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, 5a?5h, have been synthesized, characterized by 1 H-NMR and 13 C-NMR, and evaluated for their in vitro α-glucosidase and α-amylase inhibitory activities. All the synthesized compounds efficiently inhibited both enzymes. Compound 5g was the most potent derivative in the series, and powerfully inhibited both α-glucosidase and α-amylase. The IC 50 of 5g against α-glucosidase was 0.35917 ± 0.0189 µM (standard acarbose IC 50 = 6.109 ± 0.329 µM), and the IC 50 value of 5g against α-amylase was 0.4379 ± 0.0423 µM (standard acarbose IC 50 = 33.178 ± 2.392 µM). The Lineweaver-Burk plot indicated that compound 5g 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 5g interacts with the residues Trp690, Asp548, Arg425, and Glu426, which form hydrogen bonds to 5g with distances of 2.05, 2.20, 2.10 and 2.18 Å, respectively. All compounds showed high mutagenic and tumorigenic behaviors, and only 5e showed irritant properties. In addition, all the derivatives showed good antioxidant activities. The pharmacokinetic evaluation also revealed promising results.