Discovery of novel 2,5-dihydroxyterephthalamide derivatives as multifunctional agents for the treatment of Alzheimer's disease

  • Bioorg Med Chem. 2018 Dec 15;26(23-24):6115-6127. doi: 10.1016/j.bmc.2018.11.015.
Qing Song  1 ,  Yan Li  1 ,  Zhongcheng Cao  1 ,  Hongyan Liu  1 ,  Chaoquan Tian  1 ,  Ziyi Yang  1 ,  Xiaoming Qiang  1 ,  Zhenghuai Tan  2 ,  Yong Deng  3
Affiliations
  • 1. Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
  • 2. Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, PR China.
  • 3. Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China. Electronic address: [email protected].
PMID: 30470598 DOI: 10.1016/j.bmc.2018.11.015
Abstract

A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC50 = 0.56 μM and 5.12 μM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self-induced Aβ1-42 aggregation (IC50 = 3.05 μM) and Cu2+-induced Aβ1-42 aggregation (71.7% at 25.0 μM), and displayed significant disaggregation ability to self- and Cu2+-induced Aβ1-42 aggregation fibrils (75.2% and 77.2% at 25.0 μM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD.

Keywords
2,5-Dihydroxyterephthalamide derivatives; Acetylcholinesterase inhibitors; Alzheimer’s disease; Anti-neuroinflammatory agents; Antioxidant; Aβ aggregation inhibitors.
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