Structure--activity relationships of 1beta-methyl-2-(5-phenylpyrrolidin-3-ylthio)carbapenems.
Structure--activity relationship studies of 1beta-methyl-2-[(3S,5R)-5-(4-aminomethylphenyl)pyrrolidin-3-ylthio]carbapenems, especially those pertaining to the relationship between antibacterial activity and side-chain structure were conducted. These studies suggested that the trans-(3S,5R)-5-phenylpyrrolidin-3-ylthio side-chain and the aminomethyl group at the 4-position of the phenyl ring play a key role in enhancing the antibacterial activity against the MRSA and Pseudomonas aeruginosa strains. In particular, the basicity of a substituent at the 4-position of the phenyl ring were shown to greatly contribute to the antibacterial activity against MRSA and methicillin-resistant Staphyloccocus epidermidis strains. In contrast, the amidine group was shown to lead to potent antibacterial activity against P. aeruginosa strains comparable to that of imipenem, however, a good correlation between the basicity of the 4-substituent and antipseudomonal activity was not observed. In conclusion, the 4-aminomethyl or methylaminomethyl group on the phenyl ring was the best substituent for antipseudomonal activity.
Sato
Hiroki
H
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo-3, Tsukuba 300-2611, Ibaraki, Japan.
Sakoh
Hiroki
H
Hashihayata
Takashi
T
Imamura
Hideaki
H
Ohtake
Norikazu
N
Shimizu
Aya
A
Sugimoto
Yuichi
Y
Sakuraba
Shunji
S
Bamba-Nagano
Rie
R
Yamada
Koji
K
Hashizume
Terutaka
T
Morishima
Hajime
H
D000818:Animals; D001419:Bacteria / Q000187:drug effects; D015780:Carbapenems / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004150:Dipeptidases / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D004355:Drug Stability; D008826:Microbial Sensitivity Tests; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine
D015780:Carbapenems; D011759:Pyrrolidines; D004150:Dipeptidases; C038937:dipeptidase