title: Synthesis and antibacterial activity of 9-oxime ether non-ketolides, and novel binding mode of alkylides with bacterial rRNA.
abstract: 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.
authors: School of Life Science, Beijing Institute of Technology, Beijing 100081, China. ljhbit@bit.edu.cn
authors: Jian-Hua
authors: JH
authors: Liang
authors: Wei
authors: W
authors: Lv
authors: Xiao-Li
authors: XL
authors: Li
authors: Kun
authors: K
authors: An
authors: Mark
authors: M
authors: Cushman
authors: He
authors: H
authors: Wang
authors: Ying-Chun
authors: YC
authors: Xu
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017291:Clarithromycin / Q000737:chemistry / Q000494:pharmacology; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D004986:Ether / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D048628:Ketolides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012329:RNA, Bacterial / Q000378:metabolism; D012335:RNA, Ribosomal / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D010091:Oximes; D012329:RNA, Bacterial; D012335:RNA, Ribosomal; D004986:Ether; D004917:Erythromycin; D017291:Clarithromycin