Synthesis, in vitro inhibitory activity, kinetic study and molecular docking of novel N-alkyl–deoxynojirimycin derivatives as potential α-glucosidase inhibitors

Figures & data

Scheme 1. Synthesis of intermediate products and target products of N-alkyl-deoxynojirimycin derivatives. Reagents and condition: (a) K₂CO₃, acetone, dibromo alkane, 65 °C, overnight or Et₃N, acetone, dibromo alkane, 65 °C; (b) K₂CO₃, DMF, 85 °C, 6 h.

Table 1. In vitro α-glucosidase inhibitory activity of compound 25–44.

Compound	Structure	IC50(μM)^a	Compound	Structure	IC50(μM)^a
25		1094.1 ± 1.80	35		966.2 ± 0.40
26		1099.4 ± 1.10	36		>2000
27		559.3 ± 0.28	37		>2000
28		562.1 ± 0.49	38		>2000
29		976.5 ± 0.70	39		>2000
30		1272.2 ± 1.20	40		160.5 ± 0.60
31		>2000	41		571.6 ± 0.60
32		667.0 ± 1.60	42		523.5 ± 0.10
33		602.3 ± 1.20	43		30.0 ± 0.60
34		417.0 ± 0.14	44		538.1 ± 0.28
Acarbose		822.0 ± 1.50	1-DNJ		222.4 ± 0.50

^aValues are the mean ± SD. All experiments were performed at least three times.

Figure 1. The general structural formula of N-alkyl-deoxynojirimycin derivatives.

Figure 2. Kinetic analysis of α-glucosidase inhibition by compounds 43, 40, and 34. (A) The Lineweaver–Burk plots in the absence and presence of different concentrations of compound 43; (B) The Lineweaver–Burk plots in the absence and presence of different concentrations of compound 40; (C) The Lineweaver–Burk plots in the absence and presence of different concentrations of compound 34.

Table 2. The detailed information of molecular docking results of compounds 34, 40, 41, 43, and acarbose.

Compound	Interactions	Binding Site^a	Affinity(kcal/mol)
34	Hydrogen Bonds	His348, Asp349, Asp214, His279, Glu304, Asn241(3), His239	−8.0
	π–π Interactions	Phe300
	Hydrophobic Interactions	Phe158, Phe177, Tyr71, Phe300, Leu437
40	Hydrogen Bonds	Glu276(2), Gln350, Asp349, Arg439	−8.7
	π–π Interactions	Phe300, Phe157
	Hydrophobic Interactions	Ala278, Phe157, Phe158, Phe177, Leu437, Phe311
	Electrostatic Interaction	Asp349
41	Hydrogen Bonds	Glu276, Gln350, Asp349, Arg439	−8.6
	π–π Interactions	Phe300, Phe157
	Hydrophobic Interactions	Phe157, Phe177, Phe158, Ala278
	Electrostatic Interaction	Asp349
43	Hydrogen Bonds	Glu276, Asp349, Arg439, His279, Glu304, Pro309(2), Arg312(2)	−9.2
	π–π Interactions	Phe300, Phe157
	Hydrophobic Interactions	Leu218, Ala 278, Phe157, Phe300, Phe177, Phe158
	Electrostatic Interaction	Asp349
acarbose	Hydrogen Bonds	Gln350, Arg312, Asn241(4)	−7.8
	Electrostatic Interaction	Phe157, Phe158, Phe300

^aThe number in brackets means the number of hydrogen bonds formed with the residues.

Figure 3. (A) The predicted binding mode of compound 43 in the active site and substrate-binding pocket. (B) the interactions between 43 and modelled α-glucosidase. The yellow dashed lines represent hydrogen bonds and the red dashed lines represented π–π interactions.

Figure 4. The predicted binding mode of acarbose (A), 34 (B), 41 (C) and 40 (D) in the active site pocket. The yellow dashed lines represented hydrogen bonds and the red dashed lines represented π–π interactions.