RESUMO
A series of novel indanone derivatives was designed, synthesised and evaluated as potential agents for Alzheimer's disease. Among them, compound 6a, with a piperidine group linked to indone by a two-carbon spacer, exhibited the most potent inhibitor activity, with an IC(50) of 0.0018 µM for AChE; the inhibitory activity of this compound was 14-fold more potent than that of donepezil. Furthermore, these compounds also exhibited good metal-chelating ability.
Assuntos
Acetilcolinesterase/química , Quelantes/síntese química , Inibidores da Colinesterase/síntese química , Desenho de Fármacos , Indanos/síntese química , Metais/química , Piridinas/síntese química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Quelantes/química , Quelantes/uso terapêutico , Inibidores da Colinesterase/química , Inibidores da Colinesterase/uso terapêutico , Humanos , Indanos/química , Indanos/uso terapêutico , Cinética , Piridinas/química , Piridinas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
We designed and synthesized a novel class of dual pharmacology bronchodilators targeting both ß(2)-adrenoceptor and PDE4 by applying a multivalent approach. The most potent dual pharmacology molecule, compound 29, possessed good inhibitory activity on PDE4B2 (IC(50)=0.278 µM, which was more potent than phthalazinone, IC(50)=0.520 µM) and possessed excellent relaxant effects on tracheal rings precontracted by histamine (pEC(50)=9.3).
Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Asma/tratamento farmacológico , Desenho de Fármacos , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Traqueia/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Cobaias , Concentração Inibidora 50 , Estrutura Molecular , Inibidores da Fosfodiesterase 4/farmacologiaRESUMO
A series of 9-N-substituted berberine derivatives were synthesized and biologically evaluated as antioxidant and inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase and amyloid-ß aggregation. Most of these compounds exhibited very good antioxidant activities, inhibitive activities of AChE and amyloid-ß aggregation. Among them, compound 8d, (o-methylphenethyl)amino linked at the 9-position of berberine, was found to be a good antioxidant (with 4.05 µM of Trolox equivalents), potent inhibitor of AChE (an IC(50) value of 0.027 µM), and high active inhibitor of amyloid-ß aggregation (an IC(50) value of 2.73 µM).
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Antioxidantes/química , Antioxidantes/farmacologia , Berberina/análogos & derivados , Berberina/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/síntese química , Berberina/síntese química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Electrophorus , Cavalos , Humanos , Modelos MolecularesRESUMO
The nature of liquid structures with their changing behaviors remains an unsolved fundamental problem in many fields of science and technology. It has been widely accepted that liquid structures change gradually with temperature and/or pressure. With x-ray diffraction in the melt In-Sn80, however, we have confirmed that a temperature-dependent discontinuous structural change could occur in some binary liquids, which does not fall into any other up-to-date recognized liquid-liquid changes. This finding, together with the recently recognized pressure-induced liquid change, suggests that the conventional view on liquids should be revised.