Synthesis and antibacterial activity of ketolides (6-O-methyl-3-oxoerythromycin derivatives): a new class of antibacterials highly potent against macrolide-resistant and -susceptible respiratory pathogens.
In the search for new antibiotics active against macrolide-resistant pneumococci and Haemophilus influenzae, we synthesized a new class of 3-oxo-6-O-methylerythromycin derivatives, so-called "ketolides". A keto function was introduced in position 3 after removal of L-cladinose, a sugar which has long been thought essential. Further modifications of the macrolactone backbone allowed us to obtain three different series of 9-oxime, 11,12-carbamate, and 11, 12-hydrazonocarbamate ketolides. These compounds were found to be very active against penicillin/erythromycin-resistant pneumococci and noninducers of MLSB resistance. The 11,12-substituted ketolide 61 (HMR 3004) demonstrated a potent activity against multiresistant pneumococci associated with a well-balanced activity against all bacteria involved in respiratory infections including H. influenzae, Mycoplasma catarrhalis, group A streptococci, and atypical bacteria. In addition HMR 3004 displayed high therapeutic activity in animals infected by all major strains, irrespective of their resistance phenotype.
Medicinal Chemistry, Core Research Functions, and Anti-Infectives Diseases Group, Hoechst Marion Roussel, 102 route de Noisy, 93235 Romainville Cedex, France.
C
C
Agouridas
A
A
Denis
J M
JM
Auger
Y
Y
Benedetti
A
A
Bonnefoy
F
F
Bretin
J F
JF
Chantot
A
A
Dussarat
C
C
Fromentin
S G
SG
D'Ambrières
S
S
Lachaud
P
P
Laurin
O
O
Le Martret
V
V
Loyau
N
N
Tessot
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015169:Colony Count, Microbial; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D016983:Enterococcus / Q000187:drug effects; D004917:Erythromycin / Q000494:pharmacology; D006192:Haemophilus Infections / Q000188:drug therapy; D006193:Haemophilus influenzae / Q000187:drug effects; D048628:Ketolides; D018942:Macrolides; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000382:microbiology*; D013203:Staphylococcal Infections / Q000188:drug therapy; D013210:Staphylococcus / Q000187:drug effects; D013291:Streptococcus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects
D000900:Anti-Bacterial Agents; D048628:Ketolides; D018942:Macrolides; C105420:RU 64004; D004917:Erythromycin