Synthesis of novel poly-hydroxyl functionalized acridine derivatives as inhibitors of α-Glucosidase and α-Amylase

• Novel poly-hydroxyl functionalized acridine derivatives (L1–L5) with ability for α-Gls inhibition was synthesized.
• Compared to Acarbose they weakly inhibit the activity of pancreatic α-Amy.
• The PFH variable group plays an important role in their enzyme inhibitory action.
• L5 with a chromeno[3′,4′:5,6]pyrido[2,3-d]pyrimidine moiety demonstrates the highest inhibitory activity.
• These synthetic compounds potentially offer an opportunity to develop new anti-diabetic drugs.

In this study a novel series of poly-hydroxyl functionalized acridine derivatives (L1–L9) was synthesized and their inhibitory activities against α-Glucosidase (α-Gls) and α-Amylase (α-Amy) were evaluated, spectroscopically. The synthetic compounds consist of three different substructures, including a 4-(4-aminophenoxy) phenyl group (R3), an acridine moiety (R2) and a poly-hydroxy chain (R1). The results indicate that among the synthetic compounds, L5 with a chromeno[3′,4′:5,6]pyrido[2,3-d]pyrimidine moiety demonstrates the highest inhibitory activity against both yeast and rat α-Gls enzymes. Also, L2 with the thioxo-pyrido[2,3-d:6,5-d′] dipyrimidine moiety plays an important role in the inhibition of yeast α-Gls. In addition, the results may suggest a significant role for the nature of sugar moiety of the synthetic compounds in their inhibitory action against α-Gls. Moreover, in comparison with Acarbose, which is a widely used anti-diabetic drug, these compounds show negligible inhibitory activity against pancreatic α-Amy, which is important in the term of their reduced susceptibility for possible development of the intestinal disturbance side effects. Results of this study may suggest these synthetic compounds as novel molecular templates for construction of potentially anti-diabetic drugs with the ability for more convenient management of postprandial hyperglycemia.

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