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In Silico Study, Design, Synthesis, and Evaluation of Anti-Neoplastic Activity of Hybrid Natural Antioxidants as Histone Deacetylase Inhibitors

Year: 2025
Type: article
Abstract: OBJECTIVE: Aim: To design and synthesize hybridized natural antioxidants by following the pharmacophore of the reference Histone Deacetylase (HDAC) Inhibitors 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. PATIENTS AND METHODS: Materials 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, absorption, distribution, metabolism and excretion (ADME) pharmacokinetic prediction, and 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 SWISS ADME for four designated molecules are potentially as HDAC6 inhibitors with chemical synthesis for four molecules and identified by Fourier-Transform Infrared spectroscopy (FTIR), Proton Nuclear Magnetic Resonance spectroscopy (1HNMR), Carbon-13 Nuclear Magnetic Resonance (C13 NMR), Mass, and some physiochemical properties. Anti-neoplastic activity assay in MDA-MB-231 3-(4,5-di methyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay in breast cancer refers to the designated hybrid molecule-1 as significantly cytotoxic, but molecules-2, molecule-3, and molecule-4 are less significant. CONCLUSION: 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. The new hybridized molecules of natural origin showed potential anti-neoplastic activities with improved pharmacokinetic parameters compared to SAHA and Tucidinostat.
DOI: 10.36740/wlek/214627
Language: English
Open Access status: bronze
OpenAlex ID: W7126206953
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