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Structure-Activity Relationships of Novel Tryptamine-Based Inhibitors of Bacterial Transglycosylase.

Abstract：

:Penicillin-binding proteins represent well-established, validated, and still very promising targets for the design and development of new antibacterial agents. The transglycosylase domain of penicillin-binding proteins is especially important, as it catalyzes polymerization of glycan chains, using the peptidoglycan precursor lipid II as a substrate. On the basis of the previous discovery of a noncovalent small-molecule inhibitor of transglycosylase activity, we systematically explored the structure-activity relationships of these tryptamine-based inhibitors. The main aim was to reduce the nonspecific cytotoxic properties of the initial hit compound and concurrently to retain the mode of its inhibition. A focused library of tryptamine-based compounds was synthesized, characterized, and evaluated biochemically. The results presented here show the successful reduction of the nonspecific cytotoxicity, and the retention of the inhibition of transglycosylase enzymatic activity, as well as the ability of these compounds to bind to lipid II and to have antibacterial actions.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Sosič I,Anderluh M,Sova M,Gobec M,Mlinarič Raščan I,Derouaux A,Amoroso A,Terrak M,Breukink E,Gobec S

doi

10.1021/acs.jmedchem.5b01482

subject

Has Abstract

pub_date

2015-12-24 00:00:00

pages

9712-21

issue

24

eissn

0022-2623

issn

1520-4804

journal_volume

58

pub_type

杂志文章

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