Search

Herein, we describe the design, synthesis, and biological evaluation of 15 Contilisant+Tubastatin Ahybrids. These ligands are polyfunctionalized indole derivatives developed by juxtaposing selected pharmacophoric moieties of Contilisantand Tubastatin Ato act as multifunctional ligands. Compounds 3and 4were identified as potent HDAC6 inhibitors (IC50= 0.012 μM and 0.035 μM, respectively), so they were further evaluated in Drosophilaand 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 3and 4were also studied in the transgenic Caenorhabditis elegansCL2006 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 3and 4as novel multifunctional ligands that improve the features of PD and AD hallmarks in the respective animal models.