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

• Published in: Journal of medicinal chemistry Vol. 59; no. 21; pp. 9967 - 9973
• Main Authors: Benchekroun, Mohamed, Romero, Alejandro, Egea, Javier, León, Rafael, Michalska, Patrycja, Buendía, Izaskun, Jimeno, María Luisa, Jun, Daniel, Janockova, Jana, Sepsova, Vendula, Soukup, Ondrej, Bautista-Aguilera, Oscar M, Refouvelet, Bernard, Ouari, Olivier, Marco-Contelles, José, Ismaili, Lhassane
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.11.2016; Amer Chemical Soc
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Cell Death - drug effects; Cell Survival - drug effects; Chemical Sciences; Chemistry, Medicinal; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Cholinesterases - metabolism; Coumaric Acids - chemical synthesis; Coumaric Acids - chemistry; Coumaric Acids - pharmacology; Dose-Response Relationship, Drug; Hep G2 Cells; Humans; Life Sciences & Biomedicine; Melatonin - chemical synthesis; Melatonin - chemistry; Melatonin - pharmacology; Molecular Structure; NF-E2-Related Factor 2 - agonists; NF-E2-Related Factor 2 - metabolism; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; DESIGN; ACETYLCHOLINESTERASE; HYPOTHESIS; DRUG CANDIDATES; MECHANISMS; ACHE INHIBITORS; DERIVATIVES; HETERODIMERS; NEURODEGENERATIVE DISEASES; HYBRIDS; derivatives; neurodegenerative diseases; ache inhibitors; design; acetylcholinesterase; hybrids; drug candidates; heterodimers; hypothesis; mechanisms
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b01178

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.