Synthesis and antibacterial activity of O-methylazithromycin derivatives

A series of O-methylazithromycin derivatives have been synthesized and their antibacterial activities were compared with those of azithromycin (1). O-Methylation of 1 proceeded stepwise by the two main pathways beginning at the C-6 and C-11 hydroxyl groups, individually. Among O-methyl derivatives, 6-O-methylazithromycin A (11) was slightly less active than 1. The methylation of the secondary hydroxyl group at the C-11 position resulted surprisingly in an increase of their in vitro activity. The antibacterial activities of novel azalides decreased with increasing the number of the methyl groups introduced.