The synthesis and antibacterial activity of totarol derivatives. Part 3: Modification of ring-B.
Ring-B derivatization of totarol (1) afforded the series of compounds 2-22 which were screened in vitro against: beta-lactamase-positive and high level gentamycin-resistant Enterococcus faecalis, penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), and multiresistant Klebsiella pneumoniae. Several of the derivatives retained much of the antibacterial activity of totatol against the first three of these organisms (all gram-positive), but none was more active. The gram-negative Klebsiella was resistant to all compounds examined. Totarol (1) was shown to uncouple oxidative phosphorylation in isolated mitochondria at 50 microM.
Evans
G B
GB
Industrial Research Limited, Lower Hutt, New Zealand. g.evans@irl.cri.nz
Furneaux
R H
RH
Gainsford
G J
GJ
Murphy
M P
MP
D025181:ATP Synthetase Complexes; D045784:Abietanes; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D013293:Enterococcus faecalis / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D020128:Inhibitory Concentration 50; D007425:Intracellular Membranes / Q000187:drug effects; D007476:Ionophores / Q000494:pharmacology; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008099:Liver / Q000648:ultrastructure; D008928:Mitochondria / Q000378:metabolism; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship; D019802:Succinic Acid / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology
D045784:Abietanes; D000900:Anti-Bacterial Agents; D004224:Diterpenes; D007476:Ionophores; D009097:Multienzyme Complexes; D010936:Plant Extracts; D014475:Uncoupling Agents; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; C078548:totarol; D019802:Succinic Acid; D025181:ATP Synthetase Complexes; D017856:Phosphotransferases (Phosphate Group Acceptor)