Design, synthesis and biological evaluation of rasagiline-clorgyline hybrids as novel dual inhibitors of monoamine oxidase-B and amyloid-β aggregation against Alzheimer's disease.

Abstract

A series of rasagiline-clorgyline hybrids was designed, synthesized and investigated in vitro for their inhibition of monoamine oxidase and amyloid-β aggregation. Most of compounds were found to be selective and highly potent hMAO-B inhibitors showing IC50 values in the nanomolar, and exhibited a moderate inhibition of amyloid-β aggregation. 7-((5-(methyl(prop-2-yn-1-yl)amino) pentyl)oxy)chroman-4-one (6j) was the most interesting compound identified in this research, endowed with higher hMAO-B potency (IC50 = 4 nM) and selectivity (SI > 25000) compared to the reference selective inhibitor rasagiline (IC50 = 141 nM, SI > 355), and exhibited good inhibitory activity against Aβ1-42 aggregation (40.78%, 25 μM). Kinetic and molecular modeling studies revealed that 6j was a competitive reversible inhibitor for hMAO-B. Moreover, compound 6j displayed low toxicity and good neuroprotective effects in SH-SY5Y cell assay, and could penetrate the blood-brain barrier according to the parallel artificial membrane permeability assay. Pharmacokinetics assay revealed that compound 6j possessed good pharmacokinetic profiles after intravenous and oral administrations. Overall, these results highlighted that compound 6j was an effective and promising multitarget agent against Alzheimer's disease.

• Authors: Sai-Sai Xie, Jing Liu, Chunli Tang, Chengyun Pang, Qing Li, Yuelian Qin, Xiaojie Nong, Zhipeng Zhang, Jie Guo, Maojun Cheng, Weizhong Tang, Ningsheng Liang, Neng Jiang
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 202 Pg. 112475 (Sep 15 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 32652406 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Indans
• Monoamine Oxidase Inhibitors
• Neuroprotective Agents
• Peptide Fragments
• Protein Aggregates
• amyloid beta-protein (1-42)
• rasagiline
• Monoamine Oxidase
• Clorgyline

Topics

• Alzheimer Disease (drug therapy, metabolism)
• Amyloid beta-Peptides (antagonists & inhibitors, metabolism)
• Animals
• Cell Line, Tumor
• Cell Survival (drug effects)
• Clorgyline (chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Design
• Humans
• Indans (chemistry, pharmacology)
• Male
• Models, Molecular
• Molecular Structure
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Neuroprotective Agents (chemical synthesis, chemistry, pharmacology)
• Peptide Fragments (antagonists & inhibitors, metabolism)
• Protein Aggregates (drug effects)
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship