1. Multitarget 2'-hydroxychalcones as potential drugs for the treatment of neurodegenerative disorders and their comorbidities
- Author
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Carolina Marcucci, Natalia Claudia Colettis, Marina Rademacher, Stanislav Gobec, Fabiola Kamecki, Felicitas de Tezanos Pinto, Diego Carvalho, Alejandra Marcos, Mariel Marder, Josefina Higgs, Simon Žakelj, Juan Andrés Abin-Carriquiry, and Damijan Knez
- Subjects
Male ,Chalcone ,Monoamine Oxidase Inhibitors ,Monoamine oxidase ,Pharmacology ,In Vitro Techniques ,Synaptic Transmission ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Mice ,Chalcones ,In vivo ,Alzheimer Disease ,Animals ,Cholinesterases ,Rats, Wistar ,Receptor ,Monoamine Oxidase ,Amyloid beta-Peptides ,Binding Sites ,Chemistry ,GABAA receptor ,Brain ,Biological activity ,Parkinson Disease ,Receptors, GABA-A ,Acetylcholinesterase ,Monoamine neurotransmitter ,Anti-Anxiety Agents - Abstract
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.
- Published
- 2021