Structure-activity relationships of novel alkylides: 3-O-arylalkyl clarithromycin derivatives with improved antibacterial activities.
A series of novel alkylides, possessing 3-O-arylalkyl group instead of 3-O-cladinose, were designed, synthesized and evaluated for in vitro antibacterial activities. The increased potency clearly ranked by the order of 3-O-(3-aryl-2-propargyl), 3-O-(3-aryl-E-prop-2-enyl), 3-O-(3-aryl-propyl), and 3-O-(3-aryl-Z-prop-1-enyl) groups. Some alkylides, exemplified by 7a, 10a, 21, 22, 26, 27 and 33, showed improved activities against inducible MLS(B) resistance and efflux resistance compared to the second-generation macrolides. Among them, 26 possessed comparable activities against erythromycin-susceptible Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes (MICs of 0.016-0.5 μg/mL). Moreover, 26 displayed dramatically enhanced potency against both efflux resistant and inducibly MLS(B) resistant strains (MICs of 0.125-0.5 μg/mL) resistant to clarithromycin and azithromycin (MICs of 1- >254 μg/mL), independent of methicillin-susceptible and methicillin-resistant phenotypes.
School of Life Science, Beijing Institute of Technology, Beijing, China. ljhbit@bit.edu.cn
Jian-Hua
JH
Liang
Xiao-Li
XL
Li
He
H
Wang
Kun
K
An
Yue-Ying
YY
Wang
Ying-Chun
YC
Xu
Guo-Wei
GW
Yao
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D017291:Clarithromycin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000188:drug therapy; D013210:Staphylococcus / Q000187:drug effects*; D013211:Staphylococcus aureus / Q000187:drug effects; D013290:Streptococcal Infections / Q000188:drug therapy; D013291:Streptococcus / Q000187:drug effects*; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D018942:Macrolides; D017291:Clarithromycin