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

• Published in: Medicinal chemistry (Shp-sariqah, United Arab Emirates) Vol. 15; no. 1; p. 8
• Main Authors: Heydari, Zahra, Mohammadi-Khanaposhtani, Maryam, Imanparast, Somaye, Faramarzi, Mohammad A, Mahdavi, Mohammad, Ranjbar, Parviz R, Larijani, Bagher
• Format: Journal Article
• Language: English
• Published: Netherlands 01-01-2019
• Subjects: alpha-Glucosidases - chemistry; Cell Line, Tumor; Diabetes Mellitus, Type 2 - drug therapy; Enzyme Assays; Glucosides - chemistry; Glycoside Hydrolase Inhibitors - chemical synthesis; Glycoside Hydrolase Inhibitors - chemistry; Glycoside Hydrolase Inhibitors - toxicity; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - toxicity; Kinetics; Pyrans - chemical synthesis; Pyrans - chemistry; Pyrans - toxicity; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - toxicity; Saccharomyces cerevisiae - enzymology; kinetic study; type 2 diabetes; α-Glucosidase; xanthones; coumarin; pyrano[3,2-c]quinoline
• ISSN: 1875-6638
• DOI: 10.2174/1573406414666180528110104

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