Acylphloroglucinols with acetylcholinesterase inhibitory effects from the fruits of Eucalyptus robusta

Abstract

Eleven new acylphloroglucinols, including six new formylated phloroglucinol-monoterpene meroterpenoids, eucalyprobusals A-F (1-6), one monomeric acylphloroglucinol, eucalyprobusone B (7), and four dimeric acylphloroglucinols, eucalyprobusones C-F (8-11) were purified from the fruits of Eucalyptus robusta. The establishment of the structures of 1-11 was achieved by a combination of NMR and HRESIMS data analyses, electron circular dichroism (ECD), and single-crystal X-ray diffraction. Compounds 6, 8, and an inseparable mixture of 10 and 11 were found to be potent AChE inhibitors with IC₅₀ values of 3.22 ± 0.36, 3.82 ± 0.22, and 2.55 ± 0.28 μΜ, respectively. Possible interaction sites of 6, 8, 10, and 11 with AChE were investigated by means of molecular docking studies, and the results revealed that AChE residues Asn87, Ser125, Thr83, Tyr133, Tyr124, Tyr337, and Tyr341 played crucial roles in the observed activity of the aforementioned compounds.

Keywords: Acetylcholinesterase inhibitory effect; Acylphloroglucinols; Eucalyptus robusta; Molecular docking.

Fig. 1.

Structures of 1–11 isolated from E. robusta.

Fig. 2.

Selected ¹H–¹H COSY (blue bold line) and HMBC (red arrow) correlations of 1–11.

Fig. 3.

ORTEP drawing of 1.

Fig. 4.

Calculated and experimental ECD spectra for 2.

Fig. 5.

Calculated and experimental ECD spectra for 3.

Fig. 6.

Calculated and experimental ECD spectra for 4.

Fig. 7.

Calculated and experimental ECD spectra for 5.

Fig. 8.

Calculated and experimental ECD spectra of (±)-6.

Fig. 9.

Calculated and experimental ECD spectra of (±)-8.

Fig. 10.

ORTEP drawing of (±)-10 and (±)-11.

Fig. 11.

The binding modes of 6 (A), 8 (B), 10 (C), and 11 (D) with human AChE (PDB ID: 4M0F). Hydrogen bond interactions are depicted with red dashes, while π–π and π–σ stacking interactions are displayed with yellow and green dashes, respectively.