# Novel Azaborine-Based Inhibitors of Histone Deacetylases (HDACs)

## TL;DR

This paper introduces new HDAC inhibitors using azaborine rings, which improve water solubility and offer a way to bypass existing patents.

## Contribution

The study presents novel azaborine-based HDAC inhibitors with enhanced solubility and activity.

## Key findings

- Nearly half of the tested molecules showed inhibitory activity against HDAC1, HDAC4, or HDAC8.
- Three compounds had nanomolar IC50 values, indicating strong inhibitory potential.
- Azaborine rings can be effectively used as building blocks in HDAC inhibitors.

## Abstract

Aromatic ring systems appear ubiquitously in active pharmaceutical substances, such as FDA-approved histone deacetylase inhibitors. However, these rings reduce the 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 analogs 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 twenty-four molecules tested exhibited inhibitory activity against at least one of the enzymes HDAC1, HDAC4, or HDAC8, with three compounds displaying IC50 values in the nanomolar range. We have therefore demonstrated that azaborine building blocks can be successfully incorporated into HDACis, resulting in a highly active profile. Consequently, it should be feasible to develop active substances containing azaborine rings against other targets.