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.

Abstract

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.

• Authors: C Agouridas, A Denis, J M Auger, Y Benedetti, A Bonnefoy, F Bretin, J F Chantot, A Dussarat, C Fromentin, S G D'Ambrières, S Lachaud, P Laurin, O Le Martret, V Loyau, N Tessot
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 41 Issue 21 Pg. 4080-100 (Oct 08 1998) ISSN: 0022-2623 [Print] United States
• PMID: 9767644 (Publication Type: Journal Article)

Chemical References

• Anti-Bacterial Agents
• Ketolides
• Macrolides
• RU 64004
• Erythromycin

Topics

• Animals
• Anti-Bacterial Agents (chemical synthesis, chemistry, pharmacology)
• Colony Count, Microbial
• Crystallography, X-Ray
• Drug Evaluation, Preclinical
• Drug Resistance, Microbial
• Drug Resistance, Multiple
• Enterococcus (drug effects)
• Erythromycin (pharmacology)
• Haemophilus Infections (drug therapy)
• Haemophilus influenzae (drug effects)
• Ketolides
• Macrolides
• Male
• Mice
• Models, Molecular
• Molecular Conformation
• Respiratory Tract Infections (drug therapy, microbiology)
• Staphylococcal Infections (drug therapy)
• Staphylococcus (drug effects)
• Streptococcus (drug effects)
• Streptococcus pneumoniae (drug effects)