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Article

Design, Synthesis, and In Vitro Biological Activities of a Bio-Oxidizable Prodrug to Deliver Both ChEs and DYRK1A Inhibitors for AD Therapy

by
Anaïs Barré
1,2,
Rabah Azzouz
1,
Vincent Gembus
1,*,
Cyril Papamicaël
2 and
Vincent Levacher
2,*
1
VFP Therapies R&D; 1 rue Tesnière, 76130 Mont Saint-Aignan, France
2
Normandie University, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France
*
Authors to whom correspondence should be addressed.
Molecules 2019, 24(7), 1264; https://doi.org/10.3390/molecules24071264
Submission received: 4 March 2019 / Revised: 27 March 2019 / Accepted: 28 March 2019 / Published: 1 April 2019
(This article belongs to the Special Issue Cholinesterase Inhibitors)
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Abstract

Despite their side effects, cholinesterase (ChE) inhibitors remain the only approved drugs to treat Alzheimer’s disease patients, along with the N-methyl-d-aspartate (NMDA) receptor antagonist memantine. In the last few years, the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has also been studied as a promising target for the development of new drugs for this pathology. In this context, and based on our previous characterization of bio-oxidizable prodrugs of potent acetylcholinesterase (AChE) inhibitors, we envisioned a strategy involving the synthesis of a bio-oxidizable prodrug of both ChE and DYRK1A inhibitors. To this end, we fixed our interest on a known potent inhibitor of DYRK1A, namely INDY. The designed prodrug of both ChE and DYRK1A inhibitors was successfully synthesized, connecting both inhibitors by a carbonate link. This prodrug and its corresponding drug were then evaluated as ChEs and DYRK1A inhibitors. Remarkably, in vitro results were in accordance with the starting hypothesis, showing a relative inactivity of the prodrug against DYRK1A and ChEs and a potent inhibition of ChEs by the oxidized form. Molecular docking and kinetic studies of ChE inhibition by the active compound are also discussed in this report.
Keywords: Alzheimer’s; acetylcholinesterase; butyrylcholinesterase; DYRK1A kinase; prodrug; INDY Alzheimer’s; acetylcholinesterase; butyrylcholinesterase; DYRK1A kinase; prodrug; INDY
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MDPI and ACS Style

Barré, A.; Azzouz, R.; Gembus, V.; Papamicaël, C.; Levacher, V. Design, Synthesis, and In Vitro Biological Activities of a Bio-Oxidizable Prodrug to Deliver Both ChEs and DYRK1A Inhibitors for AD Therapy. Molecules 2019, 24, 1264. https://doi.org/10.3390/molecules24071264

AMA Style

Barré A, Azzouz R, Gembus V, Papamicaël C, Levacher V. Design, Synthesis, and In Vitro Biological Activities of a Bio-Oxidizable Prodrug to Deliver Both ChEs and DYRK1A Inhibitors for AD Therapy. Molecules. 2019; 24(7):1264. https://doi.org/10.3390/molecules24071264

Chicago/Turabian Style

Barré, Anaïs, Rabah Azzouz, Vincent Gembus, Cyril Papamicaël, and Vincent Levacher. 2019. "Design, Synthesis, and In Vitro Biological Activities of a Bio-Oxidizable Prodrug to Deliver Both ChEs and DYRK1A Inhibitors for AD Therapy" Molecules 24, no. 7: 1264. https://doi.org/10.3390/molecules24071264

APA Style

Barré, A., Azzouz, R., Gembus, V., Papamicaël, C., & Levacher, V. (2019). Design, Synthesis, and In Vitro Biological Activities of a Bio-Oxidizable Prodrug to Deliver Both ChEs and DYRK1A Inhibitors for AD Therapy. Molecules, 24(7), 1264. https://doi.org/10.3390/molecules24071264

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