The present review is part II in a series (part I focuses on Parkinson's Disease) that addresses the value of natural product chemistry in the discovery of medicines for the treatment of neurodegenerative disorders. Data reviewed document that a host of products from plant species and derivatives have neuroprotectant effects in vitro and in vivo. In addition, besides neuroprotection, natural products also demonstrate biological effects that target biochemical pathways underlying associated symptoms of neurdegnerative disorders that include cognitive impairments, energy/fatigue, mood, and anxiety. This part of the review series focuses specifically upon Alzheimer's Disease (AD). AD is postulated to result from extracellular formation of amyloid plaques and intracellular deposits of neurofibrilary tangles in the hippocampus, cerebral cortex and other areas of the brain essential for cognitive function. Plaques are formed mostly from the deposition β-amyloid (Aβ), a peptide derived from the amyloid precursor protein (APP). Filamentous tangles are formed from paired helical filaments composed of neurofilament and hyperphosphorilated tau protein, a microtubule-associated protein. In addition, environmental factors can engender the production of cytokines that are closely related to the installation of an inflammatory process that contributes to neuronal death and the development and the progression of AD. In this review we focus on the recent main contribuitions of natural products chemistry to the discovery of new chemical entities usefull to the control and prevention of AD installation and progression. More than sixteen plant species, including Ginseng, Celastrus paniculatus, Centella asiatica, Curcuma longa, Ginkgo biloba, Huperzia serrata, Lycoris radiate, Galanthus nivalis, Magnolia officinalis, Polygala tenuifolia, Salvia lavandulaefolia, Salvia miltiorrhiza, Coptis chinensis, Crocus sativus, Evodia rutaecarpa, Sanguisorba officinalis, Veratrum grandiflorum and Picrorhiza kurvoa, are discussed as potential sources of active extracts. In addition, more than sixty secondary metabolites are under evaluation for their efficacy on controlling symptoms and to impede the development and progression of AD.
Neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) are currently incurable pathologies with huge social and economic impacts closely related to the increasing of life expectancy in modern times. Although the clinical and neuropathological aspects of these debilitating disorders are distinct, they share a pattern of neurodegeneration in anatomically or functionally related regions. For each disease, presently available treatments only address symptoms and do not alter the course or progression of the underlying diseases. In this context, the search for new effective chemical entities, capable of acting on diverse biochemical targets, with new mechanisms of action and low toxicity are genuine challenges to research groups and the pharmaceutical industry. This medical need has led to the reemerging of modern natural products chemistry that has yielded sophisticated and complex new lead molecules for drug discovery and development. In this review we discuss some of the main contributions of the natural products chemistry that covers multiple and varied plant species. Advances in the discovery of active constituents of plants, herbs, and extracts prescribed by traditional medicine practices for the treatment of senile neurodegenerative disorders, especially for PD, in the period after the 2000s is reviewed. The most important contributions from the 1990s are also discussed. The review also focuses on the pharmacological mechanisms of action that might underlie the purported beneficial improvements in memory and cognition, neurovascular function, and in neuroprotection. It is concluded that natural product chemistry brings tremendous diversity and historical precedent to a huge area of unmet medical need.
Este artigo apresenta brevemente alguns exemplos da aplicação da modificação estrutural sobre a (-)cassina (1) e seu derivado LASSBio-767, além da hibridação molecular e simplificação molecular de compostos-protótipo como valiosas estratégias em Química Medicinal na busca por novas entidades químicas bioativas e inovadoras.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.