Novel multitarget 5-arylidenehydantoins with arylpiperazinealkyl fragment: Pharmacological evaluation and investigation of cytotoxicity and metabolic stability |
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| Institution: | 1. Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland;2. Department of Pharmacobiology, Jagiellonian University Collegium Medicum, Krakow, Poland;3. Department of Pharmaceutical Biochemistry, Jagiellonian University Collegium Medicum, Krakow, Poland;4. Chair and Department of Biochemistry, Medical University, 02-097 Warszawa, Poland;5. Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland;1. College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China;2. State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China;3. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China;4. Department of Human Anatomy, School of Medicine, Jinan University, Guangzhou 510632, China;5. Guizhou Tea Reasearch Institute, Guizhou Academy of Agricultural Science, Guiyang, Guizhou 550006, China;1. Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran;2. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran;3. Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran;1. Institute of Exact Sciences, Department of Chemistry, Federal University of Minas Gerais, Belo Horizonte 31270-901, MG, Brazil;2. Mycobacteria Laboratory, School of Medicine, Federal University of Rio Grande, Rio Grande 96200-190, RS, Brazil;3. Institute of Physics, University of São Paulo, São Carlos 13560-160, SP, Brazil;1. Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China;2. Department of Physiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China;3. Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, China;1. College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, PR China;2. College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China;3. Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., No. 9 Weidi Road, Nanjing 210046, PR China;4. College of Chemistry and Materials Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China;1. Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia;2. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia;3. School of Science, STEM College, RMIT University, Melbourne, Victoria 3000, Australia |
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| Abstract: | On the basis of the structures of serotonin modulators or drugs (NAN-190, buspirone, aripiprazole) and phosphodiesterase 4 (PDE4) inhibitors (rolipram, RO-20-1724), a series of novel multitarget 5-arylidenehydantoin derivatives with arylpiperazine fragment was synthesized. Among these compounds, 5-(3,4-dimethoxybenzylidene-3-(4-(4-(2,3-dichlorophenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (13) and 5-(3-cyclopentyloxy-4-methoxybenzylidene-3-(4-(4-(2-methoxyphenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (18) were found to be the most promising showing very high affinity toward 5-HT1A and 5-HT7 receptors (Ki = 0.2–1.0 nM) but a negligible inhibitory effect on PDE4. The high affinity of the compounds for 5-HT1A and 5-HT7 receptors was further investigated by computer-aided studies. Moreover, compounds 13 and 18 showed no significant cytotoxicity in the MTT assay, but high clearance in the in vitro assay. In addition, these compounds behaved like 5-HT1A and 5-HT7 receptor antagonists and exhibited antidepressant-like activity, similar to the reference drug citalopram, in an animal model of depression. |
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| Keywords: | Hydantoin PDE4 inhibitors Cytotoxicity Antidepressant activity |
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