A series of novel C11 substituted 14-membered 2-fluoro ketolides were synthesized and evaluated for their antibacterial activity against erythromycin-resistant and erythromycin-susceptible clinical isolates and strains from ATCC. The overall antibacterial spectra of the semi-synthetic antibiotics are similar to that of telithromycin (TEL) and most of them exhibited excellent activity against Gram-positive bacteria (S. epidermidis, S. pneumoniae, S. aureus) and several Gram-negative bacteria (M. catarrhalis, H. influenza). Compounds 11c, 11g, 11h, 11q, 12a, 12b, 12d and 12e displayed 4-16 fold more potency than TEL against all the tested erythromycin-resistant S. epidermidis strains and S. pneumonia SPN19-8 and SPN19-8. Compounds 11b, 11c, 11e, 11g, 11h, 11q, 12a, 12b and 12c showed at least 8 fold potency than TEL against erythromycin-resistant M. catarrhalis BCA19-5 and BCA19-6. Molecular docking suggested compound 12d oriented the macrolide ring and side chain similarly to solithromycin (SOL). Noticeably an additional hydrogen bond was observed between the Lys90 residue of ribosome protein L22 and the carbamate group at the C11 position, which might provide a rational explanation for the enhanced antibacterial activity of target compounds. Therefore this research would offer a new perspective for further structural optimization of the C11 side chain. Based on the results of antibacterial activity, cytotoxicity and structural diversity, 5 compounds (11a, 11b, 11h, 12d and 12i) were selected for the stability testing of human liver microsomes and compound 11a exhibited preferable metabolic stability.
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