Structural modifications in (-)-cassine and LASSBio-767: strategies for the discovery and optimization of new drug candidates

Viegas, Cláudio; Nicastro, Patrícia C.; Fossaluzza, Poliana C.; Gomes, Camila de P.; Santos, Luiz Roberto Medina dos; Bolzani, Vanderlan S.; Pivatto, Marcus; Silva, Diogo J. C. da; Melo, Gabriela Muniz de Albuquerque; Silva, Yolanda K. C. da; Alexandre-Moreira, Magna Suzana; Costa, Rodrigo S. da; Areas, Tatiana de F. M. A.; Castro, Newton G.

doi:10.5935/1984-6835.20090014

Cited by 3 publications

(3 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To prepare derivative 3x, compound 3k was reacted with anhydrous HCl in AcOEt, to furnish the desired chloridrate in quantitative yield. The structures of all the compounds were confirmed by 1 H and 13 C NMR and compared with literature data.…”

Section: General Procedures For Preparation Of Compounds 3a-r and 3xmentioning

confidence: 59%

“…[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%

“…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%

See 2 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: General Procedures For Preparation Of Compounds 3a-r and 3xmentioning

confidence: 59%

Section: -9mentioning

confidence: 99%

Section: -9mentioning

confidence: 99%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

show abstract

A divergent approach for asymmetric syntheses of (+)-spicigerine, (+)-cassine and their 3-epimers

Han

Mao

et al. 2016

Tetrahedron

View full text Add to dashboard Cite

Chemical profile and biological activities ofDeguelia duckeanaA.M.G. Azevedo (Fabaceae)

Lima

Andrade

Lima

et al. 2013

Natural Product Research

View full text Add to dashboard Cite

Deguelia duckeana is popularly known as timbó and used by indigenous people as ictiotoxic. On account of there being no literature pertaining to the chemical profile or biological activity of this plant, the hexane, methanol and aqueous crude extracts from leaves, stems and roots were assayed that presented very high cytotoxic potential against Artemia salina, achieving 100% mortality in up to 5.0 µg mL(-1) concentration, but lower antioxidant potential on 2,2-diphenyl-1-picryl-hydrazyl and Fe(3+)/Phenanthroline assays. The phytochemical analysis of crude extracts showed the presence of flavonoids and related compounds as major constituents as well as steroids in all of them, and tannins in polar extracts. All the extracts were assayed for antibacterial activity but only the hexane extract of stems showed moderate activity on Staphylococcus aureus, which was fractionated and yielded a mixture of 3,5,4'-trimethoxy-4-prenylstilbene, lonchocarpine, 4-hydroxylonchocarpine and derricidine, reported for the first time in D. duckeana and other fraction with β-sitosterol and stigmasterol mixture.

show abstract

Structural modifications in (-)-cassine and LASSBio-767: strategies for the discovery and optimization of new drug candidates

Cited by 3 publications

References 21 publications

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

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

A divergent approach for asymmetric syntheses of (+)-spicigerine, (+)-cassine and their 3-epimers

Chemical profile and biological activities ofDeguelia duckeanaA.M.G. Azevedo (Fabaceae)

Contact Info

Product

Resources

About