Design,synthesis and biological activity of novel tacrine-isatin Schiff base hybrid derivatives |
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| Affiliation: | 1. Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran;2. Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran;3. Hacettepe University, Faculty of Pharmacy, Department of Biochemistry, Sihhiye-Ankara, Turkey;4. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran;1. Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany;2. Institute of Molecular Biotechnology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany;3. Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55099 Mainz, Germany;1. Department of Biochemistry and Molecular Biology II, School of Pharmacy, University Complutense Madrid (UCM), 28040 Madrid, Spain;2. University Research Institute of Neurochemistry (IUIN), University Complutense Madrid (UCM), 28040 Madrid, Spain;3. Equipe de Synthèse de Molécules à Objectif Thérapeutique, Laboratoire des Produits Naturels d''Origine Végétale et de Synthèse Organique (PHYSYNOR), Université des frères Mentouri-Constantine, Campus de Chaabat-Ersas, Constantine 25000, Algeria;4. Department of Organic Chemistry and Inorganic Chemistry, School of Biology, Enviromental Sciences and Chemistry, University Alcalá, Ctra. Barcelona, Km. 33.5, 28817, Alcalá de Henares, Spain;5. Laboratory of Medicinal Chemistry (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain;1. Department of Chemistry, Hazara University, Mansehra 21120, Pakistan;2. Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan;3. Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia;4. Faculty of Applied Science UiTM, 40450 Shah Alam, Selangor, Malaysia;5. H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;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. School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 211189, PR China;2. Department of Medicinal Chemistry and the Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA;3. School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China;4. Suzhou Key Laboratory of Biomaterials and Technologies & Collaborative Innovation Center of Suzhou Nano Science and Technology, Suzhou 215123, PR China;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 |
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| Abstract: | A series of novel tacrine-isatin Schiff base hybrid derivatives (7a-p) were designed, synthesized and evaluated as multi-target candidates against Alzheimer’s disease (AD). The biological assays indicated that most of these compounds displayed potent inhibitory activity toward acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) and specific selectivity for AChE over BuChE. It was also found that they act as excellent metal chelators. The compounds 7k and 7m were found to be good inhibitors of AChE-induced amyloid-beta (Aβ) aggregation. Most of the compounds inhibited AChE with the IC50 values, ranging from 0.42 nM to 79.66 nM. Amongst them, 7k, 7m and 7p, all with a 6 carbon linker between tacrine and isatin Schiff base exhibited the strongest inhibitory activity against AChE with IC50 values of 0.42 nM, 0.62 nM and 0.95 nM, respectively. They were 92-, 62- and 41-fold more active than tacrine (IC50 = 38.72 nM) toward AChE. Most of the compounds also showed a potent BuChE inhibition among which 7d with an IC50 value of 0.11 nM for BuChE is the most potent one (56-fold more potent than that of tacrine (IC50 = 6.21 nM)). In addition, most compounds exhibited the highest metal chelating property. Kinetic and molecular modeling studies revealed that 7k is a mixed-type inhibitor, capable of binding to catalytic and peripheral site of AChE. Our findings make this hybrid scaffold an excellent candidate to modify current drugs in treating Alzheimer’s disease (AD). |
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| Keywords: | Alzheimer’s disease Acetylcholinesterase Butyrylcholinesterase Cholinesterase inhibitors Tacrine Isatin Schiff base Amyloid-beta aggregation Metal chelation |
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