Rio de Janeiro RJRecebido em 1/3/01; aceito em 13/6/01 MEDICINAL CHEMISTRY OF N-ACYLHYDRAZONES: NOVEL LEAD-COMPOUNDS OF ANALGESIC, ANTIINFLAMMATORY AND ANTITHROMBOTIC DRUGS. In this article are described new bioactive N-acylhydrazone (NAH) derivatives, structurally designed as optimization of aryl hydrazones precursors planned by molecular hybridization of two 5-lipoxigenase inhibitors, e.g. CBS-1108 and BW-755c. The analgesic, antiedematogenic and anti-platelet aggregating profile of several isosteric compounds was investigated by using classic pharmacological assays in vivo and ex-vivo, allowing to identify new potent peripheric analgesic lead, a new anti-inflammatory and an antithrombotic agent. During this study was discovered dozen of active NAH compounds clarifying the structure-activity relationship for this series of NAH derivatives, indicating the pharmacophore character of the N-acylhydrazone functionality.Keywords: bioactive N-acylhydrazones derivatives; antiinflammatory, analgesic and antithrombotic properties; molecular hybridization and bioisosterism in drug design. INTRODUÇÃOA Química Medicinal estuda as razões moleculares da ação dos fármacos 1 de maneira a descrever a relação entre a estrutura química e a atividade farmacológica, hierarquizando as diferentes contribuições funcionais. No contexto inverso, inclui-se o planejamento e o desenho estrutural de novas substâncias que possuam propriedades farmacoterapêuticas úteis, capazes de representarem novas entidades químicas, candidatas a protótipos de novos fármacos de uso seguro. Esta complexa tarefa envolve múltiplos fatores, responsáveis pela resposta terapêutica desejada e decorrentes da complexidade dos sistemas biológicos, abrangendo diversos conceitos de diferentes disciplinas, não podendo ser cumprida aleatoriamente. Heuristicamente para a identificação de um novo composto-protóti-po ou uma nova entidade química que possa representar novo candidato a fármaco, elege-se o melhor alvo-farmacológico para aquela aplicação terapêutica e, em função do nível de conhecimento estrutural disponível sobre este receptor, identifica-se a melhor estratégia para a construção da arquitetura molecular do novo ligante desejado. Diversas estratégias modernas de desenho molecular de novos protótipos são conhecidas 2 , em função do mecanismo de ação pretendido, seja inibição enzimática, reversível ou não, ou agonismo/antagonismo, competitivo ou não, do receptor, que dependem do nível de conhecimento de sua topografia.O conhecimento da topografia molecular tridimensional (3D) do receptor, especialmente do sítio de interação, permite o desenho de inibidores enzimáticos ou de antagonistas/agonistas de receptores, por processos de complementaridade molecular planejada, 3 que podem, por sua vez, discriminar entre interações ou ligações covalentes 4 . Quando não se conhece a estrutura do biorreceptor-alvo, a estratégia mais empregada fundamenta-se na variação da similaridade molecular do agonista natural de forma a que se identifique um análogo ativo 5 , reflexo de s...

2000 carboxylic amides carboxylic amides (benzene compounds) Q 0490 30 -077 Synthesis and Analgesic Activity of Novel N-Acylarylhydrazones and Isosters, Derived from Natural Safrole. -Starting from safrole (I) new compounds of type (VII) and (VIII) are formed. Derivative (VII) is formed as a mixture of E/Z isomers and found to be the most potent antiinflammatory and analgesic agent within this study. A similar compound without ethylene bridge (VIII) is preferentially formed in (E)-form because of steric hindrance of the second aryl group. -(LIMA, PATRICIA C.; LIMA, LIDIA M.; DA SILVA, KELLI CRISTINE M.; LEDA, PAULO HENRIQUE O.; DE MIRANDA, ANA LUISA P.; FRAGA, CARLOS A. M.; BARREIRO, ELIEZER J.; Eur.

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.

No abstract

Recebido em 13/9/00; aceito em 15/12/00 THE REBIRTH OF A DRUG: THALIDOMIDE. Thalidomide, first synthesized in 1953, was widely prescribed for morning sickness of pregnant women from 1957 to 1961, when it was found to be seriously teratogenic, having caused serious birth defect. Nowadays, a quarter of a century later, it appears that it may be a miracle drug for such diseases as leprosy, AIDS, cancer and tuberculosis.