Repositioning HDAC Inhibitors for Glioma Treatment: Synthesis and Biological Evaluation

Gliomas are a type of brain tumor associated with poor patient prognosis, with current treatment, surgical resection when feasible, followed by radiotherapy and chemotherapy (Temozolomide), yielding a median survival of approximately 15 months. In light of the urgent need for more effective therapies, histone deacetylases (HDACs) have emerged as promising targets, given their differential expression across tumor types and disease grades. Although HDAC inhibitors are well established in the treatment of hematological malignancies, their potential is now being explored in solid tumors, including glioblastoma (GBM). In this study, hydroxamate-based (<b>3a</b>) and benzamide-based (<b>6a</b>) HDAC inhibitors were synthesized and evaluated in glioma cell lines and glioblastoma stem cells (GSC). Treatment with these inhibitors resulted in cell cycle alterations, increased SubG1 populations, and enhanced apoptosis, particularly with compound <b>3a</b>. Notably, <b>6a</b> demonstrated greater potency in GSCs. The observed cytotoxic effects were linked to selective inhibition of HDAC6 by <b>3a</b> and HDAC1/3 by <b>6a</b>, as confirmed through enzymatic assays and further supported by molecular docking and molecular dynamics (MD) simulations. <i>In silico</i> analyses suggest that both compounds possess favorable pharmacokinetic profiles, underscoring their potential as promising candidates for glioma therapy and paving the way for future drug development in this field.