Synthesis and antibacterial activity of novel 15-membered macrolide derivatives: 4''-carbamate, 11,12-cyclic carbonate-4''-carbamate and 11,4''-di-O-arylcarbamoyl analogs of azithromycin.
4''-Carbamate, 11,12-cyclic carbonate-4''-carbamate and 11,4''-di-O-arylcarbamoyl analogs of azithromycin were designed, synthesized and evaluated. The 4''-carbamate analogs retained excellent activity against erythromycin-susceptible Staphylococcus pneumoniae and showed improved activity against erythromycin-resistant Staphylococcus pneumoniae. Compared with 4''-carbamate analogs, 11,12-cyclic carbonate-4''-carbamate analogs exhibited improved activity against erythromycin-resistant Staphylococcus pneumoniae encoded by the mef gene or the erm and mef genes, and 11,4''-di-O-arylalkylcarbamoyl analogs showed greatly improved activity (0.25-0.5 microg/mL) against erythromycin-resistant Staphylococcus pneumoniae encoded by the erm gene. Among them, the novel series of 11,4''-di-O-arylalkylcarbamoyl analogs 7a-k exhibited potent and balanced activity against susceptible and resistant bacteria. In particular, compounds 7f and 7k were the most effective against susceptible bacteria and resistant bacteria encoded by the erm gene or the mef gene.
Ma
Shutao
S
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China. mashutao@sdu.edu.cn
Ma
Ruixin
R
Liu
Zhaopeng
Z
Ma
Chenchen
C
Shen
Xuecui
X
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017963:Azithromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002254:Carbonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000188:drug therapy; D013210:Staphylococcus / Q000187:drug effects*; D013290:Streptococcal Infections / Q000188:drug therapy; D013296:Streptococcus pneumoniae / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D002219:Carbamates; D002254:Carbonates; D017963:Azithromycin