Design, Synthesis and Bioassays of 3-substituted-3-hydroxyoxindoles for cholinesterase inhibition

Based on the positive bioassay results of the known oxindole hit compound rac-1-benzyl-3-hydroxy-3-phenylindolin-2-one which showed significant inhibition of butyrylcholinesterase (BuChE) (IC50=7.41 μM), a library of 31 analogues of 3-substituted-3-hydroxyoxindoles was synthesized and screened for both acetylcholinesterase (AChE) and BuChE activity. Our bioassays revealed that some of the new compounds exhibited moderate inhibition of eel AChE (EeAChE) and very good inhibition of equine serum BuChE (EqBuChE) with a best IC50 of 1.02 μM. On the basis of these results, the lead compound 1-((1-benzylpiperidin-4-yl)methyl)-3-hydroxy-3-phenylindolin-2-one was designed, which was shown to interact well with the enzymes active sites by molecular docking, was synthesized and upon bioassay gave an IC50 of 6.61 μM for BuChE. Interestingly, when we separated rac-benzyl-3-hydroxy-3-phenylindolin-2-one into the individual enantiomers (R)- and (S)-benzyl-3-hydroxy-3-phenylindolin-2-one it was the latter enantiomer that gave the best IC50 of 6.19 μM for BuChE.

New cholinesterase inhibitors for Alzheimer's disease: Structure Activity Studies (SARs) and molecular docking of isoquinolone and azepanone derivatives

A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE (EeAChE) and equine serum BuChE (EqBuChE) in order to determine the compounds IC50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC50 of 89.5 mu M for EeAChE and 153.8 mu M for EqBuChE, (2a) was identified as a second hit with an IC50 of 108.4 mu M (EeAChE) and 277.8 mu M (EqBuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, (R)-(1f) along with 3 other analogues (also as the R-enantiomer) were docked into both RhAChE and hBuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark.

Hovenia dulcis (uva-do-japão) no sul do Brasil: invasão, cultura e alteração da paisagem.

Resumo: Em virtude dos impactos ambientais causados, as espécies exóticas invasoras (EEl's) tem se tornado foco de muitos estudos nas Ciências Biológicas. Entretanto, muitas EEl's tem a sua presença não evitada em novos ambientes, pois o homem e, muitas vezes, o principal vetor de dispersão, especial mente de espécies de plantas invasoras. Neste trabalho, e discutida a hipótese de uma forte influencia cultural na introdução/expansão da uva-do-Japão nesta região e o problemático cenário de invasão da espécie no sul do Brasil. Palavras-chave: espécies exóticas invasoras (EEl's); alteração da paisagem; Hovenia dulcis (uva-do-japão); cultura. Abstract: Invasive species (IS) have become focus on many studies in Biological Sciences because of environmental damages. However, the presence of lAS's is not prevented in new areas, because humans are often the main vector of dispersion, especially invasive plant species. In this work, the hypothesis of a strong cultural influence is discussed on the introduction/expansion of Japanese raisin tree in this region and the problematic scenario of invasion in southern Brazil. Keywords: invasive species (IS's); landscape changes; Hovenia dulcis ; (Japanese raisin tree); culture.