Synthesis and biological evaluation of 3-arylcoumarin derivatives as potential anti-diabetic agents

Abstract

A variety of substituted 3-arylcoumarin derivatives were synthesised through microwave radiation heating. The method has characteristics of environmental friendliness, economy, simple separation, and purification process, less by-products and high reaction yield. Those 3-arylcoumarin derivatives were screened for antioxidant, α-glucosidase inhibitory and advanced glycation end-products (AGEs) formation inhibitory. Most compounds exhibited significant antioxidant and AGEs formation inhibitory activities. Anti-diabetic activity studies showed that compounds 11 and 17 were equipotent to the standard drug glibenclamide in vivo. According to the experimental results, the target compound 35 can be used as a lead compound for the development of new anti-diabetic drugs. The whole experiment showed that anti-diabetic activity is prevalent in 3-arylcoumarins, which added a new natural skeleton to the development of anti-diabetic active drugs.

Keywords: 3-Arylcoumarin; AGEs inhibitor; antidiabetic; α-glucosidase inhibitor.

Scheme 1.

Umbelliferone is derivatised as 3-arylcoumarin and 4-arylcoumarin. They have inhibitory activity on α-glucosidase inhibitory activity and AGEs formation inhibitory activity.

Scheme 2.

General synthetic route to 3-arylcoumarin derivatives. (a) sulfur, p-toluene sulfonic acid, morpholine, 120 °C; (b) NaOH (aq), Tetrabutylammonium bromide, 100 °C; (c) Acetic anhydride, Et₃N, 112 °C; HCl.

Scheme 3.

The main synthesis step of 4-arylcoumarin derivatives. (d) montmorillonite K-10, nitrobenzene, 100 °C; (e) I₂, Al, acetonitrile.

Figure 1.

Long-term effect of the compounds 11, 17 and 35 on blood glucose levels in STZ-diabetic mice. Each value is the mean ± SEM for six mice in each group. *p < 0.05 significantly different ANOVA followed by Dunnett’s t-test for comparison with the diabetic control group at same time.

Figure 2.

Body weight changes of daily treatment with compounds 11, 17 and 35 in STZ-induced diabetic mice. Each value is the mean ± SEM for six mice in each group. *p < 0.05 significantly different ANOVA followed by Dunnett’s t-test vs. the diabetic control group at same time.

Figure 3.

Oral glucose tolerance test of compounds 11, 17, and 35 on in STZ-induced diabetic mice. Each value is the mean ± SEM for six mice in each group. *p < 0.05 significantly different ANOVA followed by Dunnett’s t-test vs. the diabetic control group at same time.