New selective acetylcholinesterase inhibitors designed from natural piperidine alkaloids

Viegas, Cláudio; Bolzani, Vanderlan S.; Pimentel, Luísa S.B.; Castro, Newton G.; Cabral, Rafael Ferracini; Costa, Rodrigo S. da; Floyd, C. Timothy; Rocha, Mariana C.; Young, Maria Cláudia Marx; Barreiro, Eliezer J.; Fraga, Carlos A.M.

doi:10.1016/j.bmc.2005.04.030

Cited by 54 publications

(24 citation statements)

References 15 publications

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“…Koelle (1975) reported that for significant effect to occur in-vivo, an anti-cholinesterase agent must generally inhibit from 50-90%. Also, several studies have reported the anti-cholinesterase activities of plant extracts (Ortega et al, 2004, Orhan et al, 2004, Viegas et al, 2005and Raffeeq et al, 2006. Furthermore, Ahmad et al (2003) and Raffeeq et al (2006) in their studies of some plants extracts reported the presence of steroidal galactoside contents which may have a role in its enzyme inhibitory activity.…”

Section: Resultsmentioning

confidence: 99%

Cholinesterase and microbial inhibitory activities of Tetrapleura tetraptera

Okoronkwo

Echeme

2012

JANS

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Abstract:The cholinesterase and microbial inhibitory activities of different parts of Tetrapleura tetraptera plant were evaluated due to their local applications. The cholinesterase results revealed that the extracts showed some levels of inhibitory effects depending on the solvents used. Tetrapleura tetraptera leaves had better inhibitory effects with maximum inhibitory activity of 70.0% at a concentration of 1.00mg/l for the water extract. Tetrapleura tetraptera bark showed highest inhibitory effect of 71.05% and (84.34%) for the ethanol and chloroform extracts at concentrations of 0.5mg/l and 1.0 mg/l respectively. While for petroleum ether, T. tetraptera bark recorded 74.34% inhibitory effect at concentration of 2.0 mg/l and also showed continuous increase in inhibitory activity as the concentration increases for aqueous methanol. The results of the antimicrobial activities showed that among all the test organisms, the ethanol and water extracts of the leaves, stem, bark and root of the plants had promising activity against Escherichia coli, Staphylococcus aureus, Proteus mirabilis, Pseudomonas aeruginosa and Klebsiella pneumonia bacteria and Aspergillus fumigatus and Rhizopus species fungi. There was no activity shown by the ethanol and water extracts of the parts of the plants with Fugarium oxysporum, Penicillium chrysogenum and Mucor species fungi. The bacteria strains were more sensitive to the tested extracts than the fungi strains.

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Section: Resultsmentioning

confidence: 99%

Cholinesterase and microbial inhibitory activities of Tetrapleura tetraptera

Okoronkwo

Echeme

2012

JANS

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“…Inibidores de AChE provocam, portanto, a persistência de maior concentração de acetilcolina garantindo extensão de seus efeitos e diminuindo os sintomas da DA. 33,35 Os fármacos em uso para diminuir os sintomas ou retardar o progresso da DA como a tacrina (12), galantamina (13), rivastigmina (14), donepezil (15) ou memantina (16) (Figura 3) apresentam eficácia modesta e provocam diversos efeitos indesejáveis, o que torna urgente a busca por novas alternativas de tratamento. A análise detalhada da estrutura da espectalina permitiu a identificação de uma subunidade correspondente à acetilcolina internalizada no anel piperidínico, o que poderia representar um ponto de reconhecimento molecular da AChE e uma possível atividade inibitória da enzima por derivados da (-)espectalina (7) (17) e LASSBio-822 (21) na reversão da amnésia induzida por escopolamina (1mg.Kg -1 ) no teste de esquiva inibitória em comparação ao grupo controle (C) e tratado com escopolamina (Sc).…”

Section: Alcaloides Piperidínicos Bioativos De Senna Spectabilisunclassified

“…35,36 Os resultados promissores evidenciados para ação sobre o SNC atraíram a atenção do setor privado possibilitando o desenvolvimento de etapas subsequentes de pesquisa em parceria com a Apsen Farmacêutica. Nessa etapa, foram planejados experimentos para a obtenção da espectalina em maior escala a partir das flores de Senna spectabilis, além da obtenção dos homólogos espectalina e cassina para avaliação da contribuição farmacofórica do tamanho da cadeia lateral em C-2.…”

Section: Perspectivas De Desenvolvimento De Um Novo Produto Farmacêuticounclassified

Spectaline, cassine and semi-synthetic analogues as potential candidate drugs for the treatment of Alzheimer disease

Silva¹,

Viegas²,

Santos³

et al. 2010

Revista Virtual De Química

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Spectaline, Cassine and Semi-Synthetic Analogues as Potential Candidate Drugs for the Treatment of Alzheimer DiseaseAbstract: This paper describes the main steps in the study of Senna spectabilis, as part of our bioprospection studies, with the isolation of spectaline, cassine and other piperidine alkaloids, as well as the preparation of semi-synthetic analogues, and the studies of their pharmacological and toxicological properties, which led to the establishment of two candidate drugs for the treatment of Alzheimer disease.Keywords: spectaline; cassine; Senna spectabilis; acetylcholinesterase inhibitor; bioprospection. ResumoEste artigo descreve o estudo fitoquímico de Senna spectabilis que conduziu ao isolamento de espectalina, cassina e outros alcaloides piperidínicos, a obtenção de análogos semi-sintéticos da espectalina e cassina, e a avaliação de suas propriedades farmacológicas e toxicológicas que resultaram no estabelecimento de dois candidatos a fármacos para o tratamento da doença de Alzheimer (DA).

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“…Thus, it is usually the first choice medicine to treat mild to moderate AD. [10][11][12] As part of an ongoing project on the search for novel anti-Alzheimer drug candidate prototypes, we have reported the design and synthesis of new series of AChEIs based on molecular simplification of donepezil 13 , preserving the common pharmacophoric substituted piperidine moiety present in donepezil (1) and the AChE i hi ito − -3-O-acetyl-spectaline hydrochloride (LASSBio-767 (2)), a semisynthetic derivative of the natural (-)-spectaline 14,15 taken as structural models (A and B, Figure 1). Considering that choosing appropriate assay is crucial when assessing the inhibitory activity of a given compound, we decide to use these series of simple small molecules for a comparative study, using the most common and fast methods describe in the literature for AChE activity identification.…”

Section: -9mentioning

confidence: 99%

“…[22][23][24][25][26][27][28][29][30][31] Our group has contributed a previous paper on the development and application of ChEIs screening methodologies using ICER-AChE and UV detection, 22 and also reported a direct method using AChE-ICER and LC/IT-MS/MS. 31 In the present work, we have used a series of substituted 3-O-acetyl-N-benzylpiperidine derivatives (3, Figure 1) 13 for evaluation of their activity by an ICER-based screening methodology 22 in comparison to inhibitory data displayed on the in vitro Ell a 's modified method, 14,17 and even by the classical qualitative TLC assays. 16,33,34 C NMR spectra were determined in chloroform-d3 and methanol-d4 with a Varian INOVA 500 spectrometer at 500 and 125 MHz, respectively.…”

Section: -9mentioning

confidence: 99%

A Comparative Evaluation of Acetylcholinesterase Inhibition by AChE-ICER and in vitro Ellman's Modified Method of Simplified Analogs 3-O-Acetyl-N-Benzyl-Piperidine of Donepezil

Silva¹,

Nicastro²,

Oliveira³

et al. 2015

Revista Virtual De Química

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Resumo: Inibidores de Acetilcolinesterase (AChEI) ainda são os melhores fármacos usados para a terapêutica da doença de Alzheirmer (DA). Dentre os IAChEs disponíveis, o donepezil apresenta a maior meia-vida, os efeitos colaterais mais brandos, além de segurança e tolerância satisfatórias; portanto, este tem sido utilizado como medicamento de primeira escolha no tratamento de DA leve a moderada. A triagem bem sucedida de novos AChEI depende de métodos rápidos e eficientes. Os ensaios empregados mais frequentemente são baseados no uso do reagente de Ellman (ensaio colorimétrico) ou do reagente Fast Blue B, além de métodos radioquímicos, espectrométricos ou cromatográficos. Uma abordagem mais recente utiliza a enzima imobilizada em reator capilar, acoplada a um sistema cromatográfico, que é conhecido como ICER (do inglês immobilized capillary enzyme reactor). Como parte de um projeto que visa à identificação de novos IAChEs, este artigo descreve a avaliação comparativa da atividade inibitória da AChE de uma série de derivados 3-O-acetil-N-benzilpiperidínicos substituídos por duas diferentes abordagens: método de Ellman modificado in vitro e uma metodologia de ICER. Embora nenhum dos compostos da série tenha apresentado alta atividade inibitória, todos os ensaios revelaram resultados consistentes, demostrando que é possível aplicar diferentes metodologias confiáveis para a busca e idendificação de novos inibidores de AChE.Palavras-chave: Química Medicinal; análogos N-benzil-piperidinícos; inibidores de acetilcolinesterase; doença de Alzheimer; enzima imobilizada; enzima imobilizada em reator capilar. AbstractAcetylcholinesterase inhibitors (AChEI) remain the best pharmacotherapy for Alzheimer´s disease (AD). Among the currently available AChEI drugs, Donepezil has longer half-life, fewer clinical side interactions, and satisfactory safety and tolerability; therefore, it is the first choice medicine to treat mild to moderate AD. Successful screening for new AChEIs relies on effective and fast assays. The ost f e ue tly e ployed assays a e ased o the use of Ell a 's eage t olo i et i ethod o the Fast Blue B salt reagent, despite of other radiochemical, spectrometric, or chromatographic methods. A more recent and interesting approach is to immobilize the target enzyme in a chromatographic system, which is known as immobilized capillary enzyme reactors (ICERs). As part of a current project aiming to search for novel AChEIs, in this paper we have reported a comparative evaluation of AChE inhibitory activity of a series of substituted 3-O-acetyl-N-benzylpiperidine derivatives by two different approaches: in vitro Ell a 's odified ethod a d a ICER-based methodology. Although none of the compounds has shown high activity, all different assays revealed consistent results, showing that is possible to apply different reliable methodologies for the screening of new AChEIs.Keywords: N-benzyl-pipe idi e a alogs; A etyl holi este ase i hi itio ; Alzhei e 's Disease; e zy e i o ilizatio ; i o ilized capillary enzyme reactor.

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New selective acetylcholinesterase inhibitors designed from natural piperidine alkaloids

Cited by 54 publications

References 15 publications

Cholinesterase and microbial inhibitory activities of Tetrapleura tetraptera

Cholinesterase and microbial inhibitory activities of Tetrapleura tetraptera

Spectaline, cassine and semi-synthetic analogues as potential candidate drugs for the treatment of Alzheimer disease

A Comparative Evaluation of Acetylcholinesterase Inhibition by AChE-ICER and in vitro Ellman's Modified Method of Simplified Analogs 3-O-Acetyl-N-Benzyl-Piperidine of Donepezil

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