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
Mireia Toledano‐Pinedo, Alicia Porro-Pérez, Linda Schäker‐Hübner, Fernando Romero, Min Dong, Abdelouahid Samadi, Pedro Almendros, Isabel Iriepa, Óscar M. Bautista‐Aguilera, M. Mercedes Rodríguez‐Fernández, Cristina Solana‐Manrique, Inmaculada Sanchis, Alba Mora-Morell, Ania Canseco Rodriguez, Ana María Sánchez‐Pérez, Damijan Knez, Stanislav Gobec, Aina Bellver‐Sanchís, Belén Pérez, Alexey V. Dobrydnev, Aizpea Artetxe-Zurutuza, Ander Matheu, Agata Siwek, Małgorzata Wolak, Grzegorz Satała, Andrzej J. Bojarski, Agata Doroż-Płonka, Jadwiga Handzlik, Justyna Godyń, Anna Więckowska, Nuria Paricio, Christian Griñán‐Ferré, Finn K. Hansen, José Marco‐Contelles
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 (IC 50 = 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.