RESUMEN
Dantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one dantrolene-like hydrazide and hydrazone analogues were synthesized with the aim of exploring structure-activity relationships (SARs) for the inhibition of human monoamine oxidases (MAOs) and acetylcholinesterase (AChE), two well-established target enzymes for anti-AD drugs. With few exceptions, the newly synthesized compounds exhibited selectivity toward MAOâ B over either MAOâ A or AChE, with the secondary aldimineâ 9 and phenylhydrazone 20 attaining IC50 values of 0.68 and 0.81â µM, respectively. While no general SAR trend was observed with lipophilicity descriptors, a molecular simplification strategy allowed the main pharmacophore features to be identified, which are responsible for the inhibitory activity toward MAOâ B. Finally, further inâ vitro investigations revealed cell protection from oxidative insult and activation of carnitine/acylcarnitine carrier as concomitant biological activities responsible for neuroprotection by hits 9 and 20 and other promising compounds in the examined series.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Hidrazinas/farmacología , Hidrazonas/farmacología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Acetilcolinesterasa/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Hidrazinas/síntesis química , Hidrazinas/química , Hidrazonas/síntesis química , Hidrazonas/química , Estructura Molecular , Monoaminooxidasa/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Relación Estructura-ActividadRESUMEN
The orphan drug dantrolene (DAN) is the only therapeutic treatment for malignant hyperthermia (MH), a pharmacogenetic pathology affecting 0.2 over 10,000 people in the EU. It acts by inhibiting ryanodine receptors, which are responsible for calcium recruitment in striatal muscles and brain. Because of its involvement in calcium homeostasis, DAN has been successfully investigated for its potential as neuroprotecting small molecule in several animal models of Alzheimer's disease (AD). Nevertheless, its effects at a molecular level, namely on putative targets involved in neurodegeneration, are still scarcely known. Herein, we present a prospective study on repurposing of DAN involving, besides the well-known calcium antagonism, inhibition of monoamine oxidase B and acetylcholinesterase, cytoprotection from oxidative insult, and activation of carnitine/acylcarnitine carrier, as concurring biological activities responsible for neuroprotection.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Calcio/metabolismo , Dantroleno/farmacología , Fármacos Neuroprotectores/farmacología , Acetilcolinesterasa/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/patología , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Carnitina/análogos & derivados , Carnitina/metabolismo , Línea Celular , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Dantroleno/química , Reposicionamiento de Medicamentos , Humanos , Hipertermia Maligna/tratamiento farmacológico , Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Fármacos Neuroprotectores/químicaRESUMEN
The effect of polyphenols, recognized as the principal antioxidant and beneficial molecules introduced with the diet, extracted from sweet cherry (Prunus avium L.) on the recombinant human mitochondrial carnitine/acylcarnitine transporter (CACT) has been studied in proteoliposomes. CACT transport activity, which was strongly impaired after oxidation by atmospheric O2 or H2O2, due to the formation of a disulfide bridge between cysteines 136 and 155, was restored by externally added polyphenols. CACT reduction by polyphenols was time dependent. Spectroscopic analysis of polyphenolic extracts revealed eight most represented compounds in four cultivars. Molecular docking of CACT structural omology model with the most either abundant and arguably bio-available phenolic compound (trans 3-O-feruloyl-quinic acid) of the mix, is in agreement with the experimental data since it results located in the active site close to cysteine 136â¯at the bottom of the translocation aqueous cavity.