Design, synthesis, and histone deacetylase inhibition study of novel 4‐(2‐aminoethyl) phenol derivatives

Histone deacetylases (HDACs) have been identified as promising targets for anticancer treatment. The study demonstrates virtual screening, molecular docking, and synthesis of 4‐(2‐aminoethyl) phenol derivatives as HDAC inhibitors. The virtual screening and molecular docking analysis led to the identification of 10 representative compounds, which were evaluated based on their drug‐like properties. The results demonstrated that these compounds effectively interacted with the active site pocket of HDAC 3 through π‐stacking, Zn2+ coordination, hydrogen bonding, and hydrophobic interactions with catalytic residues. Furthermore, a series of 4‐(2‐aminoethyl) phenol derivatives were synthesized, and their HDAC inhibitory activity was evaluated. Compounds 18 and 20 showed significant HDAC inhibitory activity of 64.94 ± 1.17% and 52.45 ± 1.45%, respectively, compared to the solvent control. The promising results of this study encourage further research on 4‐(2‐aminoethyl) phenol derivatives and may provide significant insight into the design of novel small molecule HDAC inhibitors to fight against target‐specific malignancies of chronic obstructive pulmonary disease and nonsmall cell lung cancer in the future. Histone deacetylases (HDACs) have been identified as promising targets for anticancer treatment. The study demonstrates virtual screening, molecular docking, molecular dynamic (MD) simulations, and synthesis of 4‐(2‐aminoethyl) phenol derivatives. 4‐(2‐aminoethyl) phenol derivatives were identified as HDAC3 inhibitors using a combined computational and experimental approach. Compounds 18 and 20 showed potential inhibitory activity against the HDAC3 isoform, suggesting their potential as novel and HDAC3 isoform‐selective drugs for the treatment of HDAC3‐overexpressed cancers.