Discovery of novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems.
Novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems were designed and synthesized to provide J-111,347 (1a) as the first example of an exceptionally broad-spectrum antibiotic, showing activity against methicillin-resistant Staphyloccocus aureus (MRSA) as well as Pseudomonas aeruginosa. Further derivation of 1a afforded J-111,225 (2a), J-114,870 (3a), and J-114,871 (3b). which showed improved safety profiles and retained broad-spectrum antibacterial activities.
Imamura
H
H
Banyu Tsukuba Research Institute, Ibaraki, Japan. imamrahk@banyu.co.jp
Ohtake
N
N
Shimizu
A
A
Sato
H
H
Sugimoto
Y
Y
Sakuraba
S
S
Nagano
R
R
Nakano
M
M
Abe
S
S
Suzuki-Sato
C
C
Nishimura
I
I
Kojima
H
H
Tsuchiya
Y
Y
Yamada
K
K
Hashizume
T
T
Morishima
H
H
D000818:Animals; D015780:Carbapenems / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D003292:Convulsants; D004150:Dipeptidases / Q000378:metabolism; D015195:Drug Design; D004827:Epilepsy / Q000139:chemically induced; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship
D015780:Carbapenems; D003292:Convulsants; D011758:Pyrroles; D004150:Dipeptidases; C038937:dipeptidase