Multifunctional chalcones for the treatment of neurodegenerative disorders and their comorbidities.

KAMECKI F, ; KNEZ D,; CARVALHO D,; MARCUCCI C,; RADEMACHER M,; SIMON AKELJ,; ALEJANDRA MARCOS, ; FELICITAS DE TEZANOS PINTO, ; JUAN ANDRÉS ABIN-CARRIQUIRY, ; COLETTIS N,; MARDER M

Congreso; V Congreso Internacional en Medicina Traslacional; 2021

Background and aims The complex nature of neurodegenerative diseases (NDDs), such as Alzheimer?s and Parkinson?s disease calls for multidirectional treatment. Restoring neurotransmitter levels by combined inhibition of cholinesterases (ChEs), monoamine oxidases (MAO-A and -B), with strategies to counteract amyloid-β (Aβ) aggregation, would constitute a therapeutically strong multi-target approach for treatment of NDDs.Chalcones are a subgroup of flavonoids with a broad spectrum of biological activities. Methods: 2?-hydroxychalcones were synthesized by aldolic condensation. Their capacity to bind to the benzodiazepine site of the GABAA receptor (BDZ-bs) in rat cerebral cortex homogenates, their capacity to inhibit recombinant human MAO-A and MAO-B (Amplex Red), Aβ aggregation (Thioflavin T) acetyl and butyrylcholinesterase (AChE and BChE) (Ellman) were studied in vitro and cell viability on SH-SY5Y cell line (β-hexosaminidase). Ensemble docking was performed to disclose chalcones binding mode into hMAO-B active site using DockingApp engine. Furthermore, anxiolytic/sedative properties (holeboard and locomotor activity tests) were evaluated in mice (Swiss male, 25-30 g) (CICUAL FFyB:3587-2019).Results We synthesized and evaluated twenty-five 2?-hydroxychalcones. 2?-OH-3-NO3-5?-Cl chalcone (5c, IC50 = 0.031 ± 0.001 µM), 2?-OH-3-Cl-5?-Cl chalcone (5a, IC50 =0.084 ± 0.003 µM), 2?-OH-3-NO3-4?-MeOH chalcone (2c, IC50 = 0.095 ± 0.019 µM) and 2?-OH-3-Cl-4?-MeOH chalcone (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 (2?-OH-3-Cl chalcone), 2a and 5a also inhibited murine MAO-B in vivo in mice brain homogenates. All derivatives tested were completely non-cytotoxic on SH-SY5Y cell line up to 10 μM. Molecular modelling rationalized the binding mode of 2?-hydroxychalcones in the active site of hMAO-B. Additionally, several derivatives inhibited murine AChE (IC50 from 4.37 ± 0.83 µM to 15.17 ± 6.03 µM) and reduced the propensity of Aβ for aggregation. Moreover, some derivatives bound to the BDZ-bs (1a and 2a with Ki = 4.9 ± 1.1 μM and 5.0 ± 1.1 μM, respectively), and exerted sedative like effects on mice (i.p., at 10 mg/kg and 3 mg/kg, respectively).Conclusions 2?-Hydroxychalcones biological results reported herein provide an extension to the previous studies of chalcone scaffold and drive them as a potential treatment strategy for NDDs and their associated comorbidities.