Synthesis and antibacterial activity of 9-oxime ether non-ketolides, and novel binding mode of alkylides with bacterial rRNA

We report a series of new 9-oxime ether non-ketolides, including 3-hydroxyl, 3- O -acyl and 3- O -alkyl clarithromycin derivatives, and thiophene-containing ketolides 1b–1d . Unlike previously reported ketolide 1a , none of them is comparable to telithromycin. A molecular modeling study was performed to gain insight into the binding mode of alkylides 17 – 20 with bacterial rRNA and to rationalize the great disparity of their SAR. The 3- O -sidechains of 19 and 20 point to the so-called hydrophilic side of the macrolide ring, as seen in clarithromycin. In contrast, the 3- O -sidechains of 17 and 18 bend to the backside, the so-called hydrophobic side of the macrolide ring. The results clearly indicated the alkylides with improved antibacterial activity might possess a novel binding mode, which is different from clarithromycin and the alkylides with poor activity.