Novel Azaborine-Based Inhibitors of Histone Deacetylases (HDACs)

Aromatic ring systems appear ubiquitously in active pharmaceutical substances, such as FDA-approved histone deacetylase inhibitors. However, these rings reduce water solubility of the molecules, which is a disadvantage during application. To address this problem, azaborine rings may be substituted for conventional aromatic ring systems. These are obtained by replacing two adjacent carbon atoms with boron and nitrogen. Incorporating B–N analogues in place of aromatic rings not only enhances structural diversity but also provides a strategy to navigate around patent-protected scaffolds. We synthesized azaborines, which are isosteric to naphthalene and indole and utilized them as capping units for HDAC inhibitors. These molecules were attached to various aliphatic and aromatic linkers with different zinc-binding units, used in established active compounds. Nearly half of the 24 molecules tested exhibited inhibitory activity against at least one of the enzymes HDAC1, HDAC4, or HDAC8, with three com-pounds displaying IC₅₀ values in the nanomolar range. We have therefore demon-strated that azaborine building blocks can be successfully incorporated into HDACis, resulting in a highly active profile. Consequently, it should be feasible to develop ac-tive substances containing azaborine rings against other targets.