Syntheses and biological properties of new 8-fluorocarbapenem derivatives.
8-Fluorocarbapenem derivatives having various C-3 side chains were synthesized to study for the structure-activity relationship of carbapenems by in vitro biological evaluation. The introduction of fluorine at C-8 of racemic PS-5 led to slight improvements of the antimicrobial activity and the stability to renal dehydropeptidase-I. When D-cysteine was additionally introduced to the C-3 position of (+/-)-8-fluorocarbapenem, the diastereomeric separation of the 8-fluorocarbapenems became feasible. As expected from penicillins and cephalosporins, (+)-8-fluoro-3-D-cysteinylcarbapenem (+)-7a was antimicrobially active, whereas (-)-7b was inactive. It is worth noting, however, that (+)-7a was significantly more sensitive to renal dehydropeptidase-I than (-)-7b. Irrespective of the presence of fluorine at C-8, basic S-side chains at C-3, such as the pyridyl and pyrrolidyl groups, significantly improved in antimicrobial activity and dehydropeptidase-I stability. The combination of 8-fluorination with C-3 basic side chains in 7c--g resulted in a marked improvement of antimicrobial activity and dehydropeptidase-I stability.
Watanabe
A
A
MERCIAN Corporation, Central Research Laboratories, Fujisawa, Japan.
Sakamoto
M
M
Fukagawa
Y
Y
Yoshioka
T
T
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D001419:Bacteria / Q000187:drug effects; D015780:Carbapenems / Q000138:chemical synthesis* / Q000494:pharmacology; D005461:Fluorine / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D005461:Fluorine