title: Novel ketolide antibiotics with a fused five-membered lactone ring--synthesis, physicochemical and antimicrobial properties.
abstract: In an effort to find novel semisynthetic macrolides with extended antibacterial spectrum and improved activity we prepared a series of compounds based on commercially available clarithromycin, a potent and safe antimicrobial agent of outstanding clinical and commercial interest. According to the literature, improvement of antibacterial activity of erythromycin type antibiotics can be achieved by introduction of fused heterocycles such as cyclic carbonates or carbamates at positions 11 and 12 (such as in telithromycin). In the course of the work presented here, a similar, hitherto unprecedented set of compounds bearing a five-membered lactone ring fused to positions 11 and 12 was prepared based on carbon-carbon bond formation via intramolecular Michael addition of a [(hetero)arylalkylthio]acetic acid ester enolate to an alpha,beta-unsaturated ketone as the key step. Some of the ketolide compounds described in this paper were highly active against a representative set of erythromycin sensitive and erythromycin resistant test strains. The best compound showed a similar antimicrobial spectrum and comparable activity in vitro as well as in vivo as telithromycin. Furthermore, some physicochemical properties of these compounds were determined and are presented here. On the basis of these results, the novel ketolide lactones presented in this paper emerged as valuable lead compounds with comparable properties as the commercial ketolide antibacterial telithromycin (Ketek).
authors.affiliation: F. Hoffmann-La Roche Ltd, Discovery Research, CH-4070 Basel, Switzerland. daniel.hunziker@roche.com
authors.forename: Daniel
authors.initials: D
authors.lastname: Hunziker
authors.forename: Pierre-C
authors.initials: PC
authors.lastname: Wyss
authors.forename: Peter
authors.initials: P
authors.lastname: Angehrn
authors.forename: Aranka
authors.initials: A
authors.lastname: Mueller
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Marty
authors.forename: Remy
authors.initials: R
authors.lastname: Halm
authors.forename: Laurenz
authors.initials: L
authors.lastname: Kellenberger
authors.forename: Veronique
authors.initials: V
authors.lastname: Bitsch
authors.forename: Gerard
authors.initials: G
authors.lastname: Biringer
authors.forename: Wolf
authors.initials: W
authors.lastname: Arnold
authors.forename: Andreas
authors.initials: A
authors.lastname: Stämpfli
authors.forename: Anne
authors.initials: A
authors.lastname: Schmitt-Hoffmann
authors.forename: Denis
authors.initials: D
authors.lastname: Cousot
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004917:Erythromycin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D006193:Haemophilus influenzae / Q000187:drug effects; D020128:Inhibitory Concentration 50; D048628:Ketolides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D012995:Solubility; D013237:Stereoisomerism; D013290:Streptococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D004917:Erythromycin