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

Background: Pyrano[3,2-c]quinoline derivatives 6a-n were synthesized via simple two-step reactions and evaluated for their in vitro alpha-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- alpha-glucosidase activity and kinetic study of the synthesized compounds were evaluated using alpha-glucosidase from Saccharomyces cerevisiae and p-nitrophenyl-a-D-glucopyranoside as substrate. The alpha-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 alpha-glucosidase inhibitory activity (IC50 = 63.7 +/- 0.5 mu M). Kinetic study of enzyme inhibition indicated that the most potent compound, 6e, is a non-competitive inhibitor of alpha-glucosidase with a K-i value of 72 mu M. 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.