History

As an epigenetic target, histone acetylation has great therapeutic value. Several disorders, including cancer, are associated with an increase in the activity of histone deacetylase enzymes (HDACs). The hydroxamate-group is employed in most HDAC-inhibitors, since it is a strong zinc-binding molecule (ZBG). Due to their toxicity and poor pharmacokinetic, hydroxamates are not a preferred cancer therapy option. As a result, a possible technique for increasing potency and selectivity is the development of non-hydroximate HDAC inhibitors. By using Glide's Ligand Designer, we were able to create-new HDAC inhibitors that had isoxazole moiety as ZBG. Many different aliphatic and aromatic residues were tried to find the best fit for the cap group and the linker. Using authorized Schrodinger modelling software, the potential inhibition over HDAC8 for the best-designed items was synthesized and tested. The data demonstrated the effect of different connecting group with isoxazole as zinc binding group. To estimate the pharmacokinetic parameters of the final products, an ADMET/tox study was conducted. the resulting compounds have promising drug-like attributes. Both the intermediate and final chemicals were produced using mild condition procedures and purified using column chromatography. IR and NMR spectroscopy were used to characterize the chemical structure of the intermediates and the final products. The MTT assay was used to evaluate the inhibition activity against colon cancer cell line (ST-174), which indicated that there is a comparable antiproliferative activity to vorinostat for some of the synthesized compounds.