de Andrade Ramos Giselle, Souza de Oliveira Andressa, Bartolini Manuela, Naldi Marina, Liparulo Irene, Bergamini Christian, Uliassi Elisa, Wu Ling, Fraser Paul E, Abreu Monica, Kiametis Alessandra Sofia, Gargano Ricardo, Silveira Edilberto Rocha, Brand Guilherme D, Prchal Lukas, Soukup Ondřej, Korábečný Jan, Bolognesi Maria Laura, Soares Romeiro Luiz Antonio
Department of Pharmacy, Health Sciences Faculty, University of Brasília, Campus Universitário Darcy Ribeiro 70910-900 Brasília DF Brazil
Department of Pharmacy and Biotechnology, University of Bologna Via Belmeloro 6 40126 Bologna Italy
RSC Med Chem. 2021 May 5;12(7):1154-1163. doi: 10.1039/d1md00046b. eCollection 2021 Jul 21.
As part of our efforts to develop sustainable drugs for Alzheimer's disease (AD), we have been focusing on the inexpensive and largely available cashew nut shell liquid (CNSL) as a starting material for the identification of new acetylcholinesterase (AChE) inhibitors. Herein, we decided to investigate whether cardanol, a phenolic CNSL component, could serve as a scaffold for improved compounds with concomitant anti-amyloid and antioxidant activities. Ten new derivatives, carrying the intact phenolic function and an aminomethyl functionality, were synthesized and first tested for their inhibitory potencies towards AChE and butyrylcholinesterase (BChE). and were found to inhibit human BChE at a single-digit micromolar concentration. Transmission electron microscopy revealed the potential of five derivatives to modulate Aβ aggregation, including and . In HORAC assays, and performed similarly to standard antioxidant ferulic acid as hydroxyl scavenging agents. Furthermore, in studies in neuronal cell cultures, and were found to effectively inhibit reactive oxygen species production at a 10 μM concentration. They also showed a favorable initial ADME/Tox profile. Overall, these results suggest that CNSL is a promising raw material for the development of potential disease-modifying treatments for AD.
作为我们开发阿尔茨海默病（AD）可持续药物的努力的一部分，我们一直专注于价格低廉且广泛可得的腰果壳液（CNSL），将其作为鉴定新型乙酰胆碱酯酶（AChE）抑制剂的起始原料。在此，我们决定研究腰果酚（一种酚类CNSL成分）是否可以作为具有伴随抗淀粉样蛋白和抗氧化活性的改良化合物的骨架。合成了十种带有完整酚官能团和氨甲基官能团的新衍生物，并首先测试了它们对AChE和丁酰胆碱酯酶（BChE）的抑制效力。发现[具体化合物1]和[具体化合物2]以个位数微摩尔浓度抑制人BChE。透射电子显微镜显示五种衍生物（包括[具体化合物3]和[具体化合物4]）具有调节Aβ聚集的潜力。在HORAC分析中，[具体化合物5]和[具体化合物6]作为羟基清除剂的表现与标准抗氧化剂阿魏酸相似。此外，在神经元细胞培养的[具体研究]中，发现[具体化合物7]和[具体化合物8]在10 μM浓度下有效抑制活性氧的产生。它们还显示出良好的初始ADME/Tox特性。总体而言，这些结果表明CNSL是开发潜在的AD疾病修饰治疗药物的有前途的原料。
