Toledano-Pinedo, M., Porro-Pérez, A., Schäker-Hübner, L., Romero, F., Dong, M., Samadi, A., Almendros, P., Iriepa, I., Bautista-Aguilera, 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., Dobrydnev, A.V., Artetxe-Zurutuza, A., Matheu, A., Siwek, A., Wolak, M., Satała, G., Bojarski, A.J., Doroz-Płonka, A., Handzlik, J., Godyń, J., Więckowska, A., Paricio, N., Griñán-Ferré, C., Hansen, F.K., 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.  J. Med. Chem. 67(18): 16533--16555.

FBrf0260581

Research paper

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.