Kamecki Fabiola, Knez Damijan, Carvalho Diego, Marcucci Carolina, Rademacher Marina, Higgs Josefina, Žakelj Simon, Marcos Alejandra, de Tezanos Pinto Felicitas, Abin-Carriquiry Juan Andrés, Gobec Stanislav, Colettis Natalia, Marder Mariel
Universidad de Buenos Aires. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
Neuropharmacology. 2021 Dec 15;201:108837. doi: 10.1016/j.neuropharm.2021.108837. Epub 2021 Oct 12.
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 (IC = 0.031 ± 0.001 μM), 5a (IC = 0.084 ± 0.003 μM), 2c (IC = 0.095 ± 0.019 μM) and 2a (IC = 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) (IC 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 (GABA) receptors (1a and 2a with K = 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.
神经退行性疾病（NDDs），如阿尔茨海默病（AD）和帕金森病（PD）的复杂性质需要多方向治疗。通过联合抑制胆碱酯酶（ChEs）和单胺氧化酶（MAOs，MAO - A和MAO - B）来恢复神经递质水平，再结合对抗淀粉样β（Aβ）聚集的策略，可能构成一种治疗NDDs的强大多靶点方法。查耳酮是一类具有广泛生物活性的黄酮类化合物。我们在此报告作为MAO - A和MAO - B抑制剂的2'-羟基查耳酮的合成。化合物5c（IC = 0.031±0.001μM）、5a（IC = 0.084±0.003μM）、2c（IC = 0.095±0.019μM）和2a（IC = 0.111±0.006μM）是人类（h）MAO - B亚型最有效、选择性和可逆的抑制剂。hMAO - B抑制剂1a、2a和5a在小鼠脑匀浆中也能在体内抑制小鼠MAO - B。分子模拟使2'-羟基查耳酮在hMAO - B活性位点的结合模式合理化。此外，几种衍生物抑制小鼠乙酰胆碱酯酶（mAChE）（IC值从4.37±0.83μM到15.17±6.03μM）并降低Aβ的聚集倾向。此外，一些衍生物与γ-氨基丁酸A（GABA）受体的苯二氮䓬结合位点（BDZ - bs）结合（1a和2a的K分别为4.9±1.1μM和5.0±1.1μM），并对小鼠产生镇静和/或抗焦虑样作用。这里报道的关于2'-羟基查耳酮的生物学结果扩展了先前对查耳酮支架的研究，并表明它们是治疗NDDs及其相关合并症的潜在治疗策略。
