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.

Keywords: Acetylcholinesterase; Alzheimer’s disease; COX-2; butyrylcholinesterase; dihydro-β-agarofurans; molecular docking.

Graphical abstract

Figure 1.

Synthesis scheme of synthetic Dihydro-β-agarofuranoids. a: EVK/KOH; b: Reflux/KOH; c: MCPBA/CH₂Cl₂ r.t.; d: LiAlH₄/(C₂H₅)₂O, 0 °C; e: H₂SO₄/Toluene; f: MCPBA/CH₂Cl₂ r.t.; g: CH₃COCl/Py r.t.; h: C₅H₃ClO₂/DMAP/Py 70 °C; i: C₇H₅ClO/DMAP/Py 70 °C.

Figure 2.

Key nuclear Overhauser effects (NOEs) of compounds 4 − 6, and HMBC correlation of compounds 4–7. Red arrows indicate the NOE interactions of the protons indicated in the compounds 4–6 and black arrows indicate the HMBC correlations of the compounds 4–7.

Figure 3.

Chemical structure of the natural Dihydro-β-agarofuran evaluated.

Figure 4.

Kinetic study on the inhibition mechanism of AChE by compound 4.

Figure 5.

2D and 3D schematic diagram of the docking model of a) compound 4 with AChE, b) 9 with COX-1 c) 8 with COX-2.