1. The Antioxidant Additive Approach for Alzheimer's Disease Therapy: New Ferulic (Lipoic) Acid Plus Melatonin Modified Tacrines as Cholinesterases Inhibitors, Direct Antioxidants, and Nuclear Factor (Erythroid-Derived 2)-Like 2 Activators
- Author
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José Marco-Contelles, Ondrej Soukup, Rafael León, Oscar M. Bautista-Aguilera, Alejandro Romero, Izaskun Buendia, Javier Egea, Vendula Sepsova, María Luisa Jimeno, Patrycja Michalska, Olivier Ouari, Bernard Refouvelet, Lhassane Ismaili, Daniel Jun, Jana Janockova, Mohamed Benchekroun, Ministry of Health of the Czech Republic, Instituto de Salud Carlos III, Fundación para la Investigación y la Prevención del Sida en España, Ministerio de Educación, Cultura y Deporte (España), Nanomédecine, imagerie, thérapeutique - UFC (EA 4662) (NIT / NANOMEDECINE), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Fonctions et dysfonctions épithéliales - UFC (EA 4267) (FDE), Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Nanomédecine, imagerie, thérapeutique - UFC ( NIT / NANOMEDECINE ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Université du Québec à Montréal ( UQAM ), Fonctions et dysfonctions épithéliales - UFC (EA 4267) ( FDE ), Université de Franche-Comté ( UFC ), Institut de Chimie Radicalaire ( ICR ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), and Nanomédecine, imagerie, thérapeutique - UFC (UR 4662) (NIT / NANOMEDECINE)
- Subjects
0301 basic medicine ,Antioxidant ,medicine.medical_treatment ,design ,ache inhibitors ,medicine.disease_cause ,01 natural sciences ,[ CHIM ] Chemical Sciences ,Antioxidants ,chemistry.chemical_compound ,Drug Discovery ,Cholinesterases ,neurodegenerative diseases ,Melatonin ,mechanisms ,biology ,Cell Death ,Molecular Structure ,Chemistry ,Hep G2 Cells ,acetylcholinesterase ,heterodimers ,Acetylcholinesterase ,3. Good health ,Lipoic acid ,Biochemistry ,Tacrine ,Molecular Medicine ,hypothesis ,medicine.drug ,Coumaric Acids ,Cell Survival ,NF-E2-Related Factor 2 ,Neuroprotection ,03 medical and health sciences ,Structure-Activity Relationship ,Alzheimer Disease ,medicine ,Humans ,[CHIM]Chemical Sciences ,drug candidates ,Cholinesterase ,hybrids ,Dose-Response Relationship, Drug ,010405 organic chemistry ,0104 chemical sciences ,030104 developmental biology ,biology.protein ,derivatives ,Cholinesterase Inhibitors ,Oxidative stress - Abstract
Novel multifunctional tacrines for Alzheimer's disease were obtained by Ugi-reaction between ferulic (or lipoic acid), a melatonin-like isocyanide, formaldehyde, and tacrine derivatives, according to the antioxidant additive approach in order to modulate the oxidative stress as therapeutic strategy. Compound 5c has been identified as a promising permeable agent showing excellent antioxidant properties, strong cholinesterase inhibitory activity, less hepatotoxicity than tacrine, and the best neuroprotective capacity, being able to significantly activate the Nrf2 transcriptional pathway., B.R. and L.I. thank the Regional Council of Franche-Comté (France) for financial support, and M.-J. Henriot (PHV Pharma) for support in the HPLC analyses. M.B. thanks the Regional Council of Franche-Comté(France) for a Ph.D. grant. J.E. has a grant from ISCIII (Programa Miguel Servet, CP14/00008). D.J., J.J., V.S., and O.S. thank Jitka Pichova for a skillful technical assistance. This work was supported by the project MH CZ-DRO (UHHK, 00179906) and by Long Term Development Plan-1011 of Faculty of Military Health Sciences, University of Defence (Czech Republic). R.L. thanks ISCIII (Programa Miguel Servet, CP11/00165; grant PI14/00372), Bayer AG “From targets to novel drugs” (grant 2015-03-1282) and Fundación FIPSE (grant 12-00001344-15). P.M. thanks MECD for a FPU fellowship (FPU13/03737).
- Published
- 2016