Anhydrolide Macrolides. 2. Synthesis and Antibacterial Activity of 2,3-Anhydro-6-O-methyl 11,12-Carbazate Erythromycin A Analogues

• Published in: Journal of medicinal chemistry Vol. 41; no. 10; pp. 1660 - 1670
• Main Authors: Griesgraber, George, Kramer, Mark J, Elliott, Richard L, Nilius, Angela M, Ewing, Patty J, Raney, Patti M, Bui, Mai-Ha, Flamm, Robert K, Chu, Daniel T. W, Plattner, Jacob J, Or, Yat Sun
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 07.05.1998; Amer Chemical Soc
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Chemistry, Medicinal; Clarithromycin - pharmacology; Drug Evaluation, Preclinical; Drug Resistance, Microbial; Drug Resistance, Multiple; Erythromycin - analogs & derivatives; Erythromycin - chemical synthesis; Erythromycin - chemistry; Erythromycin - pharmacology; Life Sciences & Biomedicine; Lincosamides; Macrolides - pharmacology; Medical sciences; Mice; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pneumococcal Infections - prevention & control; Science & Technology; Staphylococcal Infections - prevention & control; Staphylococcus aureus - drug effects; Streptococcus pneumoniae - drug effects; Streptococcus pyogenes - drug effects; Structure-Activity Relationship; Virginiamycin - pharmacology; CLARITHROMYCIN; ANTIBIOTICS; SERIES; STREPTOGRAMIN-B RESISTANCE; INVITRO; AZITHROMYCIN; DERIVATIVES; Organic carbazate; Structure activity relation; Bacteria; Micrococcales; Streptococcus pyogenes; Micrococcaceae; Chemical synthesis; Staphylococcus aureus; Oxygen nitrogen heterocycle; Rodentia; Oral administration; Lactone; Erythromycin; In vitro; Macrolide; Streptococcus pneumoniae; Infection; Resistance; Streptococcaceae; In vivo; Vertebrata; Chemotherapy; Chemical modification; Experimental disease; Mammalia; Treatment; Mouse; Bacteriosis; Antibacterial agent
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970548p

A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11,12-cyclic carbazate analogues was prepared and evaluated for antibacterial activity. These 2,3-anhydro macrolides were found to be potent antibacterial agents in vitro against macrolide-susceptible organisms including Staphylococcus aureus 6538P, Streptococcus pyogenes EES61, and Streptococcus pneumoniae ATCC6303. These compounds were also very active against some organisms that show macrolide resistance (S. aureus A5177, S. pyogenes PIU2584, and S. pneumoniae 5649). The compounds generally showed poor activity against organisms with constitutive MLS resistance. Selected compounds were evaluated in vivo in mouse protection studies. Although most of the compounds tested in vivo showed poor efficacy, two compounds, 38 and 57, were more active than clarithromycin against S. pneumoniae ATCC6303.