Molecular Docking and Molecular Dynamic Studies of Semi-Synthetic Piperidine Alkaloids as Acetylcholinesterase Inhibitors

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Antinociceptive profile of 2,3,6-trisubstituted piperidine alkaloids: 3-O-acetyl-spectaline and semi-synthetic derivatives of (-)-spectaline

In early studies, we have reported the antinociceptive profile of (-)-spectaline, a piperidine alkaloid from Cassia spectabilis. The present study describes the synthesis, the antinociceptive and anti-inflammatory activities of a series of 2,3,6-trialkyl-piperidine alkaloids: the natural (-)-3-O-acetyl-spectaline (LASSBio-755) and ten semi-synthetic spectaline derivatives. Structure-activity relationship (SARs) studies were performed. The structures of all synthesized derivatives were confirmed by means of nuclear magnetic resonance. Compounds were evaluated for their analgesic (acetic acid-induced mouse abdominal constrictions, hot-plate test, formalin-induced pain test) and some of them for the anti-inflammatory activities (carrageenan-induced rat paw edema test). The pharmacological results showed that several of the new compounds given orally at a dose of 100 mu mol/kg significantly inhibited the acetic acid-induced abdominal constrictions, but they were less active than (-)-spectaline. LASSBio-755 and LASSBio-776 were the most actives with 37% and 31.7% of inhibition. In the formalin-induced pain only LASSBio-776 was able to inhibit by 34.4% the paw licking response of the inflammatory phase, (-)-spectaline and LASSBio-755 did show any activity. In the carrageenan-induced rat paw edema, only (-)-spectaline exhibited an anti-inflammatory profile, showing an ED(50) value of 56.6 mu mol/kg. Our results suggest different mechanisms of action for the analgesic activity observed for LASSBio-776 (3-O-Bocspectaline), LASSBio-755 (3-O-acetyl-spectaline) and (-)-spectaline (LASSBio-754). The antinociceptive profile of some of the semi-synthetic spectaline derivatives extends our research concerning the chemical and pharmacological optimization of isolated natural products in the search of new drug candidates from brazilian biodiversity.

Lipoperoxidation and cyclooxygenase enzyme inhibitory piperidine alkaloids from Cassia spectabilis green fruits

Phytochernical work in the search for bioactive metabolites from the methanolic extract of Senna spectabilis green fruits led to the isolation of a new piperidine alkaloid, (+)-3-O-feruloylcassine (1), in addition to the known (-)-spectaline (2) and (-)-3-O-acetylspectaline (3). The isolates were submitted to in vitro evaluation of lipoperoxidation (LPO) and cyclooxygenase enzymes (COX-1 and -2) inhibitory properties and showed moderate antioxidant activities (40-70%) at 100 ppm when compared to commercial standards BHT and vitamin E and moderate inhibition of COX-1 (ca. 40%) and marginal inhibition of COX-2 enzymes (< 10%) at 100 ppm when compared to nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin, rofecoxib, and celecoxib, respectively.

Further bioactive piperidine alkaloids from the flowers and green fruits of Cassia spectabilis

The flowers of Cassia spectabilis yielded three new piperidine alkaloids, (-)-3-O-acetylspectaline (1), (-)-7-hydroxyspectaline (2), and iso-6-spectaline (3), together with the known (-)-spectaline (4). The green fruits of this plant were also investigated, resulting in the isolation of 1 and 4. Their structures were elucidated using a combination of multidimensional NMR and MS techniques, and relative stereochemistries were established by NOESY correlations and analysis of coupling constants. The DNA-damaging activity of these compounds was evaluated using a mutant yeast, Saccharomyces cerevisiae, assay.

New selective acetylcholinesterase inhibitors designed from natural piperidine alkaloids

Five new piperidine alkaloids were designed from natural (-)-3-O-acetyl-spectaline and (-)-spectaline that were obtained from the flowers of Senna spectabilis (sin. Cassia spectabilis, Leguminosae). Two semi-synthetic analogues (7 and 9) inhibited rat brain acetylcholinesterase, showing IC50 of 7.32 and 15.1 mu M, and were 21 and 9.5 times less potent against rat brain butyrylcholinesterase, respectively. Compound 9 (1 mg/kg, ip) was fully efficacious in reverting scopolamine-induced amnesia in mice. The two active compounds (7 and 9) did not show overt toxic effects at the doses tested in vivo. (c) 2005 Elsevier Ltd. All rights reserved.

BIOACTIVE AND OTHER PIPERIDINE ALKALOIDS FROM CASSIA-LEPTOPHYLLA

Four new piperidine alkaloids, leptophyllin A (4), 3-acetylleptophyllin A (5), leptophyllin B (8), and (-)-spectaline (1), and 3 known piperidine alkaloids, (-)-spectalinine (2), canavaline (3), and iso-6-canavaline (7), were isolated by a bioassay-guided fractionation of a leaf extract of Cassia leptophylla. The alkaloids 1 - 3 were active in a mechanism-based DNA-modifying yeast assay and 2 was moderately active in Vero monkey and Chinese hamster ovary cell cytotoxicity assays.

Electrospray ionization mass spectrometry screening of piperidine alkaloids from Senna spectabilis (Fabaceae) extracts: Fast identification of new constituents and co-metabolites

The fragmentation pattern of a homologous series of piperidine alkaloids isolated from S. spectabilis was investigated using electrospray ionization tandem mass spectrometry (ESI-MS/MS). The ESI-MS and ESI-MS/MS analyses of EtOH extracts and fractions from flowers and fruits of S. spectabilis allowed to elucidate the structures of four new compounds. The identification of these co-metabolites, based on the fragmentation patterns of previously isolated compounds, and further confirmed by accurate mass spectrometry defines this technique as a powerful tool to determine the metabolomic profile of species which has pharmacological importance. ©2005 Sociedade Brasileira de Química.

Leishmanicidal activity of the crude extract, fractions and major piperidine alkaloids from the flowers of Senna spectabilis

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Antimalarial activity of piperidine alkaloids from Senna spectabilis and semisynthetic derivatives

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Pyridine Alkaloids from Senna multijuga As Acetylcholinesterase Inhibitors

As part of an ongoing research project on Senna and Cassia species, five new pyridine alkaloids, namely, 12'-hydroxy-7'-multijuguinol (1), 12'-hydroxy-8'-multijuguinol (2), methyl multijuguinate (3), 7'-multijuguinol (4), and 8'-multijuguinol (5), were isolated from the leaves of Senna multijuga (syn. Cassia multijuga). Their structures were elucidated on the basis of spectroscopic data analysis. Mass spectrometry was used for confirmation of the positions of the hydroxy groups in the side-chains of 1, 2, 4, and 5. All compounds exhibited weak in vitro acetylcholinesterase inhibitory activity as compared with the standard compound physostigmine.

Mechanism for the uncoupling of oxidative phosphorylation by juliprosopine on rat brain mitochondria

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Aspectos químicos, biológicos e etnofarmacológicos do gênero Cassia

Species of Cassia are widely distributed in tropical and subtropical regions throughout the world, and have been extensively investigated chemically and pharmacologically.They are known to be a rich source of phenolic derivatives, most of them with important biological and pharmacological properties. Some Asian, African and Indian tribes use these species as a laxative, purgative, antimicrobial, antipyretic, antiviral and anti-inflammatory agent. Among a number of other classes of secondary metabolites, such as anthracene derivatives, antraquinones, steroids and stilbenoids, biologically active piperidine alkaloids are an especially important bioactive class of compounds that showed to be restricted to a small group of Cassia species. In this paper we present an overview of the chemical, biological and ethnopharmacological data on Cassia piblished in the literature.

7-Hydroxycassine: A new 2,6-dialkylpiperidin-3-ol alkaloid and other constituents isolated from flowers and fruits of senna spectabilis (Fabaceae)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Estudo fitoquímico dos frutos de Senna spectabilis e análise comparativa do perfil alcaloídico de S. spectabilis e Cassia leptophylla

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)