Evaluation of the combined activity of benzimidazole arylhydrazones as new anti-Parkinsonian agents:monoamine oxidase-B inhibition,neuroprotection and oxidative stress modulation  

作　　者：Neda Anastassova Denitsa Aluani Anton Kostadinov Miroslav Rangelov Nadezhda Todorova Nadya Hristova-Avakumova Maria Argirova Nikolay Lumov Magdalena Kondeva-Burdina Virginia Tzankova Denitsa Yancheva 

机构地区：[1]Institute of Organic Chemistry with Centre of Phytochemistry,Bulgarian Academy of Sciences,Sofia,Bulgaria [2]Department of Pharmacology,Pharmacotherapy and Toxicology,Faculty of Pharmacy,Medical University of Sofia,Sofia,Bulgaria [3]Institute of Biodiversity and Ecosystem Research,Bulgarian Academy of Sciences,Sofia,Bulgaria [4]Department of Medical Physics and Biophysics,Faculty of Medicine,Medical University of Sofia,Sofia,Bulgaria

出　　处：《Neural Regeneration Research》2021年第11期2299-2309,共11页中国神经再生研究（英文版）

基　　金：supported by the National Science Fund of Bulgaria(Young scientists project contract KП-06-М29/4;to NA,MA,NHA,and DA).

摘　　要：Neuroprotective drugs and selective monoamine oxidase inhibitors can slow down the progression and improve symptoms of Parkinson’s disease(PD).Since there is an implication of oxidative stress in the pathophysiological mechanisms of the disease,the compounds possessing an ability to reduce the oxidative stress are prime candidates for neuroprotection.Thereby our current study is focused on the development of new multi-target PD drugs capable of inhibiting the activity of monoamine oxidase-B while exerting neuroprotective and antioxidant properties.A small series of benzimidazole derivatives containing hydroxy and methoxy arylhydrazone fragments has been synthesized and the neurotoxicity of the compounds has been evaluated in vitro on neuroblastoma SH-SY5Y cells and on isolated rat brain synaptosomes by measuring the cell viability and the levels of reduced glutathione and a good safety profile has been shown.The 2-hydroxy-4-methoxy substituted arylhydrazone 7 was the least toxic on neuronal SH-SY5Y cells and showed the lowest neurotoxicity in rat brain synaptosomes.The neuroprotective properties of the test compounds were further assessed using two models:H2O2-induced oxidative stress on SH-SY5Y cells and 6-hydroxydopamine-induced neurotoxicity in rat brain synaptosomes.Compound 7 showed more pronounced neuroprotective activity on SH-SY5Y cells,compared to the referent melatonin and rasagiline.It also preserved the synaptosomal viability and the reduced glutathione levels;the effects were stronger than those of rasagiline and comparable to melatonin.All the tested compounds were capable to inhibit human monoamine oxidase-B enzyme to a significant extent,however,compound 7 exerted the most prominent inhibitory activity,similar to selegiline and rasagiline.The carried out molecular docking studies revealed that the activity is related to the appropriate molecular structure enabling the ligand to enter deeper in the narrow and highly lipophylic active site pocket of the human monoamine oxidase-B and has a favoring

关 键 词：ANTIOXIDANTS BENZIMIDAZOLES density functional theory hydr 

分 类 号：R453[医药卫生—治疗学] R364[医药卫生—临床医学]