Synthesis of sulfonamide chalcones as α-glucosidase inhibitors

Abstract

Diabetes mellitus occurs from deficiencies in insulin secretion or insulin resistance which leads over time to high risk for long-term macro-and microvascular complications. Diabetes mellitus type 2 contributes to more than 90% of all cases worldwide. One approach of treatment for this disorder is utilizing α-glucosidase inhibitors. Certain sulfonamides and chalcones are considered as viable candidates that are effective in reducing hyperglycemia. Forty-seven sulfonamide chalcones were synthesized by the Claisen-Schmidt reaction with various substituents on the A, B, and C-rings furnishing the desired products with 50-95 %yield. All compounds were-tested for α-glucosidase inhibitory activity. Twenty-nine compounds exhibited a very strong inhibitory activity with IC50 below 10 µM, eleven with strong activity (IC50 10-49.9 µM), eight with moderate activity (IC50 50-99.9 µM), five with weak activity (IC50 100-199.9 µM), and two not active (IC50 >200 µM). The sulfonamide chalcones bearing p-NHR on the A-ring (62) strongly influenced α-glucosidase inhibition, as well as 3-methoxy (65) on the B-ring. The alkyl substituents (67-72) on the B-ring gave a very strong inhibitory activity and followed by the halogen substituents (73-75). Surprisingly, 63 without any substituent also displayed a very strong inhibitory activity with IC50 0.07±0.01 µM. Moreover, disubstituents on the B-ring such as 3-hydroxy-4-methoxy (86) revealed superior activity with IC50 0.12±0.01 µM. In general, the substituent on the C-ring gave a significant increment of the α-glucosidase inhibitory activity. The 4-methoxy substituent (94) increased the activity by 783 times more than the unsubstituent one (92). Comparing with sulfonamide acetophenones, the sulfonamide chalcones increased the activity by the value of 4-38 times. From Lineweaver-Burk plot for 62 and 86, the inhibition type was disclosed to be uncompetitive while those for 63 and 94 were non-competitive and mixed-mode inhibitors, respectively.