Novel ketolide antibiotics with a fused five-membered lactone ring––synthesis, physicochemical and antimicrobial properties

• Published in: Bioorganic & medicinal chemistry 2004-07, Vol.12 (13), p.3503-3519
• Main Authors: Hunziker, Daniel, Wyss, Pierre-C, Angehrn, Peter, Mueller, Aranka, Marty, Hans-Peter, Halm, Remy, Kellenberger, Laurenz, Bitsch, Veronique, Biringer, Gerard, Arnold, Wolf, Stämpfli, Andreas, Schmitt-Hoffmann, Anne, Cousot, Denis
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotic; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiinfective; Biological and medical sciences; Erythromycin - administration & dosage; Erythromycin - chemistry; Erythromycin - pharmacology; General aspects; Haemophilus influenzae - drug effects; Inhibitory Concentration 50; Ketolide; Ketolide antibiotic; Ketolides - administration & dosage; Ketolides - chemical synthesis; Ketolides - chemistry; Ketolides - pharmacology; Macrolide; Macrolide antibiotic; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Molecular Structure; Pharmacology. Drug treatments; Solubility; Stereoisomerism; Streptococcal Infections - drug therapy; Streptococcal Infections - microbiology; Streptococcus pyogenes - drug effects
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.04.039

A new series of ketolides A with a fused five-membered lactone ring was synthesized on the basis of commercially available clarithromycin as a starting material. The chemical approach as well as chemical and biological properties of lactone ketolides A are described. 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 α,β-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 TM).