Synthesis and antibacterial activity of HMR 3647 a new ketolide highly potent against erythromycin-resistant and susceptible pathogens.

In the search for new ketolides with improved activities against erythromycin-resistant S. pneumoniae and H. influenzae we synthesized a new 11,12 carbamate ketolide substituted by an imidazo-pyridyl side chain: HMR 3647. This compound demonstrated a potent activity against erythromycin susceptible and resistant pathogens, including penicillin G/erythromycin A-resistant S. pneumoniae and H. influenzae. In vivo, HMR 3647 displayed good pharmacokinetic parameters (Cmax = 2.9 microg/ml, bioavailability=49%, AUC0.8 = 17.2 microg.h/l, t1/2=1h) and was shown to have a high therapeutic efficacy in mice infected by various respiratory pathogens, including multi-resistant S. pneumoniae and Gram negative bacteria such as H. influenzae. HMR 3647 appears to be a very promising agent for the treatment of respiratory infections and is currently in clinical trials.

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.

New ether oxime derivatives of erythromycin A. A structure-activity relationship study.

The discovery of roxithromycin is the result of a rational and scientific process, based on the fact that at least one reason for erythromycin A's resorption variability after oral administration was its instability in the gastric juice. This instability is due to the reactivity of the ketone in position 9 in acidic medium and one chemical approach was to mask it by an oxime function. Both stereoisomers of this oxime were isolated. Direct O-alkylation of this oxime allowed access to various ether oxime derivatives and of the latter the E stereoisomers were more interesting than the Z ones. The choice of the nature of the oxime substitution was made according to the lipophilic or hydrophilic character of the aliphatic ether chain and these alterations were mainly carried out by introducing heteroatoms into this chain. These different derivatives were classified in 5 groups according to the chemical nature of the chain: Aliphatic, aromatic and nitrogen-, oxygen- and sulfur-containing chains. Two classes, those containing a nitrogen or an oxygen in the ether side chains, showed differential in vitro/in vivo antibiotic activities, with improved bioavailability. Some preliminary pharmacokinetic data confirmed this improvement and led to the selection of five candidates, from which roxithromycin emerged as the best compound.