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  3. Enhancing monoamine oxidase B inhibitory activity via chiral fluorination: Structure-activity relationship, biological evaluation, and molecular docking study

Enhancing monoamine oxidase B inhibitory activity via chiral fluorination: Structure-activity relationship, biological evaluation, and molecular docking study

  • Eur J Med Chem. 2022 Jan 15;228:114025. doi: 10.1016/j.ejmech.2021.114025.
Zhizheng Wang 1,  Chao Yi 2,  Kangzhi Chen 2,  Tao Wang 2,  Kang Deng 2,  Chuanfei Jin 3,  Gefei Hao 4
Affiliations

Affiliations

  • 1 Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, China.
  • 2 Sunshine Lake Pharma Co. Ltd., Shenzhen, 518000, China; HEC Pharm Group, HEC Research and Development Center, Dongguan, 523871, China.
  • 3 Sunshine Lake Pharma Co. Ltd., Shenzhen, 518000, China; HEC Pharm Group, HEC Research and Development Center, Dongguan, 523871, China. Electronic address: chuanfeijin@163.com.
  • 4 State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Research and Development Center for Fine Chemicals, Guizhou University, Guiyang, 550025, China.
PMID: 34871839 DOI: 10.1016/j.ejmech.2021.114025
Abstract

Parkinson's disease (PD) is a common neurodegenerative disease among the elderly. Currently, Monoamine Oxidase B (MAO-B) inhibitors are extensively used for PD in clinics. In this work, a series of novel chiral fluorinated pyrrolidine derivatives were designed and synthesized. In vitro biological evaluations revealed that compound D5 was the most potent, selective MAO-B Inhibitor (IC50 = 0.019 μM, MAO-A/MAO-B selectivity index = 2440), which was 10-fold than that of miracle drug safinamide (IC50 = 0.163 μM, MAO-A/MAO-B selectivity index = 172). It was verified that the enhanced hydrophobic interaction of D5 improved the activity against MAO-B in molecular docking study. Besides, D5 exhibited excellent metabolic properties and pharmacokinetic profiles in monkeys and rats. Moreover, D5 displayed more efficacious than safinamide in vivo models. In the MPTP-induced PD mouse model, D5 significantly alleviated DA deficits and increased the effect of levodopa on dopamine concentration in the striatum. Meanwhile, D5 produced a prominent reduction in tremulous jaw movements induced by galantamine. Accordingly, we present D5 as a novel, highly potent, and selective MAO-B Inhibitor for PD therapy.

Keywords

Fluorine; MPTP mouse Model; Monoamine oxidase B inhibitor; Parkinson's disease; Safinamide.

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