Synthesis and Biological Activity Evaluation of Benzothiazole-isoquinoline Derivatives

Abstract 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 ligands (MTDLs), we synthesized a series of (R)-N-(benzo[d]thiazol-2-yl)-2-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl) acetamides. 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 MAO-B and BuChE. Among them, six compounds (4b-4d, 4f, 4g and 4i) 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 4g. In addition, the cytotoxicity of the compounds was assessed by the MTT method and AO staining, with cell viabilities found to be above 90% at effective compound concentrations, not toxic to L929 cells. Reversibility, kinetics and molecular docking studies were also performed using compound 4g, which showed the highest MAO-B and BuChE inhibitory activities. The results of these studies showed that compound 4g binds to the primary interaction sites of both enzymes and has good blood-brain barrier (BBB) penetration. The study provides new strategies for future research on neurodegenerative diseases complicated by depression.