Assessing the Potential of 1,2,3-Triazole-Dihydropyrimidinone Hybrids Against Cholinesterases

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.

http://hdl.handle.net/10362/179689

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Autores

Gastalho, Carlos M.

Sena, Ana M.

López, Óscar

Fernández-Bolaños, José G.

García-Sosa, Alfonso T.

Carreiro, Elisabete P.

Resumo(s)

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 (IC50 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 IC50 of 1 ± 0.1 μM for eqBuChE, through a mixed inhibition mechanism. Among the hybrids A, the most promising inhibitor was A1, exhibiting an IC50 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 Artemia salina toxicity below 100 μM.

Descrição

A.T.G.-S. thanks the Estonian Research Council (grant PRG1509) for financing. O.L. and J.G.F.B. thanks the Grant PID2020-116460RB-I00 funded by MCIN/AEI/10.13039/501100011033. C.M.A. and A.R.C. thank FCT for funding through the strategic projects to ICT (projects UIBD/04683/2020 and UIDP/04683/2020). F.P. gratefully acknowledges FCT, I.P., for an Assistant Research Position (CEECIND/01649/2021). © 2024 by the authors. Licensee MDPI, Basel, Switzerland.

Palavras-chave

1,2,3-triazole antioxidant activity cholinesterases dihydropyrimidinone docking STD-NMR Catalysis Molecular Biology Spectroscopy Computer Science Applications Physical and Theoretical Chemistry Organic Chemistry Inorganic Chemistry