Alain Bonnefoy

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.

β-Keto-ester chemistry and ketolides. synthesis and antibacterial activity of 2-halogeno, 2-methyl and 2,3 enol-ether ketolides

The effect of 2,3 modifications on the antibacterial activity of ketolides was evaluated by introducing substituents in position 2 and converting the C-1, C-2, C-3 beta-keto-ester into stable 2,3 enol-ether or 2,3 anhydro derivatives. Introduction of a fluorine in C-2 is beneficial with regard to the overall antibacterial spectrum whereas the enol-ether and 2,3 unsaturated compounds, as well as the bulky gem dimethyl or 2-chloro derivatives, are less active particularly against erythromycin resistant strains. A 2-fluoro ketolide derivative demonstrates good antibacterial activity and in vivo efficacy against multi-resistant Streptococcus pneumoniae. Compared to azithromycin against Haemophilus influenzae, this compound is equivalent in vitro and slightly more active in vivo. These results demonstrate that within the ketolide class, to retain good antibacterial activity, position 2 needs to remain tetrahedral and tolerates only very small substituents such as fluorine.

Structure-activity relationship in two series of aminoalkyl substituted coumarin inhibitors of gyrase B.

Two series of aminosubstituted coumarins were synthesised and evaluated in vitro as inhibitors of DNA gyrase and as potential antibacterials. Novel novobiocin-like coumarins, 4-(dialkylamino)methylcoumarins and 4-((2-alkylamino)ethoxy)coumarins, were discovered as gyrase B inhibitors with promising antibacterial activity in vitro.

Synthesis and biological evaluation of coumarincarboxylic acids as inhibitors of gyrase B. L-rhamnose as an effective substitute for L-noviose

A series of novobiocin-like coumarincarboxylic acids has been prepared bearing the L-rhamnosyl moiety as the sugar portion of the molecule. The similar DNA gyrase inhibitory activity of the novel class of coumarins to that of novobiocin demonstrates that L-rhamnose can effectively replace L-noviose. Introduction of alkyl side-chains at C-5 of coumarin leads to improved in vitro antibacterial properties in the novel series.

Fine Tuning of Physico-Chemical Parameters to Optimise a New Series of Novobiocin Analogues

A novel series of novobiocin analogues has been synthesised by removing the lipophilic aryl chain in novobiocin and introducing an amino substituent. The structural modifications have been dictated by the control of lipophilicity and the dissociation constant of the resulting compounds. Antibacterial activity of the new coumarin derivatives could be correlated with the amount of uncharged form in physiological conditions.

Synthesis of isothiochroman 2,2-dioxide and 1,2-benzooxathiin 2,2-dioxide gyrase B inhibitors

Abstract The design, synthesis and in vitro biological evaluation of isothiochroman 2,2-dioxide and 1,2-benzooxathiin 2,2-dioxide analogues of coumarin inhibitors of gyrase B are described. Compared to coumarin derivatives, compounds of the 1,2-benzooxathiin 2,2-dioxide series display improved inhibitory potency in negative supercoiling of relaxed DNA gyrase.

Synthesis of 9-oxime-11,12-carbamate ketolides through a novel N-deamination reaction of 11,12-hydrazonocarbamate ketolide.

A series of 9-oxime-11,12-carbamate ketolides was synthesized for the first time through a key 11,12-hydrazonocarbamate intermediate that was first oximated and further deaminated to give the corresponding carbamate. The N-N bond cleavage was achieved through an original new reaction using glycoaldehyde dimer as deaminating reagent. The new compounds synthesized were shown to display improved antibacterial activities against Streptococcus pneumoniae and S. pyogenes resistant to erythromycin.