Synthesis and in vitro antibiotic activity of 16-membered 9- O-arylalkyloxime macrolides

A series of novel 9- O-arylalkyloxime analogs based on three different 16-membered macrolide scaffolds—5- O-mycaminosyltylonolide (OMT), tilmicosin, and 20-deoxy-20-(3,5-dimethyl-1-piperidin-1-yl)-OMT—was synthesized. In vitro antibiotic activities were assayed against Gram-positive Streptococcus pneumoniae and Staphylococcus aureus and Gram-negative Haemophilus influenzae bacterial strains. Analogs derived from OMT ( 3– 15) showed similar or better antibacterial activities against macrolide-susceptible strains and enhanced activities against macrolide-resistant strains compared with erythromycin A, tylosin, or OMT. Similar results were observed for tilmicosin 9- O-arylalkyloxime analogs ( 18– 24). In contrast, most of the 20-deoxy-20-(3,5-dimethyl-1-piperidin-1-yl)-OMT analogs ( 25– 33) showed reduced antibacterial activities compared with OMT. Ribosome-binding studies were performed on compounds 12 (OMT derivative), 20 (tilmicosin derivative), and 29 [20-deoxy-20-(3,5-dimethyl-1-piperidin-1-yl)-OMT derivative]. It was found that these compounds interacted with both domain V and domain II of the Escherichia coli 23S rRNA.