Synthesis and identification of a novel derivative of salidroside as a selective, competitive inhibitor of monoamine oxidase B with enhanced neuroprotective properties

• Published in: European journal of medicinal chemistry 2021-01, Vol.209, p.112935-112935, Article 112935
• Main Authors: Yang, Zelin, Huang, Xin, Lai, Wenfang, Tang, Yuheng, Liu, Junjie, Wang, Yingzheng, Chu, Kedan, Brown, John, Hong, Guizhu
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Apoptosis - drug effects; Biological Transport; Blood-Brain Barrier - metabolism; Complement C3 - metabolism; Drug Evaluation, Preclinical; Gene Expression Regulation - drug effects; Glucosides - chemical synthesis; Glucosides - pharmacology; Humans; Lipophilicity; Male; Molecular Docking Simulation; Monoamine Oxidase - metabolism; Monoamine oxidase B; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine Oxidase Inhibitors - pharmacology; Neuroprotection; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - pharmacology; PC12 Cells; Phenols - chemical synthesis; Phenols - pharmacology; Protein Binding; Rats; Rats, Sprague-Dawley; Reperfusion Injury - drug therapy; Reverse virtual docking; Salidroside derivatives; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112935

Salidroside [(2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(4-hydroxyphenethoxy)tetrahy-dro-2H-pyran-3,4,5-triol] is an antioxidant, anti-inflammatory and neuroprotective agent, but its drug-like properties are unoptimized and its mechanism of actions is uncertain. We synthesized twenty-six novel derivatives of salidroside and examined them in CoCl2-treated PC12 cells using MTT assay. pOBz, synthesized by esterifying the phenolic hydroxyl group of salidroside with benzoyl chloride, was one of five derivatives that were more cytoprotective than salidroside, with an EC50 of 0.038 μM versus 0.30 μM for salidroside. pOBz was also more lipophilic, with log P of 1.44 versus −0.89 for salidroside. Reverse virtual docking predicted that pOBz would bind strongly with monoamine oxidase (MAO) B by occupying its entrance and substrate cavities, and by interacting with the inter-cavity gating residue Ile199 and Tyr435 of the substrate cavity. Enzymatic studies confirmed that pOBz competitively inhibited the activity of purified human MAO-B (Ki = 0.041 μM versus Ki = 0.92 μM for salidroside), and pOBz was highly selective for MAO-B over MAO-A. In vivo, pOBz inhibited cerebral MAO activity after middle cerebral artery occlusion with reperfusion in rats, and it reduced cerebral infarct volume, improved neurological function and NeuN expression, and inhibited complement C3 expression and apoptosis. Our results suggest that pOBz is a structurally novel type of competitive and selective MAO-B inhibitor, with potent neuroprotective properties after cerebral ischemia-reperfusion injury in rats. [Display omitted] •Twenty-six derivatives of salidroside were synthesized and tested in PC12 cells.•Compound pOBz was more cytoprotective and lipophilic than salidroside.•Reverse virtual docking predicted that pOBz would bind MAO-B.•Enzymatic studies showed pOBz was a highly selective, competitive MAO-B inhibitor.•pOBz inhibited cerebral MAO activity and was neuroprotective in MCAO rats.