Antoniolli_2026_Biochimie__

A novel series of 6,7-dimethoxyquinazoline-hydrazide hybrids 1-4 were designed, synthesized, and tested for their AChE inhibition activity using the qualitative assay, which showed that compounds 3 and 4 exhibited their activity via TLC. The compounds were characterized using HRMS, IR, (1)H NMR, and (13)C NMR spectroscopy. Further in vitro AChE and BACE-1 inhibition activities of both derivatives (3 and 4) revealed that compound 3 exhibited outstanding inhibitory activity against AChE, with IC(50) of 299 nM, in comparison to the reference standard, rivastigmine (IC(50) of 439 nM). Moreover, the same derivative showed inhibitory activity against BACE-1 with IC(50) of 1.989 microM, superior to the standard control, quercetin (IC(50) of 4.55 microM). Molecular dynamics simulations confirmed the stability of the AChE- and BACE-1-compound 3 complexes, with both systems reaching equilibrium within the first 25 ns and maintaining low RMSD values thereafter. Post-equilibration analyses revealed stable binding modes supported by key hydrogen bonds and hydrophobic interactions within the active sites. These findings highlight compound 3's strong affinity and specificity toward both targets, supporting its potential as a dual inhibitor.