Design, synthesis and biological activity of 1H-indene-2-carboxamides as multi-targeted anti-Alzheimer agents

Abstract

The aim of this study was to design new molecules and evaluate their anticholinesterase and amyloid beta (Aβ_1–42) inhibition activities as multifunctional drug candidates for the treatment of Alzheimer’s disease (AD). A series of 5,6-dimethoxy-1H-indene-2-carboxamides (1–22) was synthesized; cholinesterase inhibitory activities of the compounds were measured according to Ellman’s colorimetric assay, while the thioflavin T assay was used for measuring the inhibition of Aβ_1–42 aggregation. The results revealed that most compounds showed higher inhibitory activity against BuChE than AChE. Compounds 20 and 21 were found to be the most potent BuChE inhibitors with respective IC₅₀ values of 1.08 and 1.09 μM. Compounds 16, 20, 21 and 22 exhibited remarkable inhibition of Aβ_1–42 aggregation. Kinetic analysis showed that the most potent BuChE inhibitor (20) acted as a noncompetitive inhibitor. Docking studies suggested that inhibitor 20 displayed many potential hydrogen-bondings with the PAS of BuChE. These results suggest that compound 20 may be an especially promising multifunctional drug for the prevention and treatment of AD.

Keywords:

• AChE
• Alzheimer
• Aβ1–42
• BuChE
• molecular modeling

Acknowledgements

This research work was supported by Ataturk University Research Fund (Project No: 2015/326), Turkey. The measurement of cholinesterase inhibitions was performed at the Faculty of Pharmacy and Department of Pharmaceutical Chemistry, University of Ataturk, Turkey, under the supervision of Prof. Dr. H. Inci Gul.

Declaration of interest

The authors have declared no conflicts of interest with the presented data from this article.

Supplementary material available online