Patrick Laurin

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.

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.

Stereoselective synthesis of 5-monoalkyl and 5,5-dialkylsubstituted noviose derivatives

Abstract The stereoselective synthesis of 5-monosubstituted and 5,5-dialkylsubstituted noviose derivatives has been achieved starting from l -arabinose. These noviose derivatives could be used as useful building blocks in probing structure–activity relationships (SAR) of coumarin antibiotics that are inhibitors of DNA gyrase.

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.