Discovery of benzamide-hydroxypyridinone hybrids as potent multi-targeting agents for the treatment of Alzheimer's disease

Xiaoying Jiang; Jianan Guo; Changjun Zhang; Jinping Gu; Tao Zhou; Renren Bai; Yuanyuan Xie

doi:10.1080/14756366.2021.1978081

Discovery of benzamide-hydroxypyridinone hybrids as potent multi-targeting agents for the treatment of Alzheimer's disease

J Enzyme Inhib Med Chem. 2021 Dec;36(1):2045-2054. doi: 10.1080/14756366.2021.1978081.

Authors

Xiaoying Jiang^{1

2

3}, Jianan Guo¹, Changjun Zhang¹, Jinping Gu¹, Tao Zhou⁴, Renren Bai^{5

6}, Yuanyuan Xie¹

Affiliations

¹ College of Pharmaceutical Science, Collaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China.
² College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, China.
³ College of Chemistry and Chemical Engineering, Central South University, Changsha, China.
⁴ School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China.
⁵ School of Pharmacy, Hangzhou Normal University, Hangzhou, China.
⁶ Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China.

Abstract

A novel class of benzamide-hydroxypyridinone (HPO) derivatives were innovatively designed, synthesised, and biologically evaluated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through pharmacophores-merged approaches based on lead compounds 18d, benzyloxy phenyl analogs, and deferiprone (DFP). These hybrids possessed potent Monoamine oxidase B (MAO-B) inhibition as well as excellent iron chelation, with pFe³⁺ values ranging from 18.13 to 19.39. Among all the compounds, 8g exhibited the most potent selective MAO-B inhibitor (IC₅₀ = 68.4 nM, SI = 213). Moreover, 8g showed favourable pharmacokinetic properties and had great potential to penetrate the BBB in silico and PAMPA-BBB assay. Molecular modelling showed that 8g could adopt an extended conformation and have more enhanced interactions with MAO-B than 18d. In vitro and in vivo assays demonstrated that 8g remarkably resisted Aβ-induced oxidation and ameliorated cognitive impairment induced by scopolamine. Taken collectively, these results suggest that compound 8g is a potential multifunctional candidate for anti-AD treatment.

Keywords: Alzheimer’s disease; MAO-B inhibitors; benzamide-hydroxypyridinones; iron chelators; multifunctional candidate.

MeSH terms

Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Amyloid beta-Peptides / antagonists & inhibitors*
Amyloid beta-Peptides / metabolism
Antioxidants / chemical synthesis
Antioxidants / chemistry
Antioxidants / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery
Humans
Models, Molecular
Molecular Structure
Monoamine Oxidase / metabolism*
Monoamine Oxidase Inhibitors / chemical synthesis
Monoamine Oxidase Inhibitors / chemistry
Monoamine Oxidase Inhibitors / pharmacology*
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Antioxidants
Monoamine Oxidase Inhibitors
Neuroprotective Agents
Monoamine Oxidase

Grants and funding

This project was supported by the Zhejiang Key R&D Program (No. 2021C03085), National Natural Science Foundation of China, NSFC (Grant Nos. 21576239 and 81803340), and Zhejiang Natural Science Foundation (LY20H300004).