Regioselective synthesis,biological evaluation,and molecular docking of dihydropyrimidin‐4‐ols as acetylcholinesterase inhibitors |
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Authors: | Andreia M P W da Silva Fabio M da Silva Pablo A Nogara Eduardo J M Dutra Jonas D S Serres Rogério A Saraiva Bruna C Piccoli Cláudia S Oliveira Maria R C Schetinger Vera M M Morsch João B T Rocha Helio G Bonacorso Marcos A P Martins Nilo Zanatta |
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Institution: | 1. Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, Brazil;2. Laboratório de Bioquímica Toxicológica, Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Santa Maria, Santa Maria, Brazil;3. Laboratório de Enzimologia Toxicológica, PPGBTOX, DBBM, Universidade Federal de Santa Maria, Santa Maria, Brazil;4. Grupo de Estudos em Bioquímica, Farmacologia e Toxicologia Molecular, Unidade Acadêmica de Serra Talhada, Universidade Federal Rural de Pernambuco, Serra Talhada, Brazil |
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Abstract: | 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. |
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Keywords: | acetylcholinesterase inhibitors molecular docking pyrimidines tetrahydropyrimidines |
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