Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer's Disease

Youssef Dgachi; Oscar M Bautista-Aguilera; Mohamed Benchekroun; Hélène Martin; Alexandre Bonet; Damijan Knez; Justyna Godyń; Barbara Malawska; Stanislav Gobec; Mourad Chioua; Jana Janockova; Ondrej Soukup; Fakher Chabchoub; José Marco-Contelles; Lhassane Ismaili

doi:10.3390/molecules21050634

Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer's Disease

Molecules. 2016 May 14;21(5):634. doi: 10.3390/molecules21050634.

Authors

Affiliations

¹ Laboratory of Applied Chemistry, Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax, B.P. 802, Sfax 3000, Tunisia. [email protected].
² Laboratoire de Chimie Organique et Thérapeutique, Neurosciences Intégratives et Cliniques, EA 481, UFR SMP, Univ. Franche-Comté, Univ. Bourgogne Franche-Comté, 19, rue Ambroise Paré, Besançon F-25000, France. [email protected].
³ Laboratoire de Chimie Organique et Thérapeutique, Neurosciences Intégratives et Cliniques, EA 481, UFR SMP, Univ. Franche-Comté, Univ. Bourgogne Franche-Comté, 19, rue Ambroise Paré, Besançon F-25000, France. [email protected].
⁴ Laboratory of Cell Toxicology, EA 4267, University of Bourgogne Franche-Comté, 19 rue Ambroise Paré, Besançon Cedex 25030, France. [email protected].
⁵ Laboratory of Cell Toxicology, EA 4267, University of Bourgogne Franche-Comté, 19 rue Ambroise Paré, Besançon Cedex 25030, France. [email protected].
⁶ Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, Ljubljana 1000, Slovenia. [email protected].
⁷ Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9 Street, Krakow 30-688, Poland. [email protected].
⁸ Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9 Street, Krakow 30-688, Poland. [email protected].
⁹ Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, Ljubljana 1000, Slovenia. [email protected].
¹⁰ Laboratory of Medicinal Chemistry (IQOG, CSIC) C/Juan de la Cierva 3, Madrid 28006, Spain. [email protected].
¹¹ Biomedical Research Center, University Hospital Hradec Kralove, 500 05 Hradec Králove, Czech Republic. [email protected].
¹² Biomedical Research Center, University Hospital Hradec Kralove, 500 05 Hradec Králove, Czech Republic. [email protected].
¹³ Laboratory of Applied Chemistry, Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax, B.P. 802, Sfax 3000, Tunisia. [email protected].
¹⁴ Laboratory of Medicinal Chemistry (IQOG, CSIC) C/Juan de la Cierva 3, Madrid 28006, Spain. [email protected].
¹⁵ Laboratoire de Chimie Organique et Thérapeutique, Neurosciences Intégratives et Cliniques, EA 481, UFR SMP, Univ. Franche-Comté, Univ. Bourgogne Franche-Comté, 19, rue Ambroise Paré, Besançon F-25000, France. [email protected].

Abstract

We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.

Keywords: Alzheimer’s disease; antioxidants; cholinesterase inhibitors; hepatotoxicity; multicomponent reactions; multitarget-directed ligands; quinazolinones.

MeSH terms

Alzheimer Disease / prevention & control*
Antioxidants / chemical synthesis*
Antioxidants / pharmacology*
Cholinesterase Inhibitors / chemical synthesis*
Cholinesterase Inhibitors / pharmacology*
Humans
Inhibitory Concentration 50
Liver / drug effects
Spectrum Analysis

Substances

Antioxidants
Cholinesterase Inhibitors