Synthesis and biological assessment of KojoTacrines as new agents for Alzheimer’s disease therapy

Journal of Enzyme Inhibition and Medicinal Chemistry

Ondrej Soukup¹  Jana Janockova¹  Isabel Iriepa²  Ignacio Moraleda²  Daniel Jun³  Vendula Sepsova³  Emna Maalej⁴  Rim Malek⁵  Bernard Refouvelet⁵  Lhassane Ismaili⁵  Hélène Martin⁶  Fakher Chabchoub⁷  Youssef Dgachi⁸  José Marco-Contelles⁹  M. Carmo Carreiras^1,10 

[1] Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic;Department of Organic Chemistry and Inorganic Chemistry, School of Biology, Environmental Sciences and Chemistry, University of Alcalá, Alcalá de Henares, Spain;Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic;Laboratoire Matériaux, Traitement et Analyse (LMTA), Institut National de Recherche et d'Analyse Physico-chimique Technopole, Ariana-Tunis, Tunisia;Laboratoire de Chimie Organique et Thérapeutique, Neurosciences Intégratives et Cliniques EA 481, Univ. Bourgogne Franche-Comté, Besançon, France;Laboratoire de Toxicologie Cellulaire, Univ. Bourgogne Franche-Comté, Besançon, France;Laboratory of Applied Chemistry, Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax, Sfax, Tunisia;Laboratory of Applied Chemistry, Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax, Sfax, Tunisia;Laboratoire de Chimie Organique et Thérapeutique, Neurosciences Intégratives et Cliniques EA 481, Univ. Bourgogne Franche-Comté, Besançon, France;Laboratory of Medicinal Chemistry, IQOG, CSIC, Madrid, Spai;Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal;

关键词: Alzheimer disease;    kojic acid;    multitarget small molecules;    tacrine;   

DOI  :  10.1080/14756366.2018.1538136

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY