Exploring Basic Tail Modifications of Coumarin-Based Dual Acetylcholinesterase-Monoamine Oxidase B Inhibitors: Identification of Water-Soluble, Brain-Permeant Neuroprotective Multitarget Agents
| العنوان: | Exploring Basic Tail Modifications of Coumarin-Based Dual Acetylcholinesterase-Monoamine Oxidase B Inhibitors: Identification of Water-Soluble, Brain-Permeant Neuroprotective Multitarget Agents |
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| المؤلفون: | Roberta Farina, Cosimo Altomare, Rosa Maria Iacobazzi, Orazio Nicolotti, Leonardo Pisani, Saverio Cellamare, Angelo Carotti, Giuseppe Felice Mangiatordi, Marco Catto, Nunzio Denora, Ramón Soto-Otero, Lydia Siragusa |
| المصدر: | Journal of medicinal chemistry 59 (2016): 6791–6806. doi:10.1021/acs.jmedchem.6b00562 info:cnr-pdr/source/autori:Pisani, Leonardo; Farina, Roberta; Catto, Marco; Iacobazzi, Rosa Maria; Nicolotti, Orazio; Cellamare, Saverio; Mangiatordi, Giuseppe Felice; Denora, Nunzio; Soto-Otero, Ramon; Siragusa, Lydia; Altomare, Cosimo Damian; Carotti, Angelo/titolo:Exploring Basic Tail Modifications of Coumarin-Based Dual Acetylcholinesterase-Monoamine Oxidase B Inhibitors: Identification of Water-Soluble, Brain-Permeant Neuroprotective Multitarget Agents/doi:10.1021%2Facs.jmedchem.6b00562/rivista:Journal of medicinal chemistry/anno:2016/pagina_da:6791/pagina_a:6806/intervallo_pagine:6791–6806/volume:59 |
| بيانات النشر: | American Chemical Society (ACS), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Monoamine Oxidase Inhibitors, Cell Survival, Monoamine oxidase, 01 natural sciences, Neuroprotection, Madin Darby Canine Kidney Cells, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Dogs, Coumarins, Cell Line, Tumor, Drug Discovery, Animals, Humans, Structure–activity relationship, Cytotoxicity, Monoamine Oxidase, IC50, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Water, Rotenone, Acetylcholinesterase, 0104 chemical sciences, Oxidative Stress, Neuroprotective Agents, 030104 developmental biology, Solubility, chemistry, Biochemistry, Molecular Medicine, Cholinesterase Inhibitors, Monoamine oxidase B, Medicinal Chemistry |
| الوصف: | Aiming at modulating two key enzymatic targets for Alzheimers disease (AD), i.e., acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), a series of multitarget ligands was properly designed by linking the 3,4-dimethylcoumarin scaffold to 1,3- and 1,4-substituted piperidine moieties, thus modulating the basicity to improve the hydrophilic/lipophilic balance. After in vitro enzymatic inhibition assays, multipotent inhibitors showing potencies in the nanomolar and in the low micromolar range for hMAO B and eeAChE, respectively, were prioritized and evaluated in human SH-SY5Y cell-based models for their cytotoxicity and neuroprotective effect against oxidative toxins (H2O2, rotenone, and oligomycin-A). The present study led to the identification of a promising multitarget hit compound (5b) exhibiting high hMAO B inhibitory activity (IC50 = 30 nM) and good MAO B/A selectivity (selectivity index, SI = 94) along with a micromolar eeAChE inhibition (IC50 = 1.03 mu M). Moreover, 5b behaves as a water-soluble, brain-permeant neuroprotective agent against oxidative insults without interacting with P-gp efflux system. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5fd602b86f863e6fb085cd996912bed9 https://doi.org/10.1021/acs.jmedchem.6b00562 |
| حقوق: | RESTRICTED |
| رقم الأكسشن: | edsair.doi.dedup.....5fd602b86f863e6fb085cd996912bed9 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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