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

The synthesis and biological activity of a novel series of 2-alkyl-4-pyrrol idinylthio-beta-methylcarbapenems containing a variety of cationic heteroar omatic substituents is described. As a result of these studies, we uncovere d a relationship between in vitro antibacterial activity and the length of the alkyl spacer part, and discovered FR20950 (1c), containing a two methyl ene spacer moiety and an imidazolio group, which possesses a balanced spect rum of antibacterial activity, including Pseudomonas aeruginosa and Methici llin-resistant Staphylococcus aureus (MRSA). Furthermore, FR20950 exhibited excellent urinary recovery, and comparable stability against renal dehydro peptidase-I (DHP-I) to Biapenem. DHP-I stability could be improved by intro duction of a substituent on to the imidazole ring. (C) 1999 Elsevier Scienc e Ltd. All rights reserved.