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 α-amylase and α-glucosidase inhibitory activity. Compounds <b>8</b> and <b>44</b> demonstrated micromolar inhibition against α-amylase (IC₅₀ of 20.5 and 58.1 μM, respectively), with <b>44</b> exhibiting a remarkable ∼72% enzyme inactivation level, surpassing the efficacy of the control compound, acarbose. Conversely, <b>35</b> and <b>39</b> exhibited comparable inhibition values to acarbose against α-glucosidase (IC₅₀ of 32.9 and 26.4 μM, respectively) and a significant enhancement in enzyme inhibition at saturation (∼80-90%). Mechanistic studies revealed that the most promising compounds operated through a noncompetitive inhibition mechanism for both α-amylase and α-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.