Dicationic dithiocarbamate carbapenems with anti-MRSA activity.

Abstract

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).

• Authors: H Imamura, N Ohtake, H Jona, A Shimizu, M Moriya, H Sato, Y Sugimoto, C Ikeura, H Kiyonaga, M Nakano, R Nagano, S Abe, K Yamada, T Hashizume, H Morishima
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 9 Issue 6 Pg. 1571-8 (Jun 2001) ISSN: 0968-0896 [Print] England
• PMID: 11408176 (Publication Type: Journal Article)

Chemical References

• 1beta-methyl-2-(4-(4-carbamoylmethyl-1,4-diazabicyclo(2,2,2)octanediium-1-yl)methyl-1,2,3,6-tetrahydropyridinylthiocarbonylthio)carbapenem
• Aza Compounds
• BO 3482
• Blood Proteins
• Carbapenems
• Pyridines
• Dipeptidases
• dipeptidase

Topics

• Animals
• Aza Compounds (chemistry, metabolism, pharmacology)
• Blood Proteins (metabolism)
• Carbapenems (chemistry, metabolism, pharmacology)
• Dipeptidases (metabolism)
• Drug Evaluation, Preclinical
• Male
• Methicillin Resistance
• Mice
• Mice, Inbred ICR
• Microbial Sensitivity Tests
• Pyridines (chemistry, metabolism, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Staphylococcal Infections (drug therapy)
• Staphylococcus aureus (drug effects, physiology)
• Structure-Activity Relationship