Newly synthesized 1,2,3-triazoles based on 1,4-benzoxazin- 3-one: In silico evaluation of anti-inflammatory, antibacterial, antioxidant, anticancer, and antidiabetic properties, along with molecular dynamics simulation and ADME analysis

Abstract Based on the significant biological activity of benzoxazines and 1,2,3-triazoles, we aim to combine these active moieties to design and synthesize new compounds and evaluate their biological activity. In this context, we present the synthesis of new 1,2,3-triazoles, specifically 1,4-disubstituted, in combination with 1,4-benzoxazin-3-one. To synthesize the target compounds, the 1,3-dipolar Huisgen cycloaddition is used as a central step. This reaction occurs between ethyl azidoacetate and the terminal alkyne of 1,4-benzoxazin-3-one under catalytic conditions using Cu(I) (CuAAC). Followed by the condensation of hydrazine on the ester function and then a reaction with various aromatic aldehydes to form the corresponding hydrazones (4a–4j). Molecular docking revealed that the synthesis molecules exhibited potential antidiabetic, anti-inflammatory, anticancer, antibacterial, and antioxidant properties. Among them, 4a showed the highest affinity for these activities and 4b showed the highest affinity for antioxidant activity. To further evaluate its potential, 4a and 4b underwent molecular dynamics (MD) simulations over a 5 ns period. The stability and flexibility of the 4a-3W2S and 4b-3DK9 complex were evaluated using RMSF, RMSD, H-Bond, and Rg analyses, revealing notable interaction stability and flexibility. In addition, ADME analysis demonstrated favorable pharmacokinetic properties and oral absorption of the synthetic molecules, meeting the Lipinski and Veber criteria and suggesting their potential as oral drug candidates. This comprehensive assessment highlights the value of these novels 1,4-benzoxazin-3-one derivatives and supports further research exploring their therapeutic potential.