Novel C-2 Symmetric Molecules as α-Glucosidase and α-Amylase Inhibitors: Design, Synthesis, Kinetic Evaluation, Molecular Docking and Pharmacokinetics

Abstract

A series of symmetrical salicylaldehyde-bishydrazine azo molecules, <b>5a</b>-<b>5h</b>, have been synthesized, characterized by ¹H-NMR and ¹³C-NMR, and evaluated for their in vitro α-glucosidase and α-amylase inhibitory activities. All the synthesized compounds efficiently inhibited both enzymes. Compound <b>5g</b> was the most potent derivative in the series, and powerfully inhibited both α-glucosidase and α-amylase. The IC₅₀ of <b>5g</b> against α-glucosidase was 0.35917 ± 0.0189 µM (standard acarbose IC₅₀ = 6.109 ± 0.329 µM), and the IC₅₀ value of <b>5g</b> against α-amylase was 0.4379 ± 0.0423 µM (standard acarbose IC₅₀ = 33.178 ± 2.392 µM). The Lineweaver-Burk plot indicated that compound <b>5g</b> is a competitive inhibitor of α-glucosidase. The binding interactions of the most active analogues were confirmed through molecular docking studies. Docking studies showed that <b>5g</b> interacts with the residues Trp690, Asp548, Arg425, and Glu426, which form hydrogen bonds to <b>5g</b> with distances of 2.05, 2.20, 2.10 and 2.18 Å, respectively. All compounds showed high mutagenic and tumorigenic behaviors, and only <b>5e</b> showed irritant properties. In addition, all the derivatives showed good antioxidant activities. The pharmacokinetic evaluation also revealed promising results.