Design, synthesis, in silico docking studies and biological evaluation of novel quinoxaline-hydrazide hydrazone-1,2,3-triazole hybrids as α-glucosidase inhibitors and antioxidants

Abstract

A new series of quinoxaline-hydrazidehydrazone-1,2,3-triazole hybrids, 14a–j, 15a–j and 16a–e, was designed, synthesized and screened for in vitro α-glucosidase and antioxidant activities. For the synthesis of the target compounds, quinoxaline hydrazides were condensed with benzaldehyde triazoles in the presence of AcOH (cat) in ethanol. The key step in the preparation of compounds 8a–j was the Cu(I)-catalyzed [3+2] cycloaddition reaction (CuAAC) with appropriate alkynes (6, 7) and azides, and 13a–j were prepared from simple aldehydes utilizing the same click reaction as the final step. Quinoxaline hydrazides (3, 3a) were synthesized from o-phenylenediamine and pyruvic acid via three-step reactions comprising cyclization, alkylation and hydrazidation. Among these hybrids, 14a (IC₅₀ = 21.92 μg mL⁻¹), 14b (IC₅₀ = 22.32 μg mL⁻¹), 14c (IC₅₀ = 23.58 μg mL⁻¹) and 15a (IC₅₀ = 24.50 μg mL⁻¹) showed good α-glucosidase inhibition compared with the standard acarbose (IC₅₀ = 22.32 μg mL⁻¹). Further, the scavenging abilities of the synthesized compounds as antioxidants were studied using the DPPH, H₂O₂, and NO methods; as per the obtained results, compounds 14a, 14b, 14c and 15a displayed good antioxidant activity. Docking studies of the active compounds and acarbose as a standard with α-glucosidase (PDB ID: 2ZEO) were performed to determine the molecular interactions between the inhibitors and the active site of the enzyme. Better binding energies of the active compounds than of the standard acarbose were observed. Therefore, our new hybrid molecules may be useful for further optimization in developing new lead molecules with both α-glucosidase inhibition and antioxidant activities.