RESUMEN
Alzheimer's disease (AD) is generally recognized as a multifactorial neurodegenerative pathology with an increasing impact on society. Tenuazonic acid (TA) is a natural compound that was recently identified as a potential multitarget ligand with anti-cholinesterase, anti-amyloidogenic and antioxidant activities. Using its structure as a chemical scaffold, we synthesized and evaluated new derivatives (1-5), including tenuazonic-donepezil (TA-DNP) hybrids (4 and 5) due to the clinical importance of the anti-AD drug donepezil. These novel compounds all achieved activity in the micromolar range towards all selected targets and demonstrated to be potentially orally absorbed. Moreover, a selected compound (1) was further investigated as a chelating agent towards copper (II), zinc (II) and iron (III) and showed good chelating ability (pFe = 16.6, pCu = 11.6, pZn = 6.0 at pH 7.4). Therefore, the TA motif can be considered an interesting building block in the search for innovative multi-functional anti-neurodegenerative drugs, as exemplified by hybrid 5, a promising non-cytotoxic lead compound adequate for the early stages of AD, and capable of ameliorating the oxidative status of SH-SY5Y human neuroblastoma cells.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Ácido Tenuazónico/uso terapéutico , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Donepezilo/química , Donepezilo/farmacología , Donepezilo/uso terapéutico , Depuradores de Radicales Libres/farmacología , Humanos , Concentración de Iones de Hidrógeno , Metales/química , Simulación del Acoplamiento Molecular , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Agregado de Proteínas/efectos de los fármacos , Espectrofotometría , Ácido Tenuazónico/química , Ácido Tenuazónico/farmacocinéticaRESUMEN
Secondary metabolites from plants and fungi are stimulating growing interest in consumers and, consequently, in the food and supplement industries. The beneficial effects of these natural compounds are being thoroughly studied and there are frequent updates about the biological activities of old and new molecules isolated from plants and fungi. In this article, we present a review of the most recent literature regarding the recent discovery of secondary metabolites through isolation and structural elucidation, as well as the in vitro and/or in vivo evaluation of their biological effects. In particular, the possibility of using these bioactive molecules in the prevention and/or treatment of widely spread pathologies such as cardiovascular and neurodegenerative diseases is discussed.