfonates 12 and
13 in 40% overall yield (Scheme 3). Catalytic reduction of 12
with PdCl2 in EtOH at 60 psi of H2 gave the target
isodethiaazacephem (±)-3 in 30% yield.
We tested the antibacterial activity of the synthesized b-Lactams
(±)-2, (±)-3, and (±)-10 as well as
reference compound benzyl pencillin10in vitro against S.
aureus FDA 209P. The doses were used up to a level as high as 128
Results from biological tests revealed the interesting antimicrobial activity
of the enol sulfonate b-lactams (±)-2 (0.070 mg/mL) and
(±)-3 (0.010 mg/mL). In contrast, enol b-lactam (±)-10
exhibited much lower activity (29.50 mg/mL). Benzyl penicillin was active at
the level of 0.40 mg/mL against S. aureus FDA 209P.
The antibacterial activity of cephalosporins against sensitive pathogens is
greater by possessing a potential nucleofuge at the C-3'
position.3,4,12-16 Trifluoromethanesulfone unit in
(±)-3 possesses stronger leaving capability than the methanesulfone
unit in (±)-2. Thus, antibacterial activity is more potent for
(±)-3 than (±)-2. This is in agreement with our
hypothesis on their mode of action in biological systems as shown in Scheme
The preparation of cephalosporin 4 having an excellent leaving group at
C-3' position is in progress. The complete biological screening experiments
against different strains of five pathogenic microorganisms will be described
elsewhere. Acknowledgment. For financial support, we thank the National Science
Council of Republic of China and Academia Sinica. References
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