Structure–activity relationships of novel alkylides: 3-O-Arylalkyl clarithromycin derivatives with improved antibacterial activities

A series of novel alkylides, possessing 3-O-arylalkyl group instead of 3-O-cladinose, were designed, synthesized and evaluated for in vitro antibacterial activities. The increased potency clearly ranked by the order of 3-O-(3-aryl-2-propargyl), 3-O-(3-aryl-E-prop-2-enyl), 3-O-(3-aryl-propyl), and 3-O-(3-aryl-Z-prop-1-enyl) groups. Some alkylides, exemplified by 7a, 10a, 21, 22, 26, 27 and 33, showed improved activities against inducible MLSB resistance and efflux resistance compared to the second-generation macrolides. Among them, 26 possessed comparable activities against erythromycin-susceptible Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes (MICs of 0.016–0.5 μg/mL). Moreover, 26 displayed dramatically enhanced potency against both efflux resistant and inducibly MLSB resistant strains (MICs of 0.125–0.5 μg/mL) resistant to clarithromycin and azithromycin (MICs of 1– >254 μg/mL), independent of methicillin-susceptible and methicillin-resistant phenotypes.

3-O-Arylalkyl groups had a dramatic effect on activities (21 > 33 > 23 > 32). 21 is highly active, while 32 is inactive. Lead compound 26 was the most effective against erythromycin-resistant pathogens.Figure optionsDownload as PowerPoint slideHighlights
► 3-O-Arylalkyl groups had a dramatic effect on antibacterial activities.
► A new route to 9-E-oxime 18, 9-keto 19, and 9a-lactam 20 for further SAR studies.
► Comprehensive investigation on structure–activity relationships of alkylides.
► 26 was thus far the best candidate of alkylides.
► Alkylides proved to be promising candidates for next-generation macrolides.