Structure--activity relationships of 1beta-methyl-2-(5-phenylpyrrolidin-3-ylthio)carbapenems |
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Authors: | Sato Hiroki Sakoh Hiroki Hashihayata Takashi Imamura Hideaki Ohtake Norikazu Shimizu Aya Sugimoto Yuichi Sakuraba Shunji Bamba-Nagano Rie Yamada Koji Hashizume Terutaka Morishima Hajime |
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Institution: | Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo-3, Tsukuba 300-2611, Ibaraki, Japan. |
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Abstract: | 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. |
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