de Goni_2025_Pharmaceutics_17_

Background/Objectives: Glioblastoma is the most common and aggressive primary brain tumor in adults, with patient prognosis remaining poor. Treatment resistance and tumor recurrence are frequent, primarily due to the high intra- and inter-tumoral heterogeneity and the existence of glioma stem cells. Thus, there is an urgent need for novel and more effective therapeutic strategies. Multitarget small molecules (MSMs) are emerging as a novel therapeutic strategy for the treatment of complex diseases such as cancer. Methods: In the present work, we have generated a novel family of indole-based MSMs with pharmacophoric moieties combining the parent compounds Contilisant and the HDAC inhibitor Tubastatin A. Thus, the MSMs were designed to inhibit monoamine oxidases (MAOs), cholinesterases (ChEs) and histone deacetylases (HDACs), while acting as histamine H3 receptor (H3R) antagonists and sigma 1 receptor (S1R) agonists. We generated four different molecules and evaluated in detail the activity of the two most efficient MSM compounds in vitro and in vivo. Results: These molecules induced potent cytotoxic effects in vitro in patient-derived glioma stem cells and glioblastoma cell lines and significantly impaired tumor growth in vivo. OMIC analyses further revealed that the compounds induce dysregulation of the cell cycle in glioma stem cells. Moreover, in silico analyses indicated that these compounds are theoretically capable of crossing the blood-brain barrier, while exhibiting low toxicity in healthy cells. Conclusions: In conclusion, our findings demonstrate the potential antitumor activity of a novel family of MSMs in preclinical models of glioblastoma.