Synthesis, C-N/N-N bond conformational analysis and evaluation of naphtho[2,3-d][1,2,3]triazole-4,9-dione tethered N-acyl hydrazones as α-amylase inhibitors: Insights from molecular modeling and ADMET analysis

Abstract

In an effort to expand the repertoire of potent α-amylase inhibitors, we sought to develop novel inhibitors by combining 1,4-naphthoquinone, 1,2,3-triazole, and N-acyl hydrazone scaffolds in a single matrix. To achieve this, twelve novel naphtho[2,3-d][1,2,3]triazole-4,9‑dione tethered N-acyl hydrazones were synthesized through condensation reaction of 2-(4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-1-yl)acetohydrazide with various substituted aryl aldehydes. Structural elucidation for all the compounds was performed using 1D, 2D-NMR, FTIR, and mass spectral analyses. The synthesized molecules were evaluated for their ability to inhibit α-amylase activity using acarbose as the standard drug. All the derivatives exhibited potent inhibition of α-amylase, with IC50 values ranging between 17.26 ± 0.07 to 25.62 ± 0.03 μg/mL. Notably, compound 9c possessing –meta substituted –NO2 group displayed the highest activity (IC50 = 17.26 ± 0.07 μg/mL) among the series. Structure-activity relationship (SAR) revealed the pivotal role of aryl ring substitutions in determining inhibitory efficacy. To validate these findings and to assess the binding stability of 9c within the catalytic site α-amylase dervied for A. oryzae (PDB ID:7TAA), in silico studies were performed. The compound 9c effectively occupies the enzyme's active pocket, with minimal RMSD fluctuations observed over 100 ns simulation, indicating stable protein-ligand complex. ADMET predictions suggested favorable drug-like properties, underscoring the potential of these compounds as novel α-amylase inhibitors for managing type 2 diabetes mellitus