Chlorinated tacrine analogs: Design,synthesis and biological evaluation of their anti-cholinesterase activity as potential treatment for Alzheimer’s disease |
| |
| Institution: | 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;2. Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon;3. Noha Gouda, Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;1. Instituto de Química, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9500, Campus do Vale, 91501-970, Porto Alegre, RS, Brazil;2. Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil, 4365, 21040-360, Rio de Janeiro, RJ, Brazil;3. Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro, BR 465, Km 7, Campus Universitário, 23890-000 Seropédica, RJ, Brazil;4. Laboratório Nacional De Computação Científica-LNCC, Av. Getúlio Vargas, 333, Petrópolis 25651-075, RJ, Brazil;1. Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China;2. Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan academy of Chinese Medicine Sciences, Chengdu 610041, China;1. Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China;2. Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, PR China;1. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;2. Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran;3. Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;4. Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran;5. Department of Biology, Science and Research Branch Islamic Azad, Tehran, Iran;6. Department of Cellular Biotechnology at Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran;7. Department of Pharmacognosy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;8. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;1. School of Pharmacy, International Campus (TUMS-IC), Tehran University of Medical Sciences, Tehran, Iran;2. Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;3. Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran;4. Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran;5. Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran;1. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China;2. Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China;3. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China;4. Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, Nanjing 210009, China;5. Jiangsu Food and Pharmaceutical Science College, Huaian 223003, China |
| |
| Abstract: | In search of potent acetyl cholinesterase inhibitors with low hepatotoxicity for the treatment of Alzheimer’s disease, introduction of a chloro substitution to tacrine and some of its analogs has proven to be beneficial in maintaining or potentiating the cholinesterase inhibitory activity. Furthermore, it was found to be able to reduce the hepatotoxicity of the synthesized compounds, which is the main target of the study. Accordingly, a series of new 4-(chlorophenyl)tetrahydroquinoline derivatives, was synthesized and characterized. The synthesized compounds were evaluated for their in vitro and in vivo anti-cholinesterase activity using tacrine as a reference standard. Furthermore, they were investigated for their hepatotoxicity compared to tacrine. The obtained biological results revealed that all synthesized compounds displayed equivalent or significantly higher anti-cholinesterase activity and lower hepatotoxicity in comparison to tacrine. In addition, in silico drug-likeness of the synthesized compounds were predicted and their practical logP were assessed indicating that all synthesized compounds can be considered as promising hits/leads. Furthermore, docking study of the compound showing the highest in vitro anticholinesterase activity was performed and its binding mode was compared to that of tacrine. |
| |
| Keywords: | Alzheimer’s disease Anti-cholinesterase activity Tacrine Chlorinated phenyl tetrahydroquinolines Hepatotoxicity |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
