Assessing the Potential of 1,2,3-Triazole-Dihydropyrimidinone Hybrids Against Cholinesterases: In Silico, In Vitro, and In Vivo Studies

• Published in: International journal of molecular sciences 2024-10, Vol.25 (20), p.11153
• Main Authors: Gastalho, Carlos M, Sena, Ana M, López, Óscar, Fernández-Bolaños, José G, García-Sosa, Alfonso T, Pereira, Florbela, Antunes, Célia M, Costa, Ana R, Burke, Anthony J, Carreiro, Elisabete P
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; Alzheimer's disease; Animals; Antifungal agents; Antioxidants - chemistry; Antioxidants - pharmacology; Biological activity; Butyrylcholinesterase - chemistry; Butyrylcholinesterase - metabolism; Cancer; Chemical properties; Cholinesterase inhibitors; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Computer Simulation; Drug therapy; Enzymes; Health aspects; Humans; Molecular Docking Simulation; Oxidative stress; Pharmaceutical chemistry; Pharmaceutical research; Physiological aspects; Pyrimidines; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Toxicity; Triazoles; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms252011153

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 values between 1 and 58.4 μM). The best inhibitor was the hybrid B4, featuring two 1,2,3-triazole cores, which exhibited stronger inhibition than galantamine, with an IC of 1 ± 0.1 μM for eqBuChE, through a mixed inhibition mechanism. Among the hybrids A, the most promising inhibitor was A1, exhibiting an IC of 12 ± 2 µM, 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 toxicity below 100 μM.