Contilisant+Tubastatin A Hybrids: Polyfunctionalized Indole Derivatives as New HDAC Inhibitor-Based Multitarget Small Molecules with <i>In Vitro</i> and <i>In Vivo</i> Activity in Neurodegenerative Diseases

Abstract

Herein, we describe the design, synthesis, and biological evaluation of 15 <b>Contilisant</b>+<b>Tubastatin A</b> hybrids. These ligands are polyfunctionalized indole derivatives developed by juxtaposing selected pharmacophoric moieties of <b>Contilisant</b> and <b>Tubastatin A</b> to act as multifunctional ligands. Compounds <b>3</b> and <b>4</b> were identified as potent HDAC6 inhibitors (IC₅₀ = 0.012 μM and 0.035 μM, respectively), so they were further evaluated in <i>Drosophila</i> and human cell models of Parkinson's disease (PD). Both compounds attenuated PD-like phenotypes, such as motor defects, oxidative stress, and mitochondrial dysfunction in PD model flies. Ligands <b>3</b> and <b>4</b> were also studied in the transgenic <i>Caenorhabditis elegans</i> CL2006 model of Alzheimer's disease (AD). Both compounds were nontoxic, did not induce undesirable animal functional changes, inhibited age-related paralysis, and improved cognition in the thrashing assay. These results highlight <b>3</b> and <b>4</b> as novel multifunctional ligands that improve the features of PD and AD hallmarks in the respective animal models.