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
  • 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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