| Author/Editor | Kamecki, Fabiola; Knez, Damijan; Carvalho, Diego; Marcucci, Carolina; Rademacher, Marina; Higgs, Josefina; Žakelj, Simon; Marcos, Alejandra; Pinto, Felicitas de Tezanos; Gobec, Stanislav | |
| Title | Multitarget 2'-hydroxychalcones as potential drugs for the treatment of neurodegenerative disorders and their comorbidities | |
| Type | članek | |
| Vol. and No. | , št. Vol. 201 | |
| Publication year | 2021 | |
| Volume | str. 1-18 | |
| ISSN | 1873-7064 - Neuropharmacology | |
| Language | eng | |
| 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 [beta] (A[beta]) 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 [micro]M), 5a (IC50 = 0.084 +- 0.003 [micro]M), 2c (IC50 = 0.095 +- 0.019 [micro]M) and 2a (IC50 = 0.111 +- 0.006 [micro]M) 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 [micro]M to 15.17 +- 6.03 [micro]M) and reduced the aggregation propensity of A[beta]. Moreover, some derivatives bound to the benzodiazepine binding site (BDZ-bs) of the [gamma]-aminobutyric acid A (GABAA) receptors (1a and 2a with Ki = 4.9 +- 1.1 [micro]M and 5.0 +- 1.1 [micro], 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. | |
| Descriptors | Parkinsonova bolezen Alzheimerjeva bolezen Zdravljenje Pathology | |
| Keywords | chalcone derivatives Parkinson's disease Alzheimer's disease monoamine oxidase cholinesterase benzodiazepine binding site vezavno mesto benzodiazepinov holinesteraza derivati halkona |