2. Academic Validation
  3. Exploration of the novel phthalimide-hydroxypyridinone derivatives as multifunctional drug candidates against Alzheimer's disease

Exploration of the novel phthalimide-hydroxypyridinone derivatives as multifunctional drug candidates against Alzheimer's disease

  • Bioorg Chem. 2023 Dec:141:106817. doi: 10.1016/j.bioorg.2023.106817.
Xi Zhu 1,  Yangjing Lv 1,  Miaoliang Fan 1,  Jianan Guo 1,  Yujia Zhang 1,  Bianbian Gao 1,  Changjun Zhang 2,  Yuanyuan Xie 3
Affiliations

Affiliations

  • 1 College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, PR China.
  • 2 College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, PR China. Electronic address: [email protected].
  • 3 College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, PR China; Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, PR China; Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, Key Laboratory of Pharmaceutical Engineering of Zhejiang Province, Hangzhou, PR China. Electronic address: [email protected].
PMID: 37690318 DOI: 10.1016/j.bioorg.2023.106817
Abstract

A novel series of phthalimide-hydroxypyridinone derivatives were rationally designed and evaluated as potential anti-Alzheimer's disease (AD) agents. Bioactivity tests showed that all compounds displayed great iron ions-chelating activity (pFe3+ = 17.07-19.52), in addition to potent inhibition of human Monoamine Oxidase B (hMAO-B). Compound 11n emerged as the most effective anti-AD lead compound with a pFe3+ value of 18.51, along with selective hMAO-B inhibitory activity (IC50 = 0.79 ± 0.05 μM, SI > 25.3). The results of cytotoxicity assays demonstrated that 11n showed extremely weak toxicity in PC12 cell line at 50 μM. Additionally, compound 11n displayed a cytoprotective effect against H2O2-induced oxidative damage. Moreover, compound 11n exhibited ideal blood-brain barrier (BBB) permeability in the parallel artificial membrane permeation assay (PAMPA), and significantly improved scopolamine-induced cognitive and memory impairment in mice behavioral experiments. In conclusion, these favorable experimental results suggested compound 11n deserved further investigation as an anti-AD lead compound.

Keywords

Alzheimer's disease; HMAO-B inhibitor; Hydroxypyridinone; Iron ions chelator; Multifunctional agent.

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