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

Abstract

Herein, we describe the design, synthesis, and biological evaluation of 15 Contilisant+Tubastatin A hybrids. These ligands are polyfunctionalized indole derivatives developed by juxtaposing selected pharmacophoric moieties of Contilisant and Tubastatin A to act as multifunctional ligands. Compounds 3 and 4 were identified as potent HDAC6 inhibitors (IC₅₀ = 0.012 μM and 0.035 μM, respectively), so they were further evaluated in Drosophila 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 3 and 4 were also studied in the transgenic Caenorhabditis elegans 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 3 and 4 as novel multifunctional ligands that improve the features of PD and AD hallmarks in the respective animal models.