a Laboratory of Applied Chemistry, Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax , University of Sfax , Sfax , Tunisia.
b Laboratoire de Chimie Organique et Thérapeutique, Neurosciences Intégratives et Cliniques EA 481 , Univ. Bourgogne Franche-Comté , Besançon , France.
J Enzyme Inhib Med Chem. 2019 Dec;34(1):163-170. doi: 10.1080/14756366.2018.1538136.
In view of the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC = 4.52 ± 0.24 µM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Aβ at 3 µM and 10 µM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration.
鉴于阿尔茨海默病（AD）的多因素性质，多靶小分子（MTSM）代表了最有效和最有吸引力的治疗策略，可用于设计治疗阿尔茨海默病的新药。新的 MTSM KojoTacrines（KTs）通过将来自曲酸和他克林的选定药效团并置设计和合成。其中，11-氨基-2-（羟甲基）-12-（3-甲氧基苯基）-7,9,10,12-四氢吡喃并[2',3':5,6]吡喃并[2,3-b]喹啉-4(8H)-酮（KT2d）被鉴定为比他克林的肝毒性更小，在更高浓度下，是一种中等但选择性的人乙酰胆碱酯酶抑制剂（IC=4.52±0.24μM），也是一种抗氧化剂（TE=4.79），在 3μM 和 10μM 浓度下对 Aβ表现出显著的神经保护作用。因此，KT2d 是一种有潜力的用于 AD 治疗的新的作用配体，可进一步进行生物学探索。
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