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Cyclic acyl guanidines bearing carbamate moieties allow potent and dirigible cholinesterase inhibition of either acetyl- or butyrylcholinesterase
Institution:1. Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany;2. Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany;1. Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York;2. Department of Radiology, The Icahn School of Medicine at Mount Sinai, New York, New York;3. Department of Cytopathology, The Icahn School of Medicine at Mount Sinai, New York, New York;4. Department of Molecular Diagnostics, The Icahn School of Medicine at Mount Sinai, New York, New York;1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China;2. University of Chinese Academy of Sciences, Beijing 100049, PR China;1. Department of Radiology, School of Medicine, Washington University in Saint Louis, Saint Louis, MO 63110, United States;2. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States;1. State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China;2. Jiangsu Kanion Pharmaceutical Co. Ltd., 58 South Haichang Road, Lianyungang 222001, PR China;3. State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Lianyungang 222001, 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. 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. School of Pharmacy, Health Sciences Campus, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1;2. Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Abstract:A series of cyclic acyl guanidine with carbamate moieties have been synthesized and evaluated in vitro for their AChE and BChE inhibitory activities. Structure?activity relationships identified compound 23 as a nanomolar and selective BChE inhibitor, while compound 32 exhibited nanomolar and selective AChE inhibition, selectivity depending on both the structure of the carbamate substituent as well as the position of guanidines-N substitution. The velocity of enzyme carbamoylation was analyzed and showed similar behavior to physostigmine. Phenolic compounds formed after carbamate transfer to the active site of cholinesterases showed additional neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation.
Keywords:Alzheimer’s disease  Cholinesterase inhibitors  Pseudoirreversible inhibition  Neuroprotection  Acyl guanidines
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