Anhydrolide macrolides. 2. Synthesis and antibacterial activity of 2,3-anhydro-6-O-methyl 11,12-carbazate erythromycin A analogues.
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 Streptococcuspneumoniae 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.
Griesgraber
G
G
Anti-Infective Discovery Research, Pharmaceutical Products Research Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500, USA. george.griesgraber@abbott.com
Kramer
M J
MJ
Elliott
R L
RL
Nilius
A M
AM
Ewing
P J
PJ
Raney
P M
PM
Bui
M H
MH
Flamm
R K
RK
Chu
D T
DT
Plattner
J J
JJ
Or
Y S
YS
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017291:Clarithromycin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D055231:Lincosamides; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; 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
C112105:2,3-anhydro-5-O-desosaminyl--11-((3-(4-aminophenyl)-2-propenyl)hydrazo)-6-O-methylerythronolide A 11,12-carbamate; C112104:2,3-anhydro-5-O-desosaminyl-11-((3-(4-nitrophenyl)-2-propenyl)hydrazo)-6-O-methylerythronolide A 11,12-carbamate; D000900:Anti-Bacterial Agents; D055231:Lincosamides; D018942:Macrolides; D014769:Virginiamycin; D004917:Erythromycin; D017291:Clarithromycin