title: Tacrine-propargylamine derivatives with improved acetylcholinesterase inhibitory activity and lower hepatotoxicity as a potential lead compound for the treatment of Alzheimer's disease.
abstract: A series of tacrine-propargylamine derivatives were synthesised and evaluated as possible anti-Alzheimer's disease (AD) agents. Among these derivatives, compounds 3a and 3b exhibited superior activities and a favourable balance of AChE and BuChE activities (3a: IC50 values of 51.3 and 77.6 nM; 3b: IC50 values of 11.2 and 83.5 nM). Compounds 3a and 3b also exhibited increased hAChE inhibitory activity compared with tacrine by approximately 5- and 28-fold, respectively, and low neurotoxicity. Importantly, these compounds also had lower hepatotoxicity than tacrine. Based on these results, compounds 3a and 3b could be considered as potential lead compounds for the treatment of AD and other AChE related diseases, such as schizophrenia, glaucoma and myasthenia gravis.
authors: a Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou , China .|b Shanghai Key Laboratory of New Drug Design , School of Pharmacy, East China University of Science and Technology , Shanghai , China , and.
authors: Fei
authors: F
authors: Mao
authors: a Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou , China .
authors: Jianheng
authors: J
authors: Li
authors: c School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University , Guangzhou , China.
authors: Hui
authors: H
authors: Wei
authors: a Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou , China .
authors: Ling
authors: L
authors: Huang
authors: a Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou , China .
authors: Xingshu
authors: X
authors: Li
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000009:adverse effects* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D010293:Pargyline / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011437:Propylamines / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D011437:Propylamines; C009054:propargylamine; D013619:Tacrine; D010293:Pargyline; D000110:Acetylcholinesterase
keywords: Alzheimer’s disease; cholinesterase inhibitor; hepatotoxicity; neurotoxicity