GO/APTES-mediated bifunctional CuFe2O4@GO-NH2-facilitated synthesis of pyrazolo-triazepine scaffolds as a potent post-prandial antidiabetic agent against dual α-amylase and α-glucosidase enzymes

Abstract

Non-insulin-dependent diabetes mellitus (NIDDM) is a prevalent illness among individuals. This study elucidates the synthesis of pyrazolo-fused triazepine skeletons containing heterocycles and their assay-based in vitro and in silico antidiabetic activity against dual α-amylase and α-glucosidase enzymes followed by ab initio studies. The synthesis was assisted by acid-base bifunctional APTES-grafted magnetic nanocatalyst (CuFe₂O₄@GO-NH₂), using dibenzalacetone (1a–g) and hydrazine (2a–b) as precursors, followed by the addition of isoniazid (3). The obtained heterocyclic compounds (4a–n) were corroborated using spectroscopic techniques. The ab initio structural insights were computed at the B3LYP/6-311G++(d,p) level of theory to investigate the HOMO–LUMO energy gap, chemical reactivity and chemical potential of the synthesized compounds. Molecular docking using the CDOCKER (CHARMm-based DOCKER) algorithm revealed appreciable binding interaction modes between the active sites of the receptor (PDB ID: 2QV4 and 3W37) and heterocyclic ligands. Among all the synthesized compounds, 4,4'-(1-(2,4-dinitrophenyl)-8-hydroxy-8-(pyridin-4-yl)-2,3,5,6,7,8-hexahydro-1H-pyrazolo-[1,5-d][1,2,4]-triazepine-2,5-diyl)bis(2-methoxyphenol) (4d) (IC₅₀ = 123.79 µg mL⁻¹) exhibited superior antidiabetic activity against α-amylase compared with the existing drug acarbose (IC₅₀ = 171.8 µg mL⁻¹), which is in accordance with the in silico and DFT studies. ADMET, Lipinski's Rule and TOPKAT descriptor studies were performed to assess the remarkable biocompatibility and toxicity. Therefore, the synthesized heterocycles could emerge as potent antidiabetic drugs for first-line treatment in the near future.