Lemes Laís Flávia Nunes, de Andrade Ramos Giselle, de Oliveira Andressa Souza, da Silva Fernanda Motta R, de Castro Couto Gina, da Silva Boni Marina, Guimarães Marcos Jorge R, Souza Isis Nem O, Bartolini Manuela, Andrisano Vincenza, do Nascimento Nogueira Patrícia Coelho, Silveira Edilberto Rocha, Brand Guilherme D, Soukup Ondřej, Korábečný Jan, Romeiro Nelilma C, Castro Newton G, Bolognesi Maria Laura, Romeiro Luiz Antonio Soares
Department of Pharmacy, Health Sciences Faculty, University of Brasília, Campus Universitário Darcy Ribeiro, 70910-900, Brasília, DF, Brazil; LADETER, Catholic University of Brasília, QS 07, Lote 01, EPCT, Águas Claras, 71966-700, Brasília, DF, Brazil.
Biomedical Sciences Institute (ICB), Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
Eur J Med Chem. 2016 Jan 27;108:687-700. doi: 10.1016/j.ejmech.2015.12.024. Epub 2015 Dec 17.
Cardanol is a phenolic lipid component of cashew nut shell liquid (CNSL), obtained as the byproduct of cashew nut food processing. Being a waste product, it has attracted much attention as a precursor for the production of high-value chemicals, including drugs. On the basis of these findings and in connection with our previous studies on cardanol derivatives as acetylcholinesterase (AChE) inhibitors, we designed a novel series of analogues by including a protonable amino moiety belonging to different systems. Properly addressed docking studies suggested that the proposed structural modifications would allow the new molecules to interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, thus being able to act as dual binding inhibitors. To disclose whether the new molecules showed the desired profile, they were first tested for their cholinesterase inhibitory activity towards EeAChE and eqBuChE. Compound 26, bearing an N-ethyl-N-(2-methoxybenzyl)amine moiety, showed the highest inhibitory activity against EeAChE, with a promising IC50 of 6.6 μM, and a similar inhibition profile of the human isoform (IC50 = 5.7 μM). As another positive feature, most of the derivatives did not show appreciable toxicity against HT-29 cells, up to a concentration of 100 μM, which indicates drug-conform behavior. Also, compound 26 is capable of crossing the blood-brain barrier (BBB), as predicted by a PAMPA-BBB assay. Collectively, the data suggest that the approach to obtain potential anti-Alzheimer drugs from CNSL is worth of further pursuit and development.
腰果酚是腰果壳液（CNSL）中的一种酚类脂质成分，是腰果食品加工的副产品。作为一种废弃物，它作为生产高价值化学品（包括药物）的前体受到了广泛关注。基于这些发现，并结合我们之前关于腰果酚衍生物作为乙酰胆碱酯酶（AChE）抑制剂的研究，我们通过引入属于不同体系的可质子化氨基部分设计了一系列新型类似物。适当的对接研究表明，所提出的结构修饰将使新分子能够与AChE的催化活性位点（CAS）和外周阴离子位点（PAS）相互作用，从而能够作为双重结合抑制剂发挥作用。为了揭示新分子是否具有所需的特性，首先测试了它们对伊蚊乙酰胆碱酯酶（EeAChE）和赤道黑背库蚊乙酰胆碱酯酶（eqBuChE）的胆碱酯酶抑制活性。带有N-乙基-N-（2-甲氧基苄基）胺部分的化合物26对EeAChE表现出最高的抑制活性，IC50为6.6 μM，对人同工酶的抑制谱相似（IC50 = 5.7 μM）。作为另一个积极特征，大多数衍生物在浓度高达100 μM时对HT-29细胞没有明显毒性，这表明其具有药物样行为。此外，如PAMPA-BBB试验所预测的，化合物26能够穿过血脑屏障（BBB）。总体而言，数据表明从CNSL中获得潜在抗阿尔茨海默病药物的方法值得进一步探索和开发。
