α-Glucosidase inhibition by flavonoids: an in vitro and in silico structure–activity relationship study

Figures & data

Figure 1. Chemical structures of the tested flavonoids.

Table 1. Structures and in vitro α-glucosidase inhibition by the studied flavonoids (IC₅₀ μM, mean ± SEM).

Compounds	Structure	R^2′	R^3	R^3′	R^4′	R^6	R^7	R^8	IC50 (μM)
A1 (Flavone)		–	H	H	H	–	–	–	<20%*200 μM^a
A2		–	H	OH	H	–	–	–	<20%*200 μM^a
A3		–	H	H	OH	–	–	–	<20%*200 μM^a
A4		–	H	OH	OH	–	–	–	32 ± 4%*200 μM^a
A5		–	OH	OH	OH	–	–	–	54 ± 3
A6		–	OH	OMe	OMe	–	–	–	<20%*100 μM^a
B1		–	–	H	H	–	–	–	<20%*200 μM^a
B2		–	–	OH	OH	–	–	–	31 ± 4%*200 μM^a
B3		–	–	H	OH	–	–	–	66 ± 2
B4		–	–	OH	OH	–	–	–	66 ± 7
C1		–	H	H	H	–	OH	H	<20%*200 μM^a
C2		–	H	OH	H	–	OH	H	53 ± 4
C3		–	H	H	OH	–	OH	H	≈200
C4		–	OH	OH	H	–	OH	H	42 ± 4
C5		–	OH	H	OH	–	OH	H	96 ± 10
C6		–	H	OH	OH	–	OH	H	95 ± 7
C7		–	OH	OH	OH	–	OH	OH	7.6 ± 0.4
C8		–	OH	OMe	H	–	OMe	H	22 ± 2%*100 μM^a
C9		–	OH	H	OMe	–	OMe	H	<20%*200 μM^a
C10		–	OH	OH	OH	–	OMe	OMe	86 ± 6
C11		–	OH	OMe	OMe	–	OH	OH	31 ± 3%*200 μM^a
C12		–	OH	OBn	OBn	–	OMe	OMe	<20%*200 μM^a
C13		–	OH	OMe	OMe	–	OBn	OBn	32 ± 3%*200 μM^a
D1 (Chrysin)		H	H	H	H	H	–	H	<20%*50 μM^a
D2 (Galangin)		H	OH	H	H	H	–	H	21 ± 3%*200 μM^a
D3 (Baicalein)		H	H	H	H	OH	–	H	44 ± 3
D4		H	H	OH	H	H	–	H	89 ± 3
D5 (Apigenin)		H	H	H	OH	H	–	H	82 ± 6
D6 (Kaempferol)		H	OH	H	OH	H	–	H	32 ± 3
D7 (Luteolin)		H	H	OH	OH	H	–	H	46 ± 6
D8 (Quercetin)		H	OH	OH	OH	H	–	H	15 ± 3
D9 (Morin)		OH	OH	H	OH	H	–	H	32 ± 2
D10		H	Cl	OH	OH	H	–	H	21 ± 2
D11		H	H	OH	OH	Cl	–	H	≈200
D12		H	H	OH	OH	H	–	Cl	55 ± 2
D13		H	Cl	OH	OH	H	–	Cl	43 ± 3
D14		H	H	OH	OH	Cl	–	Cl	34 ± 3
D15 (Chrysoeriol)		H	H	OMe	OH	H	–	H	156 ± 5
D16 (Acacetin)		H	H	H	OMe	H	–	H	≈200
D17		H	H	OMe	OMe	H	–	H	<20%*200 μM^a
D18 (Rutin)		H	Rutinose	OH	OH	H	–	H	<20%*200 μM^a
E1 (Naringenin)		–	H	H	–	–	–	–	45 ± 3%*200 μM^a
E2 (Eriodictyol)		–	H	OH	–	–	–	–	35 ± 4%*200 μM^a
E3 (Taxifolin)		–	OH	OH	–	–	–	–	≈200
Positive control: Acarbose		–	–	–	–	–	–	–	607 ± 56

^a Inhibitory activity (mean ± SEM %) at the highest tested concentration (in superscript).

Table 2. K_i values (mean ± SEM, μM) for the inhibition of yeast α-glucosidase by the selected flavonoids.

Flavonoid	Type of inhibition	Ki (μM)
A5	Mixed	41 ± 7
B3	Mixed	127 ± 9
C7	Competitive	6.5 ± 0.2
D8 (quercetin)	Competitive	6.8 ± 0.6
D10	Non-competitive	51 ± 6
E3 (taxifolin)	Non-competitive	347 ± 15
Positive control: Acarbose	Competitive	457 ± 11

Figure 2. Lineweaver–Burk double reciprocal plots of α-glucosidase inhibition by A5 (A), B3 (B), C7 (C), D8 (quercetin) (D), D10 (E), E3 (taxifolin) (F) and acarbose (G).

Figure 3. Predicted binding poses for acarbose (A) and flavones A5 (B), B1 and B3 (C), C7 (D), D8 (quercetin) (E), D10 (F) and E3 (taxifolin) (G). Hydrogen bonds are represented by dashed lines. (B) B1 is coloured salmon and B3 light blue. The residues that establish the most relevant interactions are also shown. Asp214 and Glu276 are the catalytic residues that participate in the hydrolysis reaction. Asp349 is also a conserved residue.

Figure 4. Potential flavonoids ‘substitution pattern that contributes to increase the α-glucosidase inhibition.