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

Article

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

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.

11 Nov 2022·ACS Pharmacology & Translational Science

The Chemotype of Chromanones as a Privileged Scaffold for Multineurotarget Anti-Alzheimer Agents

Article

Author: Vetman, Tatiana ; Bartz, Ulrike ; López-Muñoz, Francisco ; Deuther-Conrad, Winnie ; Wille, Timo ; Marco-Contelles, José ; Chioua, Mourad ; Lemke, Carina ; Martínez-Grau, María Angeles ; Keuler, Tim ; Iriepa, Isabel ; Gütschow, Michael ; Beadle, Christopher D. ; Elsinghorst, Paul W.

The multifactorial nature of Alzheimer's disease necessitates the development of agents able to interfere with different relevant targets. A series of 22 tailored chromanones was conceptualized, synthesized, and subjected to biological evaluation. We identified one representative bearing a linker-connected azepane moiety (compound 19) with balanced pharmacological properties. Compound 19 exhibited inhibitory activities against human acetyl-, butyrylcholinesterase and monoamine oxidase-B, as well as high affinity to both the σ₁ and σ₂ receptors. Our study provides a framework for the development of further chromanone-based multineurotarget agents.

18 Nov 2020·ACS Chemical NeuroscienceQ3 · MEDICINE

In Vitro and In Silico ADME-Tox Profiling and Safety Significance of Multifunctional Monoamine Oxidase Inhibitors Targeting Neurodegenerative Diseases

Q3 · MEDICINE

Article

Author: Bucki, Adam ; Romero, Alejandro ; Ramos, Eva ; Chioua, Mourad ; Egea, Javier ; Góral, Izabella ; Kiec-Kononowicz, Katarzyna ; Szałaj, Natalia ; Farré Alíns, Victor ; Marco-Contelles, José ; Latacz, Gniewomir ; Więckowska, Anna ; González-Rodríguez, Águeda ; Bautista-Aguilera, Òscar. M. ; López-Muñoz, Francisco

Herein we report in vitro metabolic stability in human liver microsomes (HLMs), interactions with cytochrome P450 isoenzymes (CYP3A4, CYP2D6, and CYP2C9), and cytotoxicity analyses on HEK-293, HepG2, Huh7, and WTIIB cell lines of our most recent multitarget directed ligands PF9601N, ASS234, and contilisant. Based on these results, we conclude that (1) PF9601N and contilisant are metabolically stable in the HLM assay, in contrast to the very unstable ASS234; (2) CYP3A4 activity was decreased by PF9601N at all the tested concentrations and by ASS234 and contilisant only at the highest concentration; CYP2D6 activity was reduced by ASS234 at 1, 10, and 25 μM and by PF9601N at 10 and 25 μM, whereas contilisant increased its activity at the same concentrations; CYP2C9 was inhibited by the three compounds; (3) contilisant did not affect cell viability in the widest range of concentrations: up to 10 μM on HEK-293 cells, up to 30 μM on Huh7 cells, up to 50 μM on HepG2 cells, and up to 30 or 100 μM on WTIIB cells. Based on these results, we selected contilisant as a metabolically stable and nontoxic lead compound for further studies in Alzheimer's disease therapy.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Preclinical	Spain	Consejo Superior de Investigaciones Científicas	03 Jul 2018

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