Synthesis and biological evaluations of 8-biaryl-2,2-dimethylbenzopyranamide derivatives against Alzheimer's disease and ischemic stroke

  • Bioorg Chem. 2024 Feb:143:107064. doi: 10.1016/j.bioorg.2023.107064.
Ruolin Cao  1 ,  Fangyu Du  1 ,  Yuhang Cui  2 ,  Minggang Qi  1 ,  Junning Zhuang  1 ,  Jieru Wang  1 ,  Maoying Zhang  1 ,  Xiaoyu Zhang  3 ,  Zhongbo Liu  3 ,  Libo Zou  4 ,  Wei Xiao  5 ,  Guoliang Chen  6
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2. Life Science and Biology Pharmacy College, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 3. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 4. Life Science and Biology Pharmacy College, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China. Electronic address: [email protected].
  • 5. Jiangsu Kanion Pharmaceutical Co., Ltd., Jiangning Industrial City, Economic and Technological Development Zone, Lianyungang, Jiangsu 222001, China. Electronic address: [email protected].
  • 6. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
PMID: 38150937 DOI: 10.1016/j.bioorg.2023.107064
Abstract

Alzheimer's disease, the commonest cause of dementia, is a growing global health concern with huge implications for individuals and society. Stroke has still been a significant challenge in clinics for a long time, which is the second leading cause of death in the world, especially ischemic stroke. Both Alzheimer's disease and stroke are closely related to oxidative stress and HIF-1 signaling pathways in nerve cells. Herein, we describe our structure-based design, synthesis, and biological evaluation of a new class of 8-biaryl-2,2-dimethylbenzopyranamide derivatives as natural product derivatives. Our efforts have resulted in the discovery of highly potent neuroprotective agents, as exemplified by compound D13 as a HIF-1α Inhibitor, which significant improvement in the behavior of Alzheimer's disease mice and shows great potential improvement of brain infarct volume in pMCAO model rats, improves the increase of blood-brain barrier permeability after cerebral ischemia in rats, neuroprotective effect, reduce the level of apoptotic cells in rats after cerebral ischemia, better than Edaravone.

Keywords
2-dimethylbenzopyranamide derivatives; 8-Biaryl-2; Alzheimer's disease; HIF-1α inhibitor; Stroke.
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