Developing Metal-Binding Isosteres of 8‑Hydroxyquinoline as Metalloenzyme Inhibitor Scaffolds

The use of metal-binding pharmacophores (MBPs) in fragment-based drug discovery has proven effective for targeted metalloenzyme drug development. However, MBPs can still suffer from pharmacokinetic liabilities. Bioisostere replacement is an effective strategy utilized by medicinal chemists to naviga...

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Bibliographic Details
Published in:Inorganic chemistry 2022-05, Vol.61 (19), p.7631-7641
Main Authors: Seo, Hyeonglim, Jackl, Moritz K., Kalaj, Mark, Cohen, Seth M.
Format: Article
Language:English
Subjects:
Chelating Agents
Drug Discovery
Metalloproteins - chemistry
Oxyquinoline - pharmacology
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Summary:The use of metal-binding pharmacophores (MBPs) in fragment-based drug discovery has proven effective for targeted metalloenzyme drug development. However, MBPs can still suffer from pharmacokinetic liabilities. Bioisostere replacement is an effective strategy utilized by medicinal chemists to navigate these issues during the drug development process. The quinoline pharmacophore and its bioisosteres, such as quinazoline, are important building blocks in the design of new therapeutics. More relevant to metalloenzyme inhibition, 8-hydroxyquinoline (8-HQ) and its derivatives can serve as MBPs for metalloenzyme inhibition. In this report, 8-HQ isosteres are designed and the coordination chemistry of the resulting metal-binding isosteres (MBIs) is explored using a bioinorganic model complex. In addition, the physicochemical properties and metalloenzyme inhibition activity of these MBIs were investigated to establish drug-like profiles. This report provides a new group of 8-HQ-derived MBIs that can serve as novel scaffolds for metalloenzyme inhibitor development with tunable, and potentially improved, physicochemical properties.
ISSN:0020-1669
1520-510X
DOI:10.1021/acs.inorgchem.2c00891