Synthesis and structure-activity relationships of novel 9-oxime acylides with improved bactericidal activity.
9-Oxime acylides have different SAR and binding modes from 9-oxime ketolides. An aminopyridyl or carbamoylpyridyl group anchored at the end of the 9-oxime 2-propargyl group is beneficial for antimicrobial activity. Both the 2-pyridyl and 3-pyridyl groups derived from 3-OH have stacking interactions with the base pair G2505/C2610 (Escherichia coli numbering) of the bacterial rRNA. Compounds 3 presented characteristic features that belong to bactericidal agents when used against constitutive-erm resistant Staphylococcus aureus, susceptible and mef-encoded Streptococcus pneumoniae, inducible-erm resistant Streptococcus pyogenes, and Moraxella catarrhalis. A docking model indicated that the carbamoylpyridyl group of 3h may hydrogen bond to G2061 in addition to π-π stacking over the adenine of A2062 that proved to gate the tunnel for the egress of the nascent peptide. This study suggests that the 9-oxime acylides possess a bactericidal mechanism that is different from the traditional near-complete inhibition of protein synthesis. These studies provide a foundation for the rational design of macrolide antibiotics.
School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
Xu
X
Han
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, 47907, USA.
Wei
W
Lv
School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
Si-Yang
SY
Guo
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, 47907, USA.
Mark
M
Cushman
School of Life Science, Beijing Institute of Technology, Beijing 100081, China. Electronic address: ljhbit@bit.edu.cn.
Jian-Hua
JH
Liang
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004917:Erythromycin / Q000737:chemistry; D006193:Haemophilus influenzae / Q000187:drug effects; D006860:Hydrogen Bonding; D048628:Ketolides / Q000737:chemistry / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D010091:Oximes / Q000737:chemistry*; D054681:Ribosome Subunits, Large, Bacterial / Q000737:chemistry / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D048628:Ketolides; D010091:Oximes; D004917:Erythromycin
Acylide; Bactericidal activity; Erythromycin; Ketolide