Design, synthesis and cholinesterase inhibitory activity of α-mangostin derivatives

Abstract α-mangostin, a polyphenol xanthone derivative, was mainly isolated from pericarps of the mangosteen fruit (Garcinia mangostana L.). In present investigation, a series of derivatives were designed, synthesised and evaluated in vitro for their inhibitory activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among the synthesised xanthones, compounds 1, 9, 13 and 16 showed AChE selective inhibitory activity, 15 was a BuChE selective inhibitor while 2, 3, 5, 6, 7, 12 and 14 were dual inhibitors. The most potent inhibitor of AChE was 16 while 5 was the most potent inhibitor of BuChE with IC50 values of 5.26 μM and 7.55 μM respectively. Graphical Abstract


Figure 3S
Negative ESI-MS spectrum of compound 2 12

Figure 8S
Negative ESI-MS spectrum of compound 3 14

Figure 11S
Negative ESI-MS spectrum of compound 4 16

Figure 15S
Negative ESI-MS spectrum of compound 5 19

Figure 19S
Negative ESI-MS spectrum of compound 6 22

Figure 23S
Negative ESI-MS spectrum of compound 7 25

Figure 27S
Negative ESI-MS spectrum of compound 8 28

Figure 31S
Negative ESI-MS spectrum of compound 9 31

Figure 35S
Positive ESI-MS spectrum of compound 10 34

Figure 39S
Positive ESI-MS spectrum of compound 11 36

Figure 43S
Negative ESI-MS spectrum of compound 15 38

Figure 47S
Negative ESI-MS spectrum of compound 16 41

Figure 51S
Negative ESI-MS spectrum of compound 17 43

General procedure
All reagents were purchased from Sigma-Aldrich or Aladdin or Innochem and were of commercial quality. They were used as received without further purification.
Solvents were dried by standard methods prior to use. The other reagents were of analytical grade. Air and moisture sensitive reactions were performed under nitrogen atmosphere.
Sodium sulfite was added to the resulting mixture and stirring was continued for a further 30min. The mixture was diluted with water, extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a yellow solid. The residue was purified on column chromatograph using petroleum ether/ethyl acetate (1: 1) to afford 2 (4.4 mg, 10%), 3 (5 mg, 12%) and 4 (37 mg, 78%).

General procedure for synthesis of compound 5, 6 and 12
A solution of 1, 2 or 3 (44 mg, 0.1 mmol) and 10% Pd/C (5 mg) in CH 3 OH (2 mL) was placed under an atmosphere of hydrogen. After stirring for 24 h, the reaction mixture was filtered through filter paper and concentrated under reduced pressure.

General procedure for synthesis of compound 7-9
A solution of 2, 4 or 5 (0.1 mmol) in mixed reagent (2 mL, THF: H 2 O = 2: 1) was added NaIO 4 (26 mg, 0.12 mmol) at cool temperature. After the addition was completed, the reaction solution was allowed to warm to room temperature. After stirring for 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate (3 × 10 mL). The organic phase solvent was washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo to give a yellow solid. The crude product was purified on column chromatograph using petroleum ether/ethyl acetate (2:1 ~ 4:1) to afford 7, 8 or 9.

General procedure for synthesis of compound 10-11
A solution of 2 or 5 (0.1 mmol) and NaH (80 mg, 2 mM) in DMF (2 mL) was placed under an atmosphere of nitrogen, after stirring for 30 min, the reaction mixture was added CH 3 I (0.2 mL, 3 mM). After stirring for 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate (3 × 10 mL). The organic phase solvent was washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo to give a yellow solid. The crude product was purified on column chromatograph using petroleum ether/ethyl acetate (9: 1) to afford 10 or 11. 6