Dicationic dithiocarbamate carbapenems with anti-MRSA activity.
A new class of 1 beta-methylcarbapenems bearing a doubly quaternarized 1,4-diazabicyclooctane (DABCO) substituted dithiocarbamate moiety at the C-2 side chain was prepared, and the biological profiles of the compounds, including in vitro and in vivo anti-MRSA activity and DHP-I susceptibility, were evaluated to identify a carbapenem derivative that was superior to BO-3482 (1). As a result, we discovered a 1 beta-methyl-2-[4-(4-carbamoylmethyl-1,4-diazabicyclo[2,2,2]octanediium-1-yl)methyl-1,2,3,6-tetrahydropyridinylthiocarbonylthio]carbapenem, 14a showing greater than 2-fold better anti-MRSA activity in a mouse infection model and 3-fold better DHP-I susceptibility as compared with BO-3482 (1).
Imamura
H
H
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan. imamrahk@banyu.co.jp
Ohtake
N
N
Jona
H
H
Shimizu
A
A
Moriya
M
M
Sato
H
H
Sugimoto
Y
Y
Ikeura
C
C
Kiyonaga
H
H
Nakano
M
M
Nagano
R
R
Abe
S
S
Yamada
K
K
Hashizume
T
T
Morishima
H
H
D000818:Animals; D001372:Aza Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D015780:Carbapenems / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004150:Dipeptidases / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D008297:Male; D016106:Methicillin Resistance; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship
C435820:1beta-methyl-2-(4-(4-carbamoylmethyl-1,4-diazabicyclo(2,2,2)octanediium-1-yl)methyl-1,2,3,6-tetrahydropyridinylthiocarbonylthio)carbapenem; D001372:Aza Compounds; C108864:BO 3482; D001798:Blood Proteins; D015780:Carbapenems; D011725:Pyridines; D004150:Dipeptidases; C038937:dipeptidase