Gastalho_2024_Int.J.Mol.Sci_25_

Combining the pharmacological properties of the 1,2,3-triazole and dihydropyrimidinone classes of compounds, two small families of mono- and di(1,2,3-triazole)-dihydropyrimidinone hybrids, A and B, were previously synthesized. The main objective of this work was to investigate the potential anti-Alzheimer effects of these hybrids. The inhibitory activities of cholinesterases (AChE and BuChE), antioxidant activity, and the inhibitory mechanism through in silico (molecular docking) and in solution (STD-NMR) experiments were evaluated. The 1,2,3-triazole-dihydropyrimidinone hybrids (A and B) showed moderate in vitro inhibitory activity on eqBuChE (IC(50) values between 1 and 58.4 microM). The best inhibitor was the hybrid B4, featuring two 1,2,3-triazole cores, which exhibited stronger inhibition than galantamine, with an IC(50) of 1 +/- 0.1 microM for eqBuChE, through a mixed inhibition mechanism. Among the hybrids A, the most promising inhibitor was A1, exhibiting an IC(50) of 12 +/- 2 microM, similar to that of galantamine. Molecular docking and STD-NMR experiments revealed the key binding interactions of these promising inhibitors with BuChE. Hybrids A and B did not display Artemia salina toxicity below 100 microM.