Design, molecular docking, synthesis, and in vitro pharmacological evaluation of biomolecules-histone deacetylase inhibitors conjugates with carbohydrazide as a novel zinc-binding group

Histone deacetylase inhibitors (HDACIs) are newly emerging chemotherapeutic agents which have shown great potential in the treatment of many types of cancers. However, these agents have many drawbacks which may limit their clinical application such as low oral bioavailability, and low intracellular concentration in solid tumors which may require high doses leading to side and maybe toxic effects. Additionally, their zinc-binding group (ZBG) is partly responsible partly for their poor physicochemical properties. In silico design, synthesis, and characterization of new HDACIs involving biomolecules (biotin and phenylalanine) with carbohydrazide as a novel ZBG were achieved successfully and hopefully, to increase the targetability and to overcome the limitations of traditional hydroxamate-based HDACIs. MTT assay of compounds 2c and 3d (which are biotin and phenylalanine-linked derivatives respectively) showed higher antiproliferative activity than SAHA and 5-FU against MCF7 and lower cytotoxic effect against NHF cell lines which were consistent with the docking study results. Additionally, compound 1b displayed comparable cytotoxic results to SAHA against MCF7 and NHF. These results were found to be encouraging for the involvement of biomolecules in the future development of HDACIs. Therefore, carbohydrazide as a ZBG could be thought of as a counterpart to hydroxamate moiety and may be considered as a successful replacement for hydroxamate moiety upon designing new HDACIs.