Combining Experimental and Computational Methods to Produce Conjugates of Anticholinesterase and Antioxidant Pharmacophores with Linker Chemistries Affecting Biological Activities Related to Treatment of Alzheimer's Disease
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Le résumé fourni par la source
Effective therapeutics for Alzheimer's disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of 4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities pertaining to AD treatment. Here, we report significant extensions of these studies, including the use of variable-length spacers and more detailed biological characterizations. Conjugates were potent inhibitors of acetylcholinesterase (AChE, minimum IC50 15.1±0.2 nM) and butyrylcholinesterase (BChE, minimum IC50 5.96±0.58 nM), with weak inhibition of off-target carboxylesterase. Conjugates with alkylamine spacers were more effective cholinesterase inhibitors than alkylimine analogs. Optimal inhibition for AChE was exhibited by cyclohexaquinoline and for BChE by cycloheptaquinoline. Increasing spacer length elevated potency against both cholinesterases. Structure-activity relationships agreed with docking results. Mixed-type reversible AChE inhibition, dual docking to catalytic and peripheral anionic sites, and propidium iodide displacement suggested the potential of hybrids to block AChE-induced β-amyloid (Aβ) aggregation. Hybrids also exhibited inhibition of Aβ self-aggregation in the thioflavin test; those with a hexaquinoline ring and C8 spacer were the most active. Conjugates demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Quantum-chemical calculations explained antioxidant results. Computed ADMET profiles indicated favorable blood-brain barrier permeability suggesting CNS activity potential. Thus, the conjugates could be considered promising multifunctional agents for potential treatment of AD.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Combining Experimental and Computational Methods to Produce Conjugates of Anticholinesterase and Antioxidant Pharmacophores with Linker Chemistries Affecting Biological Activities Related to Treatment of Alzheimer's Disease
- Date Crossref
- 07/11/2023
- Éditeur
- MDPI AG
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Institute of Physiologically Active Compounds pays non établi dans la noticeStructure de recherche
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Institute of Biochemical Physics NM Emanuel pays non établi dans la noticeStructure de recherche
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Institute of Problems of Chemical Physics pays non établi dans la noticeStructure de recherche
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Lomonosov Moscow State University Department of Chemistry pays non établi dans la noticeUniversité ou école supérieure
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Moscow State University pays non établi dans la noticeUniversité ou école supérieure
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University of Michigan Center of Computational Medicine and Bioinformatics pays non établi dans la noticeUniversité ou école supérieure
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Emanuel Institute of Biochemical Physics Russian Academy of Sciences pays non établi dans la noticeStructure de recherche
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Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry pays non établi dans la noticeStructure de recherche
Institute of Physiologically Active Compounds, Institute of Biochemical Physics NM Emanuel et Institute of Problems of Chemical Physics, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.