2. Academic Validation
  3. HDAC1/MAO-B dual inhibitors against Alzheimer's disease: Design, synthesis and biological evaluation of N-propargylamine-hydroxamic acid/o-aminobenzamide hybrids

HDAC1/MAO-B dual inhibitors against Alzheimer's disease: Design, synthesis and biological evaluation of N-propargylamine-hydroxamic acid/o-aminobenzamide hybrids

  • Bioorg Chem. 2022 May;122:105724. doi: 10.1016/j.bioorg.2022.105724.
Chuansheng Yao 1,  Xiaoying Jiang 2,  Rui Zhao 1,  Zhichao Zhong 3,  Jiamin Ge 3,  Junlong Zhu 1,  Xiang-Yang Ye 1,  Yuanyuan Xie 4,  Zhen Liu 5,  Tian Xie 6,  Renren Bai 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; 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 311121, PR China.
  • 2 College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou 311121, PR China.
  • 3 School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; 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 311121, PR China; College of Pharmaceutical Science, Collaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, PR China.
  • 4 College of Pharmaceutical Science, Collaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, PR China.
  • 5 School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; 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 311121, PR China. Electronic address: [email protected].
  • 6 School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; 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 311121, PR China. Electronic address: [email protected].
  • 7 School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; 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 311121, PR China. Electronic address: [email protected].
PMID: 35305483 DOI: 10.1016/j.bioorg.2022.105724
Abstract

A series of N-propargylamine-hydroxamic acid/o-aminobenzamide hybrids inhibitors combining the typical pharmacophores of hydroxamic acid/o-aminobenzamide and propargylamine were designed and synthesized as HDAC1/MAO-B dual inhibitors for the treatment of Alzheimer's disease. Most of the hybrids displayed moderate to good MAO-B inhibitory activities. Among them, Hybrid If exhibited the most potent activity against MAO-B and HDAC1 (MAO-B, IC50 = 99.0 nM; HDAC1, IC50 = 21.4 nM) and excellent MAO selectively (MAO-A, IC50 = 9923.0 nM; SI = 100.2). Moreover, compound If significantly reversed Aβ1-42-induced PC12 cell damage and decreased the production of intracellular ROS, exhibiting favorable antioxidant activity. More importantly, hybrid If instantly penetrated the BBB and accumulated in brain tissue as well as markedly ameliorated cognitive dysfunction in a Morris water maze ICR mice model. In summary, HDAC1/MAO-B dual inhibitor If is a promising potential agent for the therapy of Alzheimer's disease.

Keywords

Alzheimer’s disease; HDAC inhibitor; Hydroxamic acid; MAO-B inhibitor; N-propargylamine; O-Aminobenzamide.

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