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. 2022 Jun 23:10:928295.
doi: 10.3389/fchem.2022.928295. eCollection 2022.

Synthesis and Biological Evaluation of 5-Fluoro-2-Oxindole Derivatives as Potential α-Glucosidase Inhibitors

Jing Lin  1 , Qi-Ming Liang  1 , Yuan-Na Ye  1 , Di Xiao  1 , Li Lu  1 , Meng-Yue Li  1 , Jian-Ping Li  1 , Yu-Fei Zhang  1 , Zhuang Xiong  1 , Na Feng  1 , Chen Li  1
Affiliations

Synthesis and Biological Evaluation of 5-Fluoro-2-Oxindole Derivatives as Potential α-Glucosidase Inhibitors

Jing Lin et al. Front Chem. .

Abstract

α-Glucosidase inhibitors are known to prevent the digestion of carbohydrates and reduce the impact of carbohydrates on blood glucose. To develop novel α-glucosidase inhibitors, a series of 5-fluoro-2-oxindole derivatives (3a ∼ 3v) were synthesized, and their α-glucosidase inhibitory activities were investigated. Biological assessment results showed that most synthesized compounds presented potential inhibition on α-glucosidase. Among them, compounds 3d, 3f, and 3i exhibited much better inhibitory activity with IC50 values of 49.89 ± 1.16 μM, 35.83 ± 0.98 μM, and 56.87 ± 0.42 μM, respectively, which were about 10 ∼ 15 folds higher than acarbose (IC50 = 569.43 ± 43.72 μM). A kinetic mechanism study revealed that compounds 3d, 3f, and 3i inhibited the α-glucosidase in a reversible and mixed manner. Molecular docking was carried out to simulate the affinity between the compound and α-glucosidase.

Keywords: docking; inhibition; kinetics; oxindole; α-glucosidase.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

SCHEME 1
SCHEME 1
Synthetic route to 5-fluoro-2-oxindole derivatives (3a ∼ 3u). Reagents and conditions: 5-fluoro-2-oxindole (1.0 mmol, 1.0 equiv), substituted aldehydes (1.5 mmol, 1.5 equiv), KOH (6.0 mmol, 6.0 equiv), and EtOH, r. t., 3 h.
FIGURE 1
FIGURE 1
Inhibition mechanism determination of compound 3f on α-glucosidase.
FIGURE 2
FIGURE 2
(A) Lineweaver–Burk plots of compound 3f on α-glucosidase. (B) Plot of slope vs. the concentration of compound 3f for the calculation of the inhibition constant K I. (C) Plot of intercept vs. the concentration of compound 3f for the determination of the inhibition constant K IS.
FIGURE 3
FIGURE 3
(A) The insertion of compounds 3d, 3f, and 3i into the active pocket of α-glucosidase; (B) The hydrogen-bond interaction between carbonyl of the compounds (3d, 3f, and 3i) and α-glucosidase; (C) The lipophilic interaction between the compounds (3d, 3f, and 3i) and α-glucosidase; (D) The fluorophenyl as the lipophilic fraction of compounds 3d, 3f, and 3i binding to α-glucosidase.
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