IQUIFIB   02644
INSTITUTO DE QUIMICA Y FISICOQUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"
Unidad Ejecutora - UE
artículos
Título:
Multitarget 2′-hydroxychalcones as potential drugs for the treatment of neurodegenerative disorders and their comorbidities
Autor/es:
KAMECKI, FABIOLA; MARCUCCI, CAROLINA; ?AKELJ, SIMON; ABIN-CARRIQUIRY, JUAN ANDRÉS; MARDER, MARIEL; CARVALHO, DIEGO; HIGGS, JOSEFINA; DE TEZANOS PINTO, FELICITAS; COLETTIS, NATALIA; KNEZ, DAMIJAN; RADEMACHER, MARINA; MARCOS, ALEJANDRA; GOBEC, STANISLAV
Revista:
NEUROPHARMACOLOGY
Editorial:
PERGAMON-ELSEVIER SCIENCE LTD
Referencias:
Año: 2021 vol. 201
ISSN:
0028-3908
Resumen:
The complex nature of neurodegenerative diseases (NDDs), such as Alzheimer´s disease (AD) and Parkinson´s disease (PD) calls for multidirectional treatment. Restoring neurotransmitter levels by combined inhibition of cholinesterases (ChEs) and monoamine oxidases (MAOs, MAO-A and MAO-B), in conjunction with strategies to counteract amyloid β (Aβ) aggregation, may constitute a therapeutically strong multi-target approach for the treatment of NDDs. Chalcones are a subgroup of flavonoids with a broad spectrum of biological activity. We report here the synthesis of 2′-hydroxychalcones as MAO-A and MAO-B inhibitors. Compounds 5c (IC50 = 0.031 ± 0.001 μM), 5a (IC50 = 0.084 ± 0.003 μM), 2c (IC50 = 0.095 ± 0.019 μM) and 2a (IC50 = 0.111 ± 0.006 μM) were the most potent, selective and reversible inhibitors of human (h)MAO-B isoform. hMAO-B inhibitors 1a, 2a and 5a also inhibited murine MAO-B in vivo in mouse brain homogenates. Molecular modelling rationalised the binding mode of 2′-hydroxychalcones in the active site of hMAO-B. Additionally, several derivatives inhibited murine acetylcholinesterase (mAChE) (IC50 values from 4.37 ± 0.83 μM to 15.17 ± 6.03 μM) and reduced the aggregation propensity of Aβ. Moreover, some derivatives bound to the benzodiazepine binding site (BDZ-bs) of the γ-aminobutyric acid A (GABAA) receptors (1a and 2a with Ki = 4.9 ± 1.1 μM and 5.0 ± 1.1 μM, respectively), and exerted sedative and/or anxiolytic like effects on mice. The biological results reported here on 2′-hydroxychalcones provide an extension to previous studies on chalcone scaffold and show them as a potential treatment strategy for NDDs and their associated comorbidities.