Aim Aims: This study aims to design and synthesize hybridized natural antioxidants by following the pharmacophore of the reference Histone Deacetylase Inhibitors inhibitor with potential to enhance pharmacokinetic parameters and investigate anti-neoplastic activity as a trial to replace the known HDAC inhibitor that suffers from life-threatening adverse effects and poor pharmacokinetics related to hydroxamate functionality. Material and methods Designing of new natural hybridized molecules, HDAC inhibitor consisting of cap, linker & zinc binding domain. The cap involved (natural antioxidants Thymol, Eugenol, vanillin, and Umbelliferon) linked to the bioactive molecule succinate via an ester, and on the other hand, succinate acts as a zinc zinc-binding group by anion-free carboxylate. Molecular docking analysis, an ADME pharmacokinetic prediction Analysis of the designated new antioxidants hybrid molecules. In addition, organic synthesis, chemical identification, and biological assessment for their antineoplastic activity. Results Results The results of the molecular docking and SWISSADME for four designated molecules are potentially as HDAC6 inhibitors with chemical synthesis for four molecules and identified by FTIR, 1HNMR C13 NMR, Mass, and some physiochemical properties. Anti-neoplastic activity assay in MDA-MB-231 MTT cell viability assay in breast cancer refers to the designated hybrid molecule-1 as significantly cytotoxic, but molecules-2, molecule-3and molecule-4 are less significant. Conclusions The designated hybrid molecules, especially molecule-1(Thymol-based HDAC inhibitor), exhibit exceptional in silico selectivity for HDAC6, the safety of molecule-1, and superior computational pharmacokinetics parameters, making it a building block of a new generation of HDAC inhibitors.
Mubarak et al. (Tue,) studied this question.