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Design of Promising Thiazoloindazole-Based Acetylcholinesterase Inhibitors Guided by Molecular Docking and Experimental Insights

2024-08-07Artigo científico Acesso aberto
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dc.contributor.authorLaghchioua, Fatima Ezzahra
dc.contributor.authorda Silva, Carlos F. M.
dc.contributor.authorPinto, Diana C. G. A.
dc.contributor.authorCavaleiro, José A.S.
dc.contributor.authorMendes, Ricardo F.
dc.contributor.authorPaz, Filipe A.Almeida
dc.contributor.authorFaustino, Maria A.F.
dc.contributor.authorRakib, El Mostapha
dc.contributor.authorNeves, M. Graça P.M.S.
dc.contributor.authorPereira, Florbela
dc.contributor.authorMoura, Nuno M.M.
dc.contributor.institutionLAQV@REQUIMTE
dc.contributor.institutionDQ - Departamento de Química
dc.contributor.pblACS - American Chemical Society
dc.date.accessioned2025-02-04T21:16:04Z
dc.date.available2025-02-04T21:16:04Z
dc.date.issued2024-08-07
dc.descriptionFunding Information: The authors also thank the Sultan Moulay Slimane University. R.F.M. and F.P. gratefully acknowledge FCT for a Assistant Research Position (CEECIND/01649/2021). We thank Chemaxon Ltd. for access to JChem, Reactor, and Marvin. Publisher Copyright: © 2024 The Authors. Published by American Chemical Society.
dc.description.abstractAlzheimer’s disease is characterized by a progressive deterioration of cognitive function and memory loss, and it is closely associated with the dysregulation of cholinergic neurotransmission. Since acetylcholinesterase (AChE) is a critical enzyme in the nervous system, responsible for breaking down the neurotransmitter acetylcholine, its inhibition holds a significant interest in the treatment of various neurological disorders. Therefore, it is crucial to develop efficient AChE inhibitors capable of increasing acetylcholine levels, ultimately leading to improved cholinergic neurotransmission. The results reported here represent a step forward in the development of novel thiazoloindazole-based compounds that have the potential to serve as effective AChE inhibitors. Molecular docking studies revealed that certain of the evaluated nitroindazole-based compounds outperformed donepezil, a well-known AChE inhibitor used in Alzheimer’s disease treatment. Sustained by these findings, two series of compounds were synthesized. One series included a triazole moiety (Tl45a-c), while the other incorporated a carbazole moiety (Tl58a-c). These compounds were isolated in yields ranging from 66 to 87% through nucleophilic substitution and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reactions. Among the synthesized compounds, the thiazoloindazole-based 6b core derivatives emerged as selective AChE inhibitors, exhibiting remarkable IC50 values of less than 1.0 μM. Notably, derivative Tl45b displays superior performance as an AChE inhibitor, boasting the lowest IC50 (0.071 ± 0.014 μM). Structure-activity relationship (SAR) analysis indicated that derivatives containing the bis(trifluoromethyl)phenyl-triazolyl group demonstrated the most promising activity against AChE, when compared to more rigid substituents such as carbazolyl moiety. The combination of molecular docking and experimental synthesis provides a suitable and promising strategy for the development of new efficient thiazoloindazole-based AChE inhibitors.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent17
dc.format.extent6606418
dc.identifier.doi10.1021/acschemneuro.4c00241
dc.identifier.issn1948-7193
dc.identifier.otherPURE: 98624236
dc.identifier.otherPURE UUID: b94dc555-7e3d-41e6-9017-9ea48a7fbf83
dc.identifier.otherScopus: 85199271552
dc.identifier.otherPubMed: 39037949
dc.identifier.otherORCID: /0000-0003-4392-4644/work/177366655
dc.identifier.urihttp://hdl.handle.net/10362/178412
dc.identifier.urlhttps://www.scopus.com/pages/publications/85199271552
dc.language.isoeng
dc.peerreviewedyes
dc.relationinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F50006%2F2020/PT
dc.relationinfo:eu-repo/grantAgreement/FCT/Concurso de avaliação no âmbito do Programa Plurianual de Financiamento de Unidades de I&D (2017%2F2018) - Financiamento Programático/UIDP%2F50006%2F2020/PT
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dc.relationCICECO-Aveiro Institute of Materials
dc.relationinfo:eu-repo/grantAgreement/FCT/Concurso para Atribuição do Estatuto e Financiamento de Laboratórios Associados (LA)/LA%2FP%2F0006%2F2020/PT
dc.relationFunding Information: N.M.M.M. thanks FCT for funding through program DL 57/2016 \u2013 Norma transito\u0301ria (CDL-CTTRI-048\u201388-ARH/2018). F.P. gratefully acknowledges FCT for an Assistant Research Position (CEECIND/01649/2021). info:eu-repo/grantAgreement/FCT/Concurso para Atribuição do Estatuto e Financiamento de Laboratórios Associados (LA)/LA%2FP%2F0008%2F2020/PT
dc.relationinfo:eu-repo/grantAgreement/FCT/Concurso de avaliação no âmbito do Programa Plurianual de Financiamento de Unidades de I&D (2017%2F2018) - Financiamento Programático/UIDP%2F50006%2F2020/PT
dc.relationAssociated Laboratory for Green Chemistry - Clean Technologies and Processes
dc.relationNot Available
dc.relationDesign, synthesis and evaluation of novel potential anti-leishmanial inhibitors
dc.relationinfo:eu-repo/grantAgreement/FCT//COVID%2FBD%2F151838%2F2021/PT
dc.subjectacetylcholinesterase
dc.subjectAlzheimer’s disease
dc.subjectmolecular docking
dc.subjectN-heterocycles
dc.subjectsingle-crystal X-ray diffraction
dc.subjecttarget prediction
dc.subjectthiazolo-indazoles
dc.subjectBiochemistry
dc.subjectPhysiology
dc.subjectCognitive Neuroscience
dc.subjectCell Biology
dc.titleDesign of Promising Thiazoloindazole-Based Acetylcholinesterase Inhibitors Guided by Molecular Docking and Experimental Insightsen
dc.typejournal article
degois.publication.firstPage2853
degois.publication.issue15
degois.publication.lastPage2869
degois.publication.titleAcs Chemical Neuroscience
degois.publication.volume15
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oaire.fundingStreamConcurso de avaliação no âmbito do Programa Plurianual de Financiamento de Unidades de I&D (2017/2018) - Financiamento Programático
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