Design and synthesis of indolo[2,3-a]quinolizin-7-one inhibitors of the ZipA–FtsZ interaction

doi:10.1016/j.bmcl.2004.01.028

Bioorganic & Medicinal Chemistry Letters

Volume 14, Issue 6, 22 March 2004, Pages 1427-1431

https://doi.org/10.1016/j.bmcl.2004.01.028 Get rights and content

Abstract

The binding of FtsZ to ZipA is a potential target for antibacterial therapy. Based on a small molecule inhibitor of the ZipA–FtsZ interaction, a parallel synthesis of small molecules was initiated which targeted a key region of ZipA involved in FtsZ binding. The X-ray crystal structure of one of these molecules complexed with ZipA was solved. The structure revealed an unexpected binding mode, facilitated by desolvation of a loosely bound surface water.

The binding of FtsZ to ZipA is a potential target for antibacterial therapy. Based on a small molecule inhibitor of the FtsZ–ZipA interaction, a parallel synthesis of small molecules was initiated which targeted a key region of ZipA involved in FtsZ binding.

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Acknowledgements

We would like to acknowledge Tom McDonagh and Mark Stahl for providing purified protein for crystallizations, Russell Dushin for helpful discussions, and George Ellestad for assistance with assay development.

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Citation Excerpt :
Second, an additional set of weak scaffolds (IC50 > 1 mM) were discovered in the initial FP screen. Remarkably in the face of this low affinity, crystal structures of these inhibitors bound to the FtsZ pocket of ZipA were obtained (Jennings et al., 2004). This led to additional medicinal chemistry optimization, as well as an attempt to merge two weak inhibitors to fill the entirety of the binding pocket (Sutherland et al., 2003).
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For example, FtsZ (a homologue of eukaryotic tubulin) and ZipA (a membrane-anchored protein) interact to form the septal ring that mediates cell division and this PPI has been validated as a potential target in strategies to limit infection by Gram-negative bacteria. Compounds sharing the indolo[2,3-a]quinolizin-7-one structure have been shown to inhibit this interaction in in vitro assays.81 Additionally, an nuclear magnetic resonance-based fragment screening approach revealed a hit series able to inhibit the FtsZ/ZipA interaction through binding the C-terminal domain of ZipA.82
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Design and synthesis of indolo[2,3-a]quinolizin-7-one inhibitors of the ZipA–FtsZ interaction

Abstract

Section snippets

Acknowledgements

Cell

J. Biol. Chem.

J. Antimicrobial Chemotherapy

EMBO Journal

Anal. Biochem.

J. Med. Chem.

Current Medicinal Chemistry

Org. Biomol. Chem.