title: Anhydrolide macrolides. 1. Synthesis and antibacterial activity of 2,3-anhydro-6-O-methyl 11,12-carbamate erythromycin A analogues.
abstract: A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11, 12-carbamate analogues have been synthesized and evaluated for antibacterial activity. These compounds were found to be potent antibacterial agents against Gram-positive organisms in vitro, many having MIC values below 1 microg/mL for the macrolide-susceptible Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae, as well as improved activity compared to erythromycin A against the inducibly MLS (macrolide, lincosamide, and streptogramin B)-resistant organisms. Structure-activity studies revealed that arylalkyl carbamates with two and four carbon atoms between the aromatic moiety and carbamate nitrogen have the best in vitro activity. All of the C-10 epi analogues evaluated were found to have substantially less activity than the corresponding natural C-10 isomer. Several analogues demonstrated moderate antibacterial activity against the constitutively resistant S.aureus A-5278, S. pneumoniae5979, and S.pyogenes 930. However, despite potent in vitro activity, these analogues showed only moderate in vivo activity in mouse protection studies.
authors.affiliation: Pharmaceutical Products Research Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500, USA. richard_l_elliott@groton.pfizer.com
authors.forename: R L
authors.initials: RL
authors.lastname: Elliott
authors.forename: D
authors.initials: D
authors.lastname: Pireh
authors.forename: G
authors.initials: G
authors.lastname: Griesgraber
authors.forename: A M
authors.initials: AM
authors.lastname: Nilius
authors.forename: P J
authors.initials: PJ
authors.lastname: Ewing
authors.forename: M H
authors.initials: MH
authors.lastname: Bui
authors.forename: P M
authors.initials: PM
authors.lastname: Raney
authors.forename: R K
authors.initials: RK
authors.lastname: Flamm
authors.forename: K
authors.initials: K
authors.lastname: Kim
authors.forename: R F
authors.initials: RF
authors.lastname: Henry
authors.forename: D T
authors.initials: DT
authors.lastname: Chu
authors.forename: J J
authors.initials: JJ
authors.lastname: Plattner
authors.forename: Y S
authors.initials: YS
authors.lastname: Or
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017291:Clarithromycin / Q000737:chemistry / Q000494:pharmacology; D015169:Colony Count, Microbial; D004353:Drug Evaluation, Preclinical; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D004917:Erythromycin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006193:Haemophilus influenzae / Q000187:drug effects; D055231:Lincosamides; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008968:Molecular Conformation; D011008:Pneumococcal Infections / Q000517:prevention & control; D013203:Staphylococcal Infections / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects; D013329:Structure-Activity Relationship; D014769:Virginiamycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D002219:Carbamates; D055231:Lincosamides; D018942:Macrolides; D014769:Virginiamycin; D004917:Erythromycin; D017291:Clarithromycin