Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems. Part III: Novel 2-alkyl substituents containing cationic heteroaromatics linked via a C-N bond

Bioorg Med Chem. 1999 Aug;7(8):1665-82. doi: 10.1016/s0968-0896(99)00085-1.

Abstract

The synthesis and biological activity of a novel series of 2-alkyl-4-pyrrolidinylthio-beta-methylcarbapenems containing a variety of cationic heteroaromatic substituents is described. As a result of these studies, we uncovered a relationship between in vitro antibacterial activity and the length of the alkyl spacer part, and discovered FR20950 (1c), containing a two methylene spacer moiety and an imidazolio group, which possesses a balanced spectrum of antibacterial activity, including Pseudomonas aeruginosa and Methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, FR20950 exhibited excellent urinary recovery, and comparable stability against renal dehydropeptidase-I (DHP-I) to Biapenem. DHP-I stability could be improved by introduction of a substituent on to the imidazole ring.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Carbapenems / chemical synthesis*
  • Carbapenems / chemistry
  • Carbapenems / pharmacology*
  • Male
  • Methicillin Resistance
  • Mice
  • Mice, Inbred ICR
  • Microbial Sensitivity Tests
  • Pseudomonas aeruginosa / drug effects
  • Pyrrolidines / chemistry
  • Rats
  • Spectrum Analysis
  • Staphylococcus aureus / drug effects

Substances

  • Anti-Bacterial Agents
  • Carbapenems
  • Pyrrolidines