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

Toledano Pinedo, MireiaPorro Pérez, AliciaSchäker Hübner, LindaRomero, FernandoDong, MinSamadi, AbdelouahidAlmendros, PedroIriepa, IsabelSolana Manrique, CristinaMarco Contelles, JoséEt al.2025-02-122024Toledano-Pinedo, M., Porro-Pérez, A., Schäker-Hübner, L., Romero, F., Dong, M., Samadi, A., Almendros, P., Iriepa, I., Bautista-Aguilera, Ò. M., Rodríguez-Fernández, M. M., Solana-Manrique, C., Sanchis, I., Mora-Morell, A., Rodrìguez, A. C., Sànchez-Pérez, A. M., Knez, D., Gobec, S., Bellver-Sanchis, A., Pérez, B., … Marco-Contelles, J. (2024). 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. Journal of Medicinal Chemistry, 67(18), 16533-16555. https://doi.org/10.1021/acs.jmedchem.4c013670022-26231520-4804http://hdl.handle.net/11268/13661Herein, 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.engContilisant+Tubastatin A Hybrids: Polyfunctionalized Indole Derivatives as New HDAC Inhibitor-Based Multitarget Small Molecules with In Vitro and In Vivo Activity in Neurodegenerative Diseasesjournal article10.1021/acs.jmedchem.4c01367embargoed accessFarmacologíaNeurobiologíaBiología molecularGoal 3: Ensure healthy lives and promote well-being for all at all ages