ABSTRACT
Ring-cleaved pleuromutilin derivatives comprised of a [5.3.1] bicyclic core structure have been synthesized and evaluated in vitro as antibacterial agents. Four of the compounds described were found to have MICsSubject(s)
Anti-Bacterial Agents/chemical synthesis
, Anti-Bacterial Agents/chemistry
, Anti-Bacterial Agents/pharmacology
, Diterpenes/chemical synthesis
, Diterpenes/chemistry
, Diterpenes/pharmacology
, Microbial Sensitivity Tests
, Polycyclic Compounds
, Staphylococcus aureus/drug effects
, Streptococcus pneumoniae/drug effects
, Structure-Activity Relationship
, Pleuromutilins
ABSTRACT
Nocathiacin I (1) was converted to its deoxy indole analogue, nocathiacin II (2), another natural product, by a unique and facile chemical process. This process was applied to nocathiacin IV (4), generating the lactone analogue of glycothiohexide alpha (5), which was also prepared from nocathiacin II by a mild hydrolytic process. In contrast to glycothiohexide alpha (3), this lactone analogue (5) was found to exhibit in vivo antibacterial efficacy in an animal (mouse) infection model.
Subject(s)
Anti-Bacterial Agents/chemistry , Peptides, Cyclic/chemistry , Peptides/chemistry , Animals , Anti-Bacterial Agents/pharmacology , Disease Models, Animal , Intercellular Signaling Peptides and Proteins , Mice , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Peptides/pharmacology , Peptides, Cyclic/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
A C-8 keto pleuromutilin derivative has been synthesized from the biotransformation product 8-hydroxy mutilin. A key step in the process was the selective oxidation at C-8 of 8-hydroxy mutilin using tetrapropylammonium perruthenate. The presence of the C-8 keto group precipitated interesting intramolecular chemistry to afford a compound (10) with a novel pleuromutilin-derived ring system.
Subject(s)
Diterpenes/chemical synthesis , Biotransformation , Ketones/chemistry , Oxidation-Reduction , Polycyclic Compounds/chemistry , PleuromutilinsABSTRACT
Forty-five novel cephalosporin derivatives with activity against methicillin-resistant Staphylococcus aureus (MRSA) are described. The compounds contain novel cinnamic acid moieties at C-7 that were synthesized using a key Heck reaction followed by nucleophilic aromatic substitution reactions. The most active compound (41) displayed an MIC(90) against MRSA of 1.0 microg/mL, and a PD(50) of 0.8 mg/kg. Compound 14 was found to be very safe in a mouse model of acute toxicity.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Cephalosporins/chemistry , Cephalosporins/pharmacology , Cinnamates/chemistry , Cinnamates/pharmacology , Staphylococcus aureus/drug effects , Animals , Disease Models, Animal , Lethal Dose 50 , Methicillin Resistance , Mice , Microbial Sensitivity Tests , Staphylococcal Infections/microbiology , Staphylococcus aureus/pathogenicity , Structure-Activity Relationship , Toxicity Tests, AcuteABSTRACT
Twenty-seven novel cephalosporin derivatives with activity against methicillin-resistant Staphylococcus aureus (MRSA) are described. The compounds contain novel acid moieties at C-7 that were synthesized using nucleophilic aromatic substitution reactions and Stille couplings. The most interesting compound (6) displayed an MIC(90) against MRSA of 3.7 microg/mL, and an average PD(50) of 3.9 mg/kg.
