Nicotinic Acid Derivatives As Novel Noncompetitive α-Amylase and α-Glucosidase Inhibitors for Type 2 Diabetes Treatment

A library of novel nicotinic acid derivatives, focusing on the modification of position 6 of the pyridine ring with (thio)ether functionalities, was mostly produced through an innovative green synthetic approach (Cyrene-based) and evaluated for their alpha-amylase and alpha-glucosidase inhibitory activity. Compounds 8 and 44 demonstrated micromolar inhibition against alpha-amylase (IC50 of 20.5 and 58.1 mu M, respectively), with 44 exhibiting a remarkable similar to 72% enzyme inactivation level, surpassing the efficacy of the control compound, acarbose. Conversely, 35 and 39 exhibited comparable inhibition values to acarbose against alpha-glucosidase (IC50 of 32.9 and 26.4 mu M, respectively) and a significant enhancement in enzyme inhibition at saturation (similar to 80-90%). Mechanistic studies revealed that the most promising compounds operated through a noncompetitive inhibition mechanism for both alpha-amylase and alpha-glucosidase, offering advantages for function regulation over competitive inhibitors. These inhibitors may open a new perspective for the development of improved hypoglycemic agents for type 2 diabetes treatment.