European Journal of Medicinal Chemistry p. 729 - 741 (2018)
Update date:2022-08-15
Topics:
Yu, Jui-Yin
Cheng, Hsiu-Jung
Wu, Huei-Ru
Wu, Wei-Shen
Lu, Jui-Wen
Cheng, Ting-Jen
Wu, Ying-Ta
Fang, Jim-Min
Transglycosylase (TGase) is essential to biosynthesis of peptidoglycan for formation of bacterial cell wall. Moenomycin is a potent TGase inhibitor, but not used in clinic treatment due to its poor pharmacokinetics. The E?F disaccharide, phosphoglycerate and lipid tail in moenomycin are crucial elements for TGase inhibition and antibacterial activity. Based on this scaffold, a series of truncated mimics comprising biphenyl, amine linker and 2-alkoxy-3-phosphorylpropanoate moieties were designed to test their TGase inhibitory activity. In this design, the phosphorylpropanoate group is a surrogate of phosphoglycerate with improved stability. A library of lipid tails can be constructed by a straightforward approach using Cu(I)-catalyzed (3 + 2) cycloaddition reactions, and the as-synthesized triazole ring can provide additional hydrogen bonds in the TGase active site. Our molecular docking experiments reveal that the biphenyl group provides π–π and π–cation interactions to act as a simplified alternative of the C–E disaccharide in moenomycin. To play the role of the oxonium transition state in transglycosylation, the amine linker exists as a positively charged species in physiological condition to attain electrostatic interactions with acidic residues. In this study, two biphenyl-linked 2-alkoxy-3-phosphorylpropanoate compounds (8 and 10) are found to exhibit modest inhibitory activity (IC50 ≈ 150 μM) against the TGase of Acinetobacter baumannii and good antibacterial activity against Staphylococcus aureus (MIC = 6.3 μM).
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