Search

Introduction Verbascum betonicifolium (V. betonicifolium) is a plant used in traditional medicine for several ailments. The objective of this study was to determine the antioxidant activity and acetylcholinesterase inhibitory activity of the aqueous extract together with the metabolites responsible for these activities. This paper presents the first phytochemical characterization and bioactivities of aqueous extracts from aerial parts. Methods The compounds present in the aerial part aqueous extract were identified by high performance liquid chromatography, coupled to a diode-array detector (HPLC-DAD) and by high-resolution mass spectrometry (HRMS), using LC–MS/MS analyses. Antioxidant activity was measured as the capacity to scavenge the free radical DPPH and the AChE activity was determined using the Ellman test. The cytotoxicity was determined used HepG2 cell lines. Results Several types of metabolites were found, primary metabolites (malic, citric and gluconic acids), phenolic compounds (verbascoside, luteolin), terpenoids (iridoid glycoside, unedide), among others. The total phenol content of 28 μg of gallic acid equivalents/mg of extract was determined. The aqueous extract antioxidant activity had and EC50 of 70 μg/mL and the AChE inhibitory activity an IC50 of 750 μg/mL. No cytotoxicity towards HepG2 cells was detected, even using a concentration of 1 mg/mL. Conclusions The phenolic compounds present in the extract may be the main contributors to the bioactivities of V. betonicifolium. These results show for the first time the richness of phytochemicals and the strong bioactivities of V. betonicifolium and that the aqueous extract could be used as new natural sources of bioactive molecules.

From a screening study of various potential inhibitors for cholinesterases (ChEs), compound (rac)-1 (4-((3-hydroxy-2-oxo-3-phenylindolin-1-yl) methyl) piperidin-1-ium chloride) showed an IC50 of 18 μM for butyrylcholinesterase (BuChE). Herein we present a toxicological and pharmacological evaluation of (rac)-1 to determine its potential for use as an alternative ChE inhibitor for the treatment of Alzheimer’s disease. The strategy adopted included in vivo and ex vivo studies with mouse models, Molecular Modelling and Saturation Transfer Difference (STD) NMR studies. Preliminary molecular docking studies were conducted with both (R) and (S)-1 with acetylcholinesterase (AChE) and BuChE, prior to advancing to the mouse model, and indeed favorable interactions were observed, with (R)-1 showing the best binding with AChE and (S)-1 with BuChE. STD-NMR studies were used to successfully validate these results. Toxicological studies were also conducted using the Artemia salina model, with donepezil as reference. It was found that in the in vivo mouse studies that (rac)-1 presented a slightly better inhibition of AChE (0.096 µmol.min−1.mg−1) than donepezil (0.112 µmol.min−1.mg−1) and the same level of inhibition for BuChE as donepezil (0.014 µmol.min−1.mg−1).

© 2014 Elsevier Masson SAS. All rights reserved., A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforward aldol condensation reactions of benzofuranones and the appropriately substituted benzaldehydes. Microwave enhanced synthesis using palladium catalyzed protocols was introduced as a powerful strategy for extending the chemical space around the aurone scaffold. Additionally, Mannich-base derivatives, containing a 7-aminomethyl-6-hydroxy substitution pattern at ring A, were also prepared. Screening against the chloroquine resistant Plasmodium falciparum W2 strain identified novel aurones with IC50 values in the low micromolar range. The most potent compounds contained a basic moiety, with the ability to accumulate in acidic digestive vacuole of the malaria parasite. However, none of those aurones revealed significant activity against hemozoin formation and falcipain-2, two validated targets expressed during the blood stage of P. falciparum infection and functional in digestive vacuole of the parasite. Overall, this study highlight (i) the usefulness of aurones as platforms for synthetic procedures using palladium catalyzed protocols to rapidly deliver lead compounds for further optimization and (ii) the potential of novel aurone derivatives as promising antimalarial compounds., This work was supported by Fundação para a Ciência e Tecnologia (FCT, Portugal) through projects PTDC/SAU-FAR/118459/2010 and Pest-OE/SAL/UI4013/2011. A.S.N. and M.P.C. acknowledge FCT for grants SFRH/BD/41276/2007 and SFRH/BD/61611/2009, respectively. P.J.R. is a Doris Duke Charitable Foundation Distinguished Clinical Scientist.

The design, synthesis and evaluation of 3-methylene-substituted indolinones as falcipain inhibitors and antiplasmodial agents are described. These compounds react readily with thiols via an addition-elimination mechanism, indicating their potential as cysteine protease inhibitors. Several indolinones containing a Leu-i-amyl recognition moiety were found to be moderate inhibitors of the Plasmodium falciparum cysteine protease falcipain-2, but not of the related protease falcipain-3, and displayed antiplasmodial activity against the chloroquine-resistant P. falciparum W2 strain in the low micromolar range. Coupling a 7-chloroquinoline moiety to the 3-methylene-substituted indolinone scaffold led to a significant improvement in antiplasmodial activity.

The first structure-activity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for two downstream caspases (caspases-3 and -7). Dipeptidyl derivatives were significantly superior to their counterparts containing only Asp at P(1), as caspase-3 inhibitors. Fmoc-Val-Asp-trans-CH=CH-SO(2)Me was the most potent inhibitor of caspase-3 in the series, with a IC(50) of 29 microM and a second-order rate constant of inactivation, k(inact)/K(i), of 1.5 M(-1) s(-1). Computational studies suggest that the second amino acid occupies position S(3) of the enzyme. In addition, Fmoc-Val-Asp-trans-CH=CH-SO(2)Ph was inactive for caspase-7 for the tested concentrations.