2. Academic Validation
  3. 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

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. 2024 Sep 26;67(18):16533-16555. doi: 10.1021/acs.jmedchem.4c01367.
Mireia Toledano-Pinedo 1,  Alicia Porro-Pérez 1,  Linda Schäker-Hübner 2,  Fernando Romero 1,  Min Dong 1,  Abdelouahid Samadi 3,  Pedro Almendros 1,  Isabel Iriepa 4 5,  Òscar M Bautista-Aguilera 4,  M Mercedes Rodríguez-Fernández 6,  Cristina Solana-Manrique 7 8 9,  Inmaculada Sanchis 7 8,  Alba Mora-Morell 7 8,  Ania Canseco Rodrìguez 10,  Ana M Sànchez-Pérez 10,  Damijan Knez 11,  Stanislav Gobec 11,  Aina Bellver-Sanchis 12 13,  Belén Pérez 14,  Alexey V Dobrydnev 15,  Aizpea Artetxe-Zurutuza 16,  Ander Matheu 16 17 18,  Agata Siwek 19,  Małgorzata Wolak 19,  Grzegorz Satała 20,  Andrzej J Bojarski 20,  Agata Doroz-Płonka 21,  Jadwiga Handzlik 21,  Justyna Godyń 22,  Anna Więckowska 22,  Nuria Paricio 7 8,  Christian Griñán-Ferré 12 13 23,  Finn K Hansen 2,  José Marco-Contelles 1
Affiliations

Affiliations

  • 1 Institute of General Organic Chemistry (CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
  • 2 Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
  • 3 Department of Chemistry, College of Science, United Arab Emirates University, Al Ain 15551, UAE.
  • 4 Universidad de Alcalá, Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química "Andrés M. del Río" (IQAR), 28805 Alcalá de Henares, Madrid, Spain.
  • 5 Grupo DISCOBAC, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), 28805 Alcalá de Henares, Madrid, Spain.
  • 6 Department of Organic Chemistry, Universidad Autónoma de Madrid, Cantoblanco 28049 Madrid, Spain.
  • 7 Departamento de Genética, Facultad CC Biológicas, Universidad de Valencia, 46100 Burjassot, Spain.
  • 8 Instituto Universitario de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, 46100 Burjassot, Spain.
  • 9 Departamento de Fisioterapia, Facultad de Ciencias de la Salud, Universidad Europea de Valencia, 46010 Valencia, Spain.
  • 10 Insitute of Advanced Materials, INAM, University of Jaume I, Castellón 12071, Spain.
  • 11 University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia.
  • 12 Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, Universitat de Barcelona (NeuroUB), Av. Joan XXIII 27-31, 08028 Barcelona, Spain.
  • 13 Institut de Neurociències, Universitat de Barcelona (NeuroUB), 08035 Barcelona, Spain.
  • 14 Department of Pharmacology, Therapeutic and Toxicology. Universitat Autònoma de Barcelona, E-08193 Barcelona, Spain.
  • 15 Chemistry Department, Taras Shevchenko National University of Kyiv, Lva Tolstoho Street 12, Kyiv 01033, Ukraine.
  • 16 Cellular Oncology group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain.
  • 17 CIBERfes, Carlos III Institute, 28029 Madrid, Spain.
  • 18 IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain.
  • 19 Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
  • 20 Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland.
  • 21 Department of Technology and Biotechnology of Drugs, Medical College, Jagiellonian University, 9 Medyczna St., 30-688 Krakow, Poland.
  • 22 Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
  • 23 Spanish Biomedical Research Center in Neurodegenerative Diseases (CIBERNED)-Instituto de Salud Carlos III, 28029 Madrid, Spain.
PMID: 39256214 DOI: 10.1021/acs.jmedchem.4c01367
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.

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