3 years ago

Regioselective synthesis, biological evaluation, and molecular docking of dihydropyrimidin-4-ols as acetylcholinesterase inhibitors

Regioselective synthesis, biological evaluation, and molecular docking of dihydropyrimidin-4-ols as acetylcholinesterase inhibitors
Andreia M. P. W. Silva, Cláudia S. Oliveira, Rogério A. Saraiva, Eduardo J. M. Dutra, Fabio M. Silva, João B. T. Rocha, Vera M. M. Morsch, Jonas D. S. Serres, Marcos A. P. Martins, Maria R. C. Schetinger, Nilo Zanatta, Helio G. Bonacorso, Bruna C. Piccoli, Pablo A. Nogara
A new series of 3,6-disubstituted 2-(methylthio)-4-(trifluoromethyl)-3,4-dihydropyrimidin-4-ols displaying methyl, phenyl, aryl, and heteroaryl groups at the 6-position; and methyl, ethyl, allyl, and phenyl groups at the 3-position of the dihydropyrimidine ring, were synthesized and evaluated in vitro for acetylcholinesterase inhibitory activity. Seven compounds showed activity with IC50 values in the lower micromolar range. The compound 4-trifluoromethyl-6-(4-fluorophenyl)-3-methyl-2-methylthio-3,4-dihydropyrimidin-4-ol (6e) had the best inhibitory activity (IC50 2.2 ± 0.9 μm) and this inhibition was characterized as competitive. The molecular docking study showed that the acetylcholinesterase enzyme accommodates compound 6e in its catalytic site. The enantiomers of compound 6e, present similar interactions: π–π stacking interactions between the aromatic ring of the ligand's 4-fluorophenyl moiety and the aromatic rings of the electron-rich Trp84; and H-bonds between the hydroxyl group of Tyr121 and the hydroxyl moiety from 6e. The antioxidant effect of the dihydropyrimidin-4-ols was also investigated. A series of 3,6-disubstituted 2-(methylthio)-4-(trifluoromethyl)-3,4-dihydropyrimidin-4-ols derivatives were synthesized and screened for acetylcholinesterase (AChE) inhibition. Many of the new compounds were capable to inhibit the AChE, among them, compound 6e was identified to be the most potent (IC50 = 2.2 ± 0.9 µm, in vitro), and its inhibition was characterized as competitive. The molecular docking study showed that the compound 6e accommodates in the catalytic site of AChE enzyme. In addition, some dihydropyrimidin-4-ols exhibited significant antioxidant effect.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.13036

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