Design, synthesis and α-glucosidase inhibition study of novel embelin derivatives

Figures & data

Scheme 1. Synthesis of novel embelin derivatives.

Figure 1. Design of novel embelin derivatives.

Figure 2. ¹³C-NMR spectrum of compound 5d.

Figure 3. Tautomerism between two forms of para-benzoquinone.

Table 1. Inhibition rate of all compounds at 250 μM against α-glucosidase.

Comp.	Inhibition rate	Comp.	Inhibition rate	Comp.	Inhibition rate	Comp.	Inhibition rate
4a	9.0%	4b	10.4%	4c	14.9%	4d	18.1%
5a	11.5%	5b	14.9%	5c	16.4%	5d	19.0%
6a	1.5%	6b	5.4%	6c	16.1%	6d	80.8%
7a	13.5%	7b	20.9%	7c	33.2%	7d	99.4%
8a	12.5%	8b	12.0%	8c	0.6%	Embelin	100%
9a	nt	9b	nt	9c	nt	9d	100%
10a	nt	10b	nt	10c	nt	10d	100%
11a	1.5%	11b	2.6%	11c	3.3%	11d	37.6%
12a	nt	12b	nt	12c	nt	12d	100%
13a	0%	13b	0%	13c	0%	13d	0%
14a	70.1%	14b	71.1%	14c	74.7%	14d	85.2%
15a	nt	15b	nt	15c	nt	15d	100%
16a	6.0%	16b	4.3%	16c	37.2%	16d	81.4%
17a	5.1%	17b	14.3%	17c	59.7%	17d	99.5%

nt: not tested.

Figure 4. Inhibition curves of embelin and its derivatives.

Table 2. IC₅₀ values of selected compounds against α-glucosidase.

Compound	R	IC50 (μM)
6d	n-C7H15	126.8
7d	n-C9H19	5.7
embelin	n-C11H23	4.2
9d	n-C13H27	2.3
10d	n-C15H31	1.8
12d		3.3
14d		45.3
15d		3.6
16d		74.8
17d		11.2
Acarbose		584.0
Ursolic acid		4.3

Figure 5. Determination of the mechanism of the inhibition of α-glucosidase by 10d, 12d, 15d, and embelin.

Figure 6. A1–D1: Lineweaver–Burk double-reciprocal plots; A2–D2: Plots of slope versus concentration of inhibitors for the determination of the inhibition constant K_i; A3–D3: Plots of Y-intercept versus concentration of inhibitors for the determination of the inhibition constant K_is.

Table 3. K_i, K_is, and inhibition type of selected compounds against α-glucosidase.

Compound	Ki value (μM)	Kis value (μM)	Inhibition type
Embelin	3.72	1.37	Mixed-type
10d	1.24	0.60	Mixed-type
12d	3.71	1.93	Mixed-type
15d	2.40	0.33	Mixed-type

Figure 7. Docking binding model of 10d with yeast α-glucosidase. (A): Binding mode of 10d docked with the prototype molecular of the active site. (B) and (C): Active site MOLCAD surface representation of lipophilic potential. (D): The interaction of 10d with the surrounding amino acids. (E) and (F): Active site MOLCAD surface representation of hydrogen bonding.

Figure 8. Docking binding model of 15d with yeast α-glucosidase. (A): Binding mode of 15d docked with the prototype molecular of the active site. (B) and (C): Active site MOLCAD surface representation of lipophilic potential. (D): The interaction of 15d with the surrounding amino acids. (E) and (F): Active site MOLCAD surface representation of hydrogen bonding.