2. Academic Validation
  3. Design, synthesis, and biological evaluation of highly potent and selective hMAO-B inhibitors featuring a tetrahydrobenzo[f][1,4]oxazepine core

Design, synthesis, and biological evaluation of highly potent and selective hMAO-B inhibitors featuring a tetrahydrobenzo[f][1,4]oxazepine core

  • Eur J Med Chem. 2025 Dec 5:299:118080. doi: 10.1016/j.ejmech.2025.118080.
Mingxing Zhu 1,  Xiang-Peng Xie 2,  Suqiang Wang 1,  Xing Xing Zhang 3,  Zhouling Xie 1,  Yajun Duan 4,  Zhiwei Zhao 5,  Chenzhong Liao 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China.
  • 2 Department of Cardiovascular Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
  • 3 School of Biology, Food and Environment, Hefei University, Hefei, 230601, China.
  • 4 Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
  • 5 Department of Cardiovascular Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China. Electronic address: zzw2020@ustc.edu.cn.
  • 6 Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China. Electronic address: czliao@hfut.edu.cn.
PMID: 40865143 DOI: 10.1016/j.ejmech.2025.118080
Abstract

The advancement of human Monoamine Oxidase B (hMAO-B) inhibitors for the management of Parkinson's disease (PD) has seen notable progress, however, the clinical application of existing hMAO-B inhibitors is hindered by their limited efficacy and associated adverse effects. This article presents highly potent and selective hMAO-B inhibitors characterized by either a 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine core or a 2,3,4,5-tetrahydro-1H-benzo[c]azepine core. These compounds were designed through the cyclization of the amine group with the phenyl ring of safinamide, a second-generation hMAO-B inhibitor that has received approval for PD treatment. Among the synthesized compounds, ZM24 and ZM26, which possess the 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane core structure, exhibited a significant increase in both efficacy and isoform selectivity relative to safinamide. Subsequent biological assessments revealed that these two compounds act as reversible hMAO-B inhibitors, demonstrate substantial neuroprotective properties, and significantly improve motor dysfunction in MPTP-induced mouse models of PD, thereby reinforcing their potential therapeutic applications in the treatment of PD.

Keywords

Isoform selectivity; Structure activity relationship; Structure-based drug design; hMAO-B; tetrahydrobenzo[f][1,4]oxazepane.

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