Pyridoxine-resveratrol hybrids as novel inhibitors of MAO-B with antioxidant and neuroprotective activities for the treatment of Parkinson's disease

  • Bioorg Chem. 2020 Apr;97:103707. doi: 10.1016/j.bioorg.2020.103707.
Wei Li  1 ,  Xia Yang  1 ,  Qing Song  1 ,  Zhongcheng Cao  1 ,  Yichun Shi  1 ,  Yong Deng  2 ,  Li Zhang  3
Affiliations
  • 1. Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 611041, China.
  • 2. Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 611041, China. Electronic address: [email protected].
  • 3. Department of Elderly Digestive, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, China. Electronic address: [email protected].
PMID: 32146176 DOI: 10.1016/j.bioorg.2020.103707
Abstract

A series of pyridoxine-resveratrol hybrids were designed and synthesized as Monoamine Oxidase B inhibitors for the treatment of Parkinson's disease. Most of them exhibited potent inhibitory activities on MAO-B with high selectivity. Specifically, compounds 12a, 12g and 12l showed the most excellent inhibition to hMAO-B with the IC50 values of 0.01 μM, 0.01 μM and 0.02 μM, respectively. Further reversibility study demonstrated that 12a and 12l were reversible and 12g was irreversible MAO-B inhibitors. Molecular docking studies of MAO revealed the binding mode and high selectivity of these compounds with MAO-B. In addition, these three representative compounds also exhibited low cytotoxicity and excellent neuroprotective effect in the test on H2O2-induced PC-12 cell injury. Moreover, 12a, 12g and 12l showed good antioxidant activities and high blood-brain barrier permeability. Overall, all of these results highlighted 12a, 12g and 12l were potential and excellent MAO-B inhibitors for PD treatment.

Keywords
Antioxidant; MAO-B inhibitors; Neuroprotective agents; Parkinson’s disease; Pyridoxine-resveratrol hybrids; Reversibility.
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