Synthesis and in vitro evaluation of novel rhodanine derivatives as potential cholinesterase inhibitors |
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| Institution: | 1. Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic;2. Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic;1. Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland;2. Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland;3. Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland;4. Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland;5. Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland;6. Institute of Psychiatry and Neurology, 9 Sobieskiego Str., 02-957, Warsaw, Poland;7. Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000, Ljubljana, Slovenia;1. Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia;2. Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia;3. Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abd. Aziz, 50300 Kuala Lumpur, Malaysia;4. Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia;1. Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China;2. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China;3. National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China;4. School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, 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. Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Prédio Anexo, 90035-003, Porto Alegre, RS, Brazil;3. Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av Ipiranga, 2752, Santana, 90610000, Porto Alegre, RS, Brazil;4. Laboratório Nacional De Computação Científica-LNCC, Av. Getulio Vargas, 333, Petrópolis, 25651-075, RJ, Brazil;1. Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Pre-Incubator for Innovative Drugs & Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China;2. Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, 280 South Chongqing Road, Shanghai 200025, China;1. Department of Pharmacy Engineering, Tianjin University of Technology, Tianjin 300384, PR China;2. College of Traditional Chinese Medicine, Tianjin Univerisity of Traditional Chinese Medicine, Tianjin 300193, PR China |
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| Abstract: | Based on a broad spectrum of biological activities of rhodanines, we synthesized aromatic amides and esters of 2-(4-oxo-2-thioxothiazolidin-3-yl)acetic acid (rhodanine-3-acetic acid) via carbodiimide- or PCl3-mediated coupling. Both esters and amides were investigated for their in vitro inhibitory potency and selectivity against acetylcholinesterase (AChE) from electric eel and butyrylcholinesterase (BChE) from equine serum using Ellman’s spectrophotometric method. The derivatives exhibited mostly a moderate activity against both cholinesterases. IC50 values for AChE were in a closer concentration range of 24.05–86.85 μM when compared to BChE inhibition (7.92–227.19 μM). The esters caused the more efficient inhibition of AChE than amides and parent acid. The esterification and amidation of the rhodanine-3-acetic acid increased inhibition of BChE, even up to 26 times. Derivatives of 4-nitroaniline/phenol showed the activity superior to other substituents (H, Cl, CH3, OCH3, CF3). Rhodanines produced a balanced inhibition of both cholinesterases. Seven derivatives produced the more potent inhibition of AChE than rivastigmine, a clinically used drug; additional three compounds were comparable. Two amides exceeded inhibitory potency of rivastigmine towards BChE. Importantly, this is the first evidence that rhodanine-based compounds are able to inhibit BChE. |
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| Keywords: | Acetylcholinesterase Butyrylcholinesterase Enzyme inhibition 2-(4-Oxo-2-thioxothiazolidin-3-yl)acetic acid Rhodanine |
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