New anti-MRSA and anti-VRE carbapenems; synthesis and structure-activity relationships of 1beta-methyl-2-(thiazol-2-ylthio)carbapenems.
Discovery of novel antimicrobial agents effective against infections caused by drug-resistant pathogens is an important objective. In order to find a new parenteral carbapenem antibiotic, which has potent antibacterial activity especially against methicillin-resistant staphylococci, vancomycin-resistant enterococci and penicillin-resistant Streptococcus pneumoniae, a series of 1beta-methylcarbapenems with thiazol-2-ylthio groups at the C-2 position have been synthesized. Structure-activity relationships were investigated which led to SM-197436 (27), SM-232721 (44) and SM-232724 (41), being selected for further evaluation.
Sunagawa
Makoto
M
Sumitomo Pharmaceuticals Research Division, Osaka, Japan. sunagawa@sumitomopharm.co.jp
Itoh
Masanori
M
Kubota
Katsumi
K
Sasaki
Akira
A
Ueda
Yutaka
Y
Angehrn
Peter
P
Bourson
Anne
A
Goetschi
Erwin
E
Hebeisen
Paul
P
Then
Rudolf L
RL
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015780:Carbapenems / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016983:Enterococcus / Q000187:drug effects*; D006801:Humans; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests / Q000379:methods; D010403:Penicillin Resistance; D013211:Staphylococcus aureus / Q000187:drug effects*; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship; D020713:Vancomycin Resistance
C467216:3-((4-(2,5-dihydro-1H-pyrrol-3-yl)-1,3-thiazol-2-yl)thio)-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid; C467218:6-(1-hydroxyethyl)-3-((4-(2-(hydroxymethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,3-thiazol-2-yl)thio)-4-methyl-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid; C467217:6-(1-hydroxyethyl)-4-methyl-3-((4-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3-thiazol-2-yl)thio)-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid; D000900:Anti-Bacterial Agents; D015780:Carbapenems