N-Substituted 3-Aminooxindoles and N-Propargyl Derivatives: Potential Biological Activities against Alzheimer’s Disease
The oxindole core is an important structural motif in many natural and synthetic substances with various biological activities including anticancer, antineurodegenerative, and antimicrobial properties. This report focuses on the synthesis and biological activity of a series of novel N-substituted 3-...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Results in Chemistry |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211715623002710 |
| _version_ | 1797398630553878528 |
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| author | Tereza Hofmanova Carolina Marques Alfonso T. García-Sosa Óscar López Luisa Leitzbach Elisabete P. Carreiro Aday González-Bakker Adrián Puerta Holger Stark José M. Padrón José G. Fernández-Bolaños Anthony J. Burke |
| author_facet | Tereza Hofmanova Carolina Marques Alfonso T. García-Sosa Óscar López Luisa Leitzbach Elisabete P. Carreiro Aday González-Bakker Adrián Puerta Holger Stark José M. Padrón José G. Fernández-Bolaños Anthony J. Burke |
| author_sort | Tereza Hofmanova |
| collection | DOAJ |
| description | The oxindole core is an important structural motif in many natural and synthetic substances with various biological activities including anticancer, antineurodegenerative, and antimicrobial properties. This report focuses on the synthesis and biological activity of a series of novel N-substituted 3-aminooxindoles and their assessment in cholinesterase (ChE) and monoamine oxidase (MAO) inhibition. With regard to MAO inhibition, a series of N-propargyl containing derivatives was synthesized and screened. Despite being weak inhibitors of MAO-A and MAO-B, the compounds were selective for butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE). Most of them were strong inhibitors of BuChE with IC50's of less than 1 µM, and one compound showed an IC50 = 27 nM. The mechanism of action of the inhibition was pin-pointed through molecular modeling, and was validated using saturation-transfer-difference (STD) NMR. Some of the compounds were screened for anti-oxidant properties, but showed no activity. The same compounds were screened in the neurodegenerative disease model cell-line SH-SY5Y and although some were found to be non-cytotoxic, others were moderately cytotoxic. Continuous live cell imaging experiments showed that the compounds do not induce relevant cell damage and thus, the compounds might be interesting drug candidates for Alzheimer’s disease. Furthermore, the most active compounds showed excellent drug-likeness and pharmacological properties predicted using Swiss-ADME, and the pharmacokinetic simulations indicated that all these compounds cross the blood-brain-barrier. |
| first_indexed | 2024-03-09T01:28:20Z |
| format | Article |
| id | doaj.art-75d359ef21d247a498f7e6bdb867b7b7 |
| institution | Directory Open Access Journal |
| issn | 2211-7156 |
| language | English |
| last_indexed | 2024-03-09T01:28:20Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Results in Chemistry |
| spelling | doaj.art-75d359ef21d247a498f7e6bdb867b7b72023-12-10T06:14:58ZengElsevierResults in Chemistry2211-71562023-12-016101032N-Substituted 3-Aminooxindoles and N-Propargyl Derivatives: Potential Biological Activities against Alzheimer’s DiseaseTereza Hofmanova0Carolina Marques1Alfonso T. García-Sosa2Óscar López3Luisa Leitzbach4Elisabete P. Carreiro5Aday González-Bakker6Adrián Puerta7Holger Stark8José M. Padrón9José G. Fernández-Bolaños10Anthony J. Burke11LAQV-REQUIMTE, University of Évora, Institute for Research and Advanced Studies, Rua Romão Ramalho, 59, 7000-671 Évora, Portugal; Chemistry and Biochemistry Department, School of Science and Technology, University of Évora, Rua Romão Ramalho 59, 7000-671 Évora, Portugal; Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanského 62, 50003 Hradec Králové, Czech RepublicLAQV-REQUIMTE, University of Évora, Institute for Research and Advanced Studies, Rua Romão Ramalho, 59, 7000-671 Évora, PortugalInstitute of Chemistry, University of Tartu, Ravila 14 A, Tartu 50411, EstoniaDepartamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, SpainBioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Universidad de La Laguna, c/ Astrofísico Francisco Sánchez 2, E-38206 La Laguna, SpainLAQV-REQUIMTE, University of Évora, Institute for Research and Advanced Studies, Rua Romão Ramalho, 59, 7000-671 Évora, PortugalBioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Universidad de La Laguna, c/ Astrofísico Francisco Sánchez 2, E-38206 La Laguna, SpainBioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Universidad de La Laguna, c/ Astrofísico Francisco Sánchez 2, E-38206 La Laguna, SpainHeinrich Heine University Düsseldorf, Institute of Pharmaceutical and Medicinal Chemistry. Universitaetsstr. 1, 40225 Duesseldorf, GermanyBioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Universidad de La Laguna, c/ Astrofísico Francisco Sánchez 2, E-38206 La Laguna, SpainDepartamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, SpainLAQV-REQUIMTE, University of Évora, Institute for Research and Advanced Studies, Rua Romão Ramalho, 59, 7000-671 Évora, Portugal; Chemistry and Biochemistry Department, School of Science and Technology, University of Évora, Rua Romão Ramalho 59, 7000-671 Évora, Portugal; Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Centro de Química de Coimbra, Institute of Molecular Sciences, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, 3004-535 COIMBRA, Portugal; Center for Neurosciences and Cellular Biology (CNC), Polo I, Universidade de Coimbra Rua Larga Faculdade de Medicina, Polo I, 1°andar, 3004–504, Coimbra, Portugal; Corresponding author at: LAQV-REQUIMTE, University of Évora, Institute for Research and Advanced Studies, Rua Romão Ramalho, 59, 7000-671 Évora, Portugal.The oxindole core is an important structural motif in many natural and synthetic substances with various biological activities including anticancer, antineurodegenerative, and antimicrobial properties. This report focuses on the synthesis and biological activity of a series of novel N-substituted 3-aminooxindoles and their assessment in cholinesterase (ChE) and monoamine oxidase (MAO) inhibition. With regard to MAO inhibition, a series of N-propargyl containing derivatives was synthesized and screened. Despite being weak inhibitors of MAO-A and MAO-B, the compounds were selective for butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE). Most of them were strong inhibitors of BuChE with IC50's of less than 1 µM, and one compound showed an IC50 = 27 nM. The mechanism of action of the inhibition was pin-pointed through molecular modeling, and was validated using saturation-transfer-difference (STD) NMR. Some of the compounds were screened for anti-oxidant properties, but showed no activity. The same compounds were screened in the neurodegenerative disease model cell-line SH-SY5Y and although some were found to be non-cytotoxic, others were moderately cytotoxic. Continuous live cell imaging experiments showed that the compounds do not induce relevant cell damage and thus, the compounds might be interesting drug candidates for Alzheimer’s disease. Furthermore, the most active compounds showed excellent drug-likeness and pharmacological properties predicted using Swiss-ADME, and the pharmacokinetic simulations indicated that all these compounds cross the blood-brain-barrier.http://www.sciencedirect.com/science/article/pii/S2211715623002710OxindoleAlzheimer’s diseaseCholinesteraseMono-amine oxidaseMolecular dockingSTD-NMR |
| spellingShingle | Tereza Hofmanova Carolina Marques Alfonso T. García-Sosa Óscar López Luisa Leitzbach Elisabete P. Carreiro Aday González-Bakker Adrián Puerta Holger Stark José M. Padrón José G. Fernández-Bolaños Anthony J. Burke N-Substituted 3-Aminooxindoles and N-Propargyl Derivatives: Potential Biological Activities against Alzheimer’s Disease Results in Chemistry Oxindole Alzheimer’s disease Cholinesterase Mono-amine oxidase Molecular docking STD-NMR |
| title | N-Substituted 3-Aminooxindoles and N-Propargyl Derivatives: Potential Biological Activities against Alzheimer’s Disease |
| title_full | N-Substituted 3-Aminooxindoles and N-Propargyl Derivatives: Potential Biological Activities against Alzheimer’s Disease |
| title_fullStr | N-Substituted 3-Aminooxindoles and N-Propargyl Derivatives: Potential Biological Activities against Alzheimer’s Disease |
| title_full_unstemmed | N-Substituted 3-Aminooxindoles and N-Propargyl Derivatives: Potential Biological Activities against Alzheimer’s Disease |
| title_short | N-Substituted 3-Aminooxindoles and N-Propargyl Derivatives: Potential Biological Activities against Alzheimer’s Disease |
| title_sort | n substituted 3 aminooxindoles and n propargyl derivatives potential biological activities against alzheimer s disease |
| topic | Oxindole Alzheimer’s disease Cholinesterase Mono-amine oxidase Molecular docking STD-NMR |
| url | http://www.sciencedirect.com/science/article/pii/S2211715623002710 |
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