Dyhidro-β-agarofurans natural and synthetic as acetylcholinesterase and COX inhibitors: interaction with the peripheral anionic site (AChE-PAS), and anti-inflammatory potentials

Abstract

In order to find molecules of natural origin with potential biological activities, we isolate and synthesise compounds with agarofuran skeletons (epoxyeudesmanes). From the seeds of Maytenus disticha and Maytenus magellanica we obtained six dihydro-β-agarofurans, and by means of the Robinson annulation reaction we synthesised five compounds with the same skeleton. The structures were established on the basis of NMR, IR, and MS. The evaluated compounds showed inhibitory activity on the acetylcholinesterase enzyme and on the COX enzymes. Compound 4 emerged as the most potent in the acetylcholinesterase inhibition assay with IC₅₀ 17.0 ± 0.016 µM on acetylcholinesterase (AChE). The compounds evaluated were shown to be selective for AChE. The molecular docking, and the propidium displacement assay suggested that the compounds do not bind to the active site of the enzyme AChE, but rather bind to the peripheral anionic site (PAS) of the enzyme, on the other hand, the natural compound 8, showed the best inhibitory activity on the COX-2 enzyme with an IC₅₀ value of 0.04 ± 0.007 µM. The pharmacokinetic profile calculated in silico using the SWISSADME platform shows that these molecules could be considered as potential drugs for the treatment of neurodegenerative diseases such as AD.

Graphical Abstract

Keywords:

• Acetylcholinesterase
• butyrylcholinesterase
• dihydro-β-agarofurans
• COX-2
• molecular docking
• Alzheimer’s disease

Acknowledgements

To CONICYT FONDECYT N°1130463 and CONICYT FONDECYT N° 1161157. The authors want to thank an internal grant from Dirección de Investigación, Universidad del Bío Bío, Chillán, Chile: DIUBB # 083009-2R, # 122509 and # 132209 GI/C, and scholarship for "Doctorado Nacional 2014" 21140017.

Disclosure statement

No potential conflicto of interest was reported by the authors.

Additional information

Funding

The authors want to thank an internal grant from Dirección de Investigación, Universidad del Bío Bío, Chillán, Chile: DIUBB # 083009-2R, # 122509 and # 132209 GI/C, and scholarship for "Doctorado Nacional 2014" 21140017.