Synthesis, Characterization and Biological Evaluation of Benzothiazole-Isoquinoline Derivative

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-12, Vol.27 (24), p.9062
• Main Authors: Liu, Weihua, Zhao, Donghai, He, Zhiwen, Hu, Yiming, Zhu, Yuxia, Zhang, Lingjian, Jin, Lianhai, Guan, Liping, Wang, Sihong
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amine oxidase (flavin-containing); antidepressant; Antidepressants; Benzothiazole; Benzothiazoles - pharmacology; benzothiazole–isoquinoline derivatives; Blood-brain barrier; BuChE; Butyrylcholinesterase - metabolism; Cell viability; Cholinesterase; Cholinesterase Inhibitors - pharmacology; Cytotoxicity; Depression, Mental; Enzymatic activity; Enzyme activity; Humans; Isoquinolines; MAO–B; Medical research; Medicine, Experimental; Mental depression; Molecular docking; Molecular Docking Simulation; Molecular Structure; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - pharmacology; Nervous system diseases; Neurodegeneration; neurodegenerative disease; Oxidases; Resveratrol; Structure-Activity Relationship; Tetrahydroisoquinoline
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27249062

Currently, no suitable clinical drugs are available for patients with neurodegenerative diseases complicated by depression. Based on a fusion technique to create effective multi-target-directed ligands (MTDLs), we synthesized a series of ( )- -(benzo[d]thiazol-2-yl)-2-(1-phenyl-3,4-dihydroisoquinolin-2(1 )-yl) acetamides with substituted benzothiazoles and ( -1-phenyl-1,2,3,4-tetrahydroisoquinoline. All compounds were tested for their inhibitory potency against monoamine oxidase (MAO) and cholinesterase (ChE) by in vitro enzyme activity assays, and further tested for their specific inhibitory potency against monoamine oxidase B (MAO-B) and butyrylcholinesterase (BuChE). Among them, six compounds ( - , , and ) displayed excellent activity. The classical antidepressant forced swim test (FST) was used to verify the in vitro results, revealing that six compounds reduced the immobility time significantly, especially compound . The cytotoxicity of the compounds was assessed by the MTT method and Acridine Orange (AO) staining, with cell viability found to be above 90% at effective compound concentrations, and not toxic to L929 cells reversibility, kinetics and molecular docking studies were also performed using compound , which showed the highest MAO-B and BuChE inhibitory activities. The results of these studies showed that compound binds to the primary interaction sites of both enzymes and has good blood-brain barrier (BBB) penetration. This study provides new strategies for future research on neurodegenerative diseases complicated by depression.