Synthesis of novel di- and tricationic carbapenems with potent anti-MRSA activity

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 2; pp. 447 - 450
• Main Authors: Maruyama, Takahisa, Yamamoto, Yasuo, Kano, Yuko, Kurazono, Mizuyo, Shitara, Eiki, Iwamatsu, Katsuyoshi, Atsumi, Kunio
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-01-2009; Elsevier
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Beta-lactam; Biological and medical sciences; Carbapenem; Carbapenems - chemical synthesis; Carbapenems - chemistry; Carbapenems - pharmacology; Cationic charge; Cations; Imidazo[5,1- b]thiazol; Medical sciences; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; MRSA; Pharmacology. Drug treatments; Solubility; Staphylococcus aureus; Carbapenem; Beta-lactam; Imidazo[5,1- b]thiazol; Cationic charge; MRSA; Angular nitrogen heterocycle; Nitrogen heterocycle; Lactam; Imidazo[5.1-b]thiazol; Meticillin; Penicillin derivatives; Carbapenem derivatives; Structure activity relation; Bicyclic compound; Imidazothiazole derivatives; Bacteria; Micrococcales; Micrococcaceae; Chemical synthesis; Staphylococcus aureus; Sulfur nitrogen heterocycle; Iminium compounds; In vitro; Quaternary ammonium compound; Resistance; Antibacterial agent; Organic dication
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.11.039

A new series of 1β-methyl carbapenems possessing a 6,7,-disubstituted imidazo[5,1-
b]thiazol-2-yl group was prepared. Among them, introduction of cationic benzyl moiety to the 6 position of imidazo[5,1-
b]thiazole resulted in excellent anti-MRSA activity.
A new series of 1β-methyl carbapenems possessing a 6,7-disubstituted imidazo[5,1-
b]thiazol-2-yl group directly attached to the C-2 position of the carbapenem nucleus was prepared, and their activities against methicillin-resistant
Staphylococcus aureus (MRSA) were evaluated. First, a benzyl moiety was introduced at the C-6 position of imidazo[5,1-
b]thiazole attached to the carbapenem. These benzylated molecules showed potent anti-MRSA activity, but poor water solubility. In order to overcome this drawback, we designed and synthesized di- and tricationic carbapenems and finally discovered a novel carbapenem (
15i), which exhibited excellent anti-MRSA activity and good water solubility.