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Medicinal Chemistry

Author(s): Zahra Heydari, Maryam Mohammadi-Khanaposhtani, Somaye Imanparast, Mohammad A. Faramarzi, Mohammad Mahdavi *, Parviz R. Ranjbar* and Bagher Larijani

DOI: 10.2174/1573406414666180528110104

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Pyrano[3,2-c]quinoline Derivatives as New Class of α-glucosidase Inhibitors to Treat Type 2 Diabetes: Synthesis, in vitro Biological Evaluation and Kinetic Study

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Abstract

Background: Pyrano[3,2-c]quinoline derivatives 6a–n were synthesized via simple two-step reactions and evaluated for their in vitro α-glucosidase inhibitory activity.

Methods: Pyrano[3,2-c]quinoline derivatives 6a–n derivatives were prepared from a two-step reaction: cycloaddition reaction between 1-naphthyl amine 1 and malonic acid 2 to obtain benzo[h]quinoline-2(1H)-one 3 and reaction of 3 with aryl aldehydes 4 and Meldrum’s acid 5. The anti- α-glucosidase activity and kinetic study of the synthesized compounds were evaluated using α-glucosidase from Saccharomyces cerevisiae and p-nitrophenyl-a-D-glucopyranoside as substrate. The α-glucosidase inhibitory activity of acarbose was evaluated as positive control.

Results: All of the synthesized compounds, except compounds 6i and 6n, showed more inhibitory activity than the standard drug acarbose and were also found to be non-cytotoxic. Among the synthesized compounds, 1-(2-bromophenyl)-1H-benzo[h]pyrano[3,2-c]quinoline-3,12(2H,11H)-dione 6e displayed the highest α-glucosidase inhibitory activity (IC50 = 63.7 ± 0.5 µM). Kinetic study of enzyme inhibition indicated that the most potent compound, 6e, is a non-competitive inhibitor of α-glucosidase with a Ki value of 72 µM. Additionally, based on the Lipinski rule of 5, the synthesized compounds were found to be potential orally active drugs.

Conclusion: Our results suggest that the synthesized compounds are promising candidates for treating type 2 diabetes.

Keywords: α-Glucosidase, type 2 diabetes, kinetic study, pyrano[3, 2-c]quinoline, coumarin, xanthones.

Graphical Abstract

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