Artículo
N-Substituted 3-Aminooxindoles and N-Propargyl Derivatives: Potential Biological Activities against Alzheimer's Disease
Autor/es | Hofmanova, Tereza
Marques, Carolina García-Sosa, Alfonso T. López López, Óscar Leitzbach, Luisa Carreiro, Elisabete P. Fernández-Bolaños Guzmán, José María Burke, Anthony J. |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2023-07-08 |
Fecha de depósito | 2024-05-23 |
Publicado en |
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Resumen | 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 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 Npropargyl 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 cellline 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. |
Agencias financiadoras | Fundação para a Ciência e a Tecnologia (FCT) Ministerio de Ciencia e Innovación (MICIN). España Junta de Andalucía Estonian Research Council Gobierno de España European Commission. Fondo Social Europeo (FSO) Islas Canarias ACIISI Asociación Española Contra el Cáncer (AECC) European Cooperation in Science and Technology (COST) Universidad de Hadrec Králové (Facultad de Ciencias) Erasmus+ |
Identificador del proyecto | UIDB/50006/2020|UIDP/50006/2020
PID2020-116460RB-100 FQM-134 PRG1509 PID2021-123059OB-I00 TESIS2020010055 15135 2019-1-CZ01-KA103-060058 |
Cita | Hofmanova, T., Marques, C., García-Sosa, A.T., López López, Ó., Leitzbach, L., Carreiro, E.P.,...,Burke, A.J. (2023). N-Substituted 3-Aminooxindoles and N-Propargyl Derivatives: Potential Biological Activities against Alzheimer's Disease. Results in chemistry, 6, 101032. https://doi.org/10.1016/j.rechem.2023.101032. |
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N-Substituted.pdf | 3.747Mb | [PDF] | Ver/ | |