Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems Part IV. 2-Alkyl substituents containing cationic heteroaromatics linked via a C–C bond

• Published in: Bioorganic & medicinal chemistry 2001-04, Vol.9 (4), p.961-982
• Main Authors: Azami, Hidenori, Barrett, David, Tanaka, Akira, Sasaki, Hiroshi, Matsuda, Keiji, Sakurai, Minoru, Terasawa, Takeshi, Shirai, Fumiyuki, Chiba, Toshiyuki, Matsumoto, Yoshimi, Tawara, Shuichi
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Area Under Curve; Bacteria - drug effects; Bacterial Outer Membrane Proteins - drug effects; Bacterial Outer Membrane Proteins - metabolism; Biological and medical sciences; Carbapenems - chemical synthesis; Carbapenems - chemistry; Carbapenems - pharmacology; Dogs; Haplorhini; Humans; Indicators and Reagents; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Pharmacology. Drug treatments; Pseudomonas aeruginosa - drug effects; Pseudomonas Infections - drug therapy; Pseudomonas Infections - microbiology; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Rats; Spectrophotometry, Infrared; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus aureus - drug effects; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(00)00314-X

The synthesis and biological activity of a novel series of 2-alkyl-4-pyrrolidinylthio-β-methylcarbapenems containing a variety of cationic heteroaromatic substituents linked via a C–C bond is described. As a result of these studies, we selected FR21818 (1n) as a candidate compound for development. FR21818 exhibited a well balanced spectrum of antibacterial activity, including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), excellent urinary recovery, good stability against renal dehydropeptidase-I (DHP-I), no antigenicity and mutagenicity, weak toxicities, and good efficacy and therapeutic effect on mice systemic infections. Affinities to PBP's, permeability of outer membrane, and plasma levels in mice, dog, and cynomolgous monkey of FR21818 are also reported. The synthesis and biological activity of a novel series of 2-alkyl-4-pyrrolidinylthio-β-methylcarbapenems is described. We selected FR21818 (1n) as a candidate compound for development.