The exploitation of metal-binding pharmacophores (MBPs) for use in fragment-based drug discovery (FBDD) has proven effective for targeting metalloenzymes. However, these MBPs can still suffer from pharmacokinetic liabilities, such as poor solubility and low membrane permeability, which limit the usefulness of lead compounds and can undermine the development of such compounds into clinically effective therapeutics. Bioisostere replacement has become a commonplace and useful strategy utilized by medicinal chemists in navigating these issues during new drug design. The quinoline pharmacophore and its bioisosteres, such as quinazoline, are important building blocks to modulate drug-target interactions and physicochemical properties in the design of new drugs. Specific to metalloenzyme inhibition, 8-hydroxyquinoline (8-HQ) and its derivatives can serve as MBPs for metalloenzyme targets. In this presentation, an isosteric replacement of 8-HQ was performed and their coordination chemistry was explored using a (Tp<sup>Ph,Me</sup>)Zn (Tp<sup>Ph,Me</sup> = hydrotris{3-phenyl-5-methyl-1-pyrazolyl}borate) model complex. In addition, their physicochemical properties and related metalloenzyme inhibition activity were investigated to establish drug-like profiles. This work will provide an overview of 8-HQ metal-binding isosteres (MBIs) as potential novel building blocks of metalloenzyme inhibitors and will lead to the discovery of more clinically relevant fragments.

Developing metal-binding isosteres as metalloenzyme inhibitor scaffolds

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.