DNA Binding Ligands with Improved in Vitro and in Vivo Potency against Drug-Resistant Staphylococcus aureus

• Published in: Journal of medicinal chemistry Vol. 47; no. 18; pp. 4352 - 4355
• Main Authors: Hu, Wenhao, Bürli, Roland W, Kaizerman, Jacob A, Johnson, Kirk W, Gross, Matthew I, Iwamoto, Mari, Jones, Peter, Lofland, Denene, Difuntorum, Stacey, Chen, Hsiu, Bozdogan, Bülent, Appelbaum, Peter C, Moser, Heinz E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.08.2004; Amer Chemical Soc
• Subjects: Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Chemistry, Medicinal; Distamycins - chemical synthesis; Distamycins - pharmacology; Distamycins - therapeutic use; DNA - metabolism; Dose-Response Relationship, Drug; Drug Resistance; Kinetics; Life Sciences & Biomedicine; Ligands; Medical sciences; Methicillin; Mice; Peritonitis - drug therapy; Peritonitis - microbiology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Staphylococcal Infections - drug therapy; Staphylococcus aureus; Staphylococcus aureus - drug effects; Structure-Activity Relationship; Survival Rate; Vancomycin; BACTERIA; VANCOMYCIN; PYRROLE; AMINO-ACIDS; PHARMACOLOGY; IMIDAZOLE; POLYAMIDES; Ligand binding; Imidazole derivatives; Isoquinoline derivatives; Rodentia; In vitro; Biological activity; Meticillin; Pyrrole derivatives; Resistance; In vivo; Vertebrata; Biological fixation; Mammalia; Mouse; Animal; DNA; Bacteria; Micrococcales; Carboxamide; Micrococcaceae; Antibacterial agent; Chemical synthesis; Staphylococcus aureus
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049712g

Potent in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA) has been difficult to achieve with previously reported DNA binding antibacterials. Herein, we describe an efficient access to a focused library of new analogues yielding compounds with improved activity in a mouse peritonitis model. The most potent molecules (14 and 19) exhibit efficacy against MRSA at ED50 values of ∼1 and ∼5 mg/kg, respectively, and display excellent in vitro activity against vancomycin-resistant S. aureus.