Ana Paula Murray

Natural AChE Inhibitors from Plants and their Contribution to Alzheimer's Disease Therapy.

As acetylcholinesterase (AChE) inhibitors are an important therapeutic strategy in Alzheimer’s disease, efforts are being made in search of new molecules with anti-AChE activity. The fact that naturally-occurring compounds from plants are considered to be a potential source of new inhibitors has led to the discovery of an important number of secondary metabolites and plant extracts with the ability of inhibiting the enzyme AChE, which, according to the cholinergic hypothesis, increases the levels of the neurotransmitter acetylcholine in the brain, thus improving cholinergic functions in patients with Alzheimer’s disease and alleviating the symptoms of this neurological disorder. This review summarizes a total of 128 studies which correspond to the most relevant research work published during 2006-2012 (1st semester) on plant-derived compounds, plant extracts and essential oils found to elicit AChE inhibition.

Triterpenoids with acetylcholinesterase inhibition from Chuquiraga erinacea D. Don. subsp. erinacea (Asteraceae).

A bioactivity-guided approach was taken to identify the acetylcholinesterase (AChE) inhibitory agents in the ethanolic extract of Chuquiraga erinacea D. Don. subsp. erinacea leaves using a bioautographic method. This permitted the isolation of the pentacyclic triterpenes calenduladiol (1), faradiol (2), heliantriol B2 (3), lupeol (4), and a mixture of alpha-and beta-amyrin ( 5A and 5B) as active constituents. Pseudotaraxasterol (6) and taraxasterol (7) were also isolated from this extract and showed no activity at the same analytical conditions. Compound 1 showed the highest AChE inhibitory activity with 31.2 % of inhibition at 0.5 mM. Looking forward to improve the water solubility of the active compounds, the sodium sulfate ester of 1 was prepared by reaction with the (CH3)3N.SO3 complex. The semisynthetic derivative disodium calenduladiol disulfate (8) elicited higher AChE inhibition than 1 with 94.1 % of inhibition at 0.5 mM (IC (50) = 0.190 +/- 0.003 mM). Compounds 1, 2, 3, 5, 6, and 7 are reported here for the first time in C. erinacea. This is the first report of AChE inhibition from calenduladiol (1) as well as from a sulfate derived from a natural product.

Synthesis of 3,16,30-trioxolup-20(29)-ene, a selective butyrylcholinesterase inhibitor, from a natural triterpene

According to the cholinergic hypothesis, the inhibition of cholinesterase increases the levels of acetylcholine in the brain, thus improving cholinergic functions in Alzheimer´s Disease (AD) patients. Butyrylcholinesterase (BChE), is one of the enzymes involved in the metabolic degradation of acetylcholine, together with acetylcholinesterase (AChE). BChE activity increases as AD progresses, which suggests that BChE may play an important role at the latter stages of AD. Therefore, selective BChE inhibitors attract interest nowadays.Lup-20(29)-ene-3β,16β-diol (calenduladiol, 1), is a pentacyclic lupane-type triterpene with the interesting feature of being hydroxylated at C-16. Continuing our previous work on semisynthesis of derivatives obtained from the natural triterpene calenduladiol and their evaluation as potential cholinesterase inhibitors, we report here the synthesis of six new lupanes (3-8). These compounds have been obtained by sequential oxidations and reaction with NH2OH of the starting compounds, the natural calenduladiol (1) and its analog 30-oxocalenduladiol (2), previously obtained by allylic oxidation with Se2O. Their structures were confirmed by analysis of their 1H and 13C NMR and ESI-MS spectra. The complete assignation of the signals was achieved with the aid of 2D NMR experiments (COSY, HSQC, HMBC, NOESY). All of the new derivatives were evaluated as potential in vitro BChE inhibitors by the Ellman´s colorimetric method. In order to determine the BChE/AChE selectivity of compounds 3-8, their antiAChE activity was evaluated. All of them failed to inhibit AChE, but we found that the best BChE inhibition was observed for 3,16,30-trioxolup-20(29)-ene (4) with an IC50 value of 21.5 μM, which elicited a selective inhibitor profile

Essential oil from fruits and leaves of Schinus areira L. with acetylcholinesterase inhibitory activity

Currently available drugs for the symptomatic treatment of Alzheimers disease (AD) are based on the inhibition of the enzyme acetylcholinesterase (AChE). Recently, essential oils as well as terpenoids have been shown to inhibit AChE in in vitro assays [1], [2]. In the present communication we are reporting the evaluation of the essential oils from fruits and leaves of Schinus areira L (Anacardiaceae), extensively used in folk medicine in South America [3], for their activity towards AChE. The enzymatic activity was evaluated using an adaptation of a previously described method [4]. The composition of the essential oils was determined by GC and GC-MS [5]. The essential oil from fruits showed a 29.00±4.84% AChE inhibition while the essential oil from leaves showed a 13.67±0.67% AChE inhibition under the same conditions (0.1μL/mL). Chromatographic fractionation of the essential oils guided by the bioassay led to the isolation of the active fractions. GC-MS analysis of those fractions revealed the presence of sesquiterpenes like β-eudesmol and elemol, which have been reported as compounds that may have potential therapeutic use against amnesia-inducing diseases like AD [6], [7].