Bioisostere replacement involves replacing functional groups that may cause adverse effects with groups that can avoid liabilities but retain biological activity. This strategy has become a commonplace and useful strategy utilized by medicinal chemists in navigating 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 metal-binding pharmacophores (MBPs) for druglike molecules that inhibit anticancer and antiviral targets. Numerous investigations of 8-HQ in fragment-based drug discovery (FBDD) for metalloenzyme inhibitors have demonstrated that its isosteric forms, also known as metal-binding isosteres (MBIs), can be exploited to explore unchartered territory in chemical and biological space, and may improve potency and selectivity. In this presentation, a library of 8-HQ MBIs was designed 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 8HQ MBIs as potential novel building blocks of metalloenzyme inhibitors and will lead to the discovery of more clinically relevant fragments.

8-Hydroxyquinoline metal-binding isosteres for metalloenzyme inhibitors

ACS Fall 2021

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