Synthesis and antibacterial activity of novel 3-O-descladinosylazithromycin derivatives.
Novel series of novel 3-O-arylalkylcarbamoyl descladinosylazithromycin derivatives with the 2'-O-acetyl and 11,12-cyclic carbonate groups, the 11,12-cyclic carbonate group and the 11-O-arylalkylcarbamoyl side chain, and 2'-O-arylalkylcarbamoyl descladinosylazithromycin with the 11,12-cyclic carbonate group were designed, synthesized and evaluated for their antibacterial activity using broth microdilution method. The results showed that the majority of the target compounds showed moderate to favorable activity against six kinds of susceptible strains and almost all of them displayed significantly improved activity compared with references against three erythromycin-resistant strains of S. pneumoniae B1 expressing the ermB gene, S. pneumoniae AB11 expressing the ermB and mefA genes, and S. pyogenes R1. In particular, compound 6h exhibited the most potent activity against susceptible B. subtilis ATCC9372 (0.5 μg/mL), penicillin-resistant S. epidermidis (0.125 μg/mL), and erythromycin-resistant S. pneumoniae B1 (1 μg/mL) and S. pneumoniae AB11 (1 μg/mL), which were 2-, 2-, 256-, 256-fold better activity than azithromycin, respectively. Additionally, compounds 6f (0.5 μg/mL) and 6g (0.25 μg/mL) were the most active against S. pneumoniae A22072, which were 8- and 16-fold better activity than azithromycin (4 μg/mL). As for erythromycin-resistant S. pyogenes R1, compound 5a presented the most excellent activity (8 μg/mL), showing 32- and 32-fold higher activity than azithromycin (256 μg/mL) and clarithromycin (256 μg/mL).
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China.
Mi
M
Yan
The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266003, China.
Ruixin
R
Ma
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China.
Li
L
Jia
School of Pharmacy & Medical Sciences, Sansom Institute for Health Research, University of South Australia, GPO Box 2471, Adelaide 5001, Australia.
Henrietta
H
Venter
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China. Electronic address: mashutao@sdu.edu.cn.
Shutao
S
Ma
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017963:Azithromycin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D017963:Azithromycin
3-O-Descladinosylazithromycin; Antibacterial activity; Erythromycin-resistant bacteria; Synthesis