Kamecki_2021_Neuropharmacol_201_108837

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 (Abeta) 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 (IC(50) = 0.031 +/- 0.001 microM), 5a (IC(50) = 0.084 +/- 0.003 microM), 2c (IC(50) = 0.095 +/- 0.019 microM) and 2a (IC(50) = 0.111 +/- 0.006 microM) 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) (IC(50) values from 4.37 +/- 0.83 microM to 15.17 +/- 6.03 microM) and reduced the aggregation propensity of Abeta. Moreover, some derivatives bound to the benzodiazepine binding site (BDZ-bs) of the gamma-aminobutyric acid A (GABA(A)) receptors (1a and 2a with K(i) = 4.9 +/- 1.1 microM and 5.0 +/- 1.1 microM, 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.