In view of the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC50 = 4.52 ± 0.24 µM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Aβ1-40 at 3 µM and 10 µM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration.

b Laboratoire de Chimie Organique et Thérapeutique Neurosciences Intégratives et Cliniques EA 481 Univ Bourgogne Franche Comté Besançon France

c Laboratoire de Toxicologie Cellulaire Univ Bourgogne Franche Comté Besançon France

Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences University of Defence Hradec Kralove Czech Republic

e Biomedical Research Center University Hospital Hradec Kralove Hradec Kralove Czech Republic

f Department of Organic Chemistry and Inorganic Chemistry School of Biology Environmental Sciences and Chemistry University of Alcalá Alcalá de Henares Spain

g Laboratoire Matériaux Traitement et Analyse Institut National de Recherche et d'Analyse Physico chimique Technopole Ariana Tunis Tunisia

h Research Institute for Medicines Faculty of Pharmacy Universidade de Lisboa Lisboa Portugal

i Laboratory of Medicinal Chemistry IQOG CSIC Madrid Spain

Laboratory of Applied Chemistry Heterocycles Lipids and Polymers Faculty of Sciences of Sfax University of Sfax Sfax Tunisia

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