Synthesis and biological properties of 1-oxapenems.
Several 2-substituted oxapenems, 1a, 1b and 1c, bearing the hydroxyethyl side-chain at 6 alpha were synthesized in a highly stereoselective manner starting from the commercially available 3 alpha-hydroxyethyl-4 beta-acetoxyazetidinone (5). The stability, in vitro antibacterial activity, and beta-lactamase inhibitory properties of these oxapenems were examined. The 2-isopropyl penem 1c had considerable stability as shown by its t1/2 of 200 minutes in pH 7.0 buffer solution and at 37 degrees C, while the other two 1a and 1b were labile. Interestingly, the antibacterial activity of these compounds paralleled their stability and thus penem 1c showed appreciable MICs, whereas the other two were virtually inactive. All three penems inhibited certain cephalosporinases strongly, but penicillinases only weakly. Thus, the inhibitory spectrum was similar to that for epi-thienamycin B and not the spectrum for clavulanic acid.
Murakami
M
M
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Aoki
T
T
Matsuura
M
M
Nagata
W
W
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D004355:Drug Stability; D006207:Half-Life; D007769:Lactams; D015394:Molecular Structure; D013237:Stereoisomerism; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D007769:Lactams; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; C066801:6-(1-hydroxyethyl)-2-methyl-1-oxa-2-penem-3-carboxylic acid; C066802:6-(1-hydroxyethyl)-2-phenyl-1-oxa-2-penem-3-carboxylic acid; C066803:6-(1-hydroxyethyl)-2-isopropyl-1-oxa-penem-3-carboxylic acid