Aminotriazoloquinazoline- and Aminotriazolo-based Hydroxamic Acids are Novel Potent and Selective HDAC6 Inhibitors with Subnanomolar Activity

Histone deacetylase 6 (HDAC6) inhibitors are deeply involved in the regulation of several biological responses, which results in anti-inflammatory and anti-cancer effects. From the structural point of view, HDAC6 inhibitors reported so far share recurring features: (i) a zinc binding group (ZBG), which establishes a stable coordination complex with the catalytic Zn2+; (ii) a hydrophobic linker that inserts into the catalytic tunnel of the active site, and; (iii) a CAP moiety interacting with the residues that line the entrance of the pocket.3,4 In our work, by means of chemoinformatic analyses, the aminotriazoloquinazoline ring system was identified as a new potential CAP group: compound 1 and the opened-ring aminotriazole derivative 2 were synthesized and biologically evaluated, revealing to act as potent and selective HDAC6 inhibitors (Figure 1).5 1 and 2 inhibited HDAC6 respectively 3- and 15-fold more potently compared to the reference compound trichostatin A, displaying activity in the subnanomolar range. Considering that the aminotriazole scaffold has never been explored as a CAP group for HDAC6 inhibitors, the present study constitutes a valid starting point for further optimization of potential anticancer compounds, placing such chemical moiety into a relevant and new area of investigation.