RESUMEN
In the search for effective multifunctional agents for the treatment of Alzheimer's disease (AD), a series of novel hybrids incorporating benzofuran and chalcone fragments were designed and synthesized. These hybrids were screened by using a transgenic Caenorhabditis elegans model that expresses the human ß-amyloid (Aß) peptide. Among the hybrids investigated, (E)-3-(7-methyl-2-(4-methylbenzoyl)benzofuran-5-yl)-1-phenylprop-2-en-1-one (4 f), (E)-3-(2-benzoyl-7-methylbenzofuran-5-yl)-1-phenylprop-2-en-1-one (4 i), and (E)-3-(2-benzoyl-7-methylbenzofuran-5-yl)-1-(thiophen-2-yl)prop-2-en-1-one (4 m) significantly decreased Aß aggregation and increased acetylcholine (ACh) levels along with the overall availability of ACh at the synaptic junction. These compounds were also found to decrease acetylcholinesterase (AChE) levels, reduce oxidative stress in the worms, lower lipid content, and to provide protection against chemically induced cholinergic neurodegeneration. Overall, the multifunctional effects of these hybrids qualify them as potential drug leads for further development in AD therapy.
Asunto(s)
Antioxidantes/síntesis química , Benzofuranos/química , Chalcona/química , Chalconas/química , Tiofenos/química , Acetilcolina/metabolismo , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Animales Modificados Genéticamente/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Sitios de Unión , Caenorhabditis elegans/metabolismo , Chalconas/farmacología , Chalconas/uso terapéutico , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Humanos , Microscopía Fluorescente , Conformación Molecular , Simulación del Acoplamiento Molecular , Estrés Oxidativo/efectos de los fármacos , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Tiofenos/farmacología , Tiofenos/uso terapéuticoRESUMEN
The concept of molecular hybridization led us to discover a novel series of coumarin-dihydropyridine hybrids that have potent osteoblastic bone formation in vitro and that prevent ovariectomy-induced bone loss in vivo. In this context, among all the compounds screened for alkaline phosphatase activity, four compounds 10, 14, 18, and 22 showed significant activity at picomolar concentrations. A series of other in vitro data strongly suggested compound 18 as the most promising bone anabolic agent, which was further evaluated for in vivo studies. From these studies compound 18 proved to be useful, which at low oral dose of 1 (mg/kg)/day body weight increased bone mass density and volume, expression of osteogenic genes (RUNX2, BMP-2, and ColI), bone formation rate (BFR), and mineral apposition rate (MAR), improved the trabecular microarchitecture, and decreased bone turn over markers in an ovariectomized rodent model for postmenopausal osteoporosis.