beta-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 der ivatives. Introduction of a fluorine in C-2. is beneficial with regard to t he overall antibacterial spectrum whereas the enol-ether and 2,3 unsaturate d compounds, as well as the bulky gem dimethyl or 2-chloro derivatives, are less active particularly against erythromycin resistant strains. A 2-fluor o ketolide derivative demonstrates good antibacterial activity and in vivo efficacy against multi-resistant Streptococcus pneumoniae. Compared to azit hromycin against Haemophilus influenzae, this compound is equivalent in vit ro and slightly more active in vivo. These results demonstrate that within the ketolide class, to retain good antibacterial activity, position needs t o remain tetrahedral and tolerates only very small substituents such as flu orine. (C) 2000 Elsevier Science Ltd. All rights reserved.