Synthesis of N‐aminophalimides derived from α‐amino acids: Theoretical study to find them as HDAC8 inhibitors by docking simulations and in vitro assays

Phthalimides are valuable for synthesis and biological properties. New acetamides 3 ( a–c ) and 4 ( a–c ) were synthesized and characterized as precursors for novel N‐aminophalimides 5 ( a–c ) and 6 ( a–c ). Structures of 4a , 5 ( a–b ), and 6 ( a–b ) were confirmed by single crystal X‐ray. Docking studies identified compounds with favorable Gibbs free energy values for binding to histone deacetylase 8 (HDAC8), an enzyme targeted for anticancer drug development. These compounds bound to both the orthosteric and allosteric pockets of HDAC8, similar to Trichostatin A (TSA), an HDAC8 inhibitor. 6 ( a–c ) contain hydroxyacetamide moiety as a zinc‐binding group, a phthalimide moiety as a capping group, and aminoacetamide moiety as a linker group, which are important for ligand‐receptor binding. Δ G values indicated that compounds 5b , 6b , and 6c had higher affinity for HDAC8 in the allosteric pocket compared to TSA. In vitro evaluation of inhibitory activities on HDAC8 revealed that compounds 3 ( a–c ) and 5 ( a–c ) showed similar inhibitory effects (IC 50 ) ranging from 0.445 to 0.751 μM. Compounds 6 ( a–c ) showed better affinity, with 6a (IC 50 = 28 nM) and 6b (IC 50 = 0.18 μM) showing potent inhibitory effects slightly lower than TSA (IC 50 = 26 nM). These findings suggest that the studied compounds hold promise as potential candidates for further biological investigations.