Discovery of Potent Cholinesterase Inhibition-Based Multi-Target-Directed Lead Compounds for Synaptoprotection in Alzheimer's Disease.

Autor: Turgutalp B; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, 34755 Istanbul, Turkey.; German Centre for Neurodegenerative Diseases (DZNE), Helmholtz Association, 01307 Dresden, Germany., Bhattarai P; German Centre for Neurodegenerative Diseases (DZNE), Helmholtz Association, 01307 Dresden, Germany.; Department of Neurology, Columbia University Irving Medical Center, 10032 New York, United States., Ercetin T; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Eastern Mediterranean University, TRNC, via Mersin 10, 99628 Famagusta, Turkey., Luise C; Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-Universität Halle-Wittenberg, 6099 Halle (Saale), Germany., Reis R; Department of Toxicology, Faculty of Pharmacy, Yeditepe University, 34755 Istanbul, Turkey.; Department of Toxicology, Faculty of Pharmacy, Acibadem Mehmet Ali Aydinlar University, 34758 Istanbul, Turkey., Gurdal EE; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, 34755 Istanbul, Turkey.; Institute of Chemistry, Martin-Luther-Universität Halle-Wittenberg, 06120 Halle, Germany., Isaak A; European Institute for Molecular Imaging (EIMI), der Westfälischen Wilhelms-Universität, D-48149 Münster, Germany., Biriken D; German Centre for Neurodegenerative Diseases (DZNE), Helmholtz Association, 01307 Dresden, Germany.; Department of Medical Microbiology, Ankara University Faculty of Medicine, 06620 Ankara, Turkey., Dinter E; German Centre for Neurodegenerative Diseases (DZNE), Helmholtz Association, 01307 Dresden, Germany.; Department of Neurology, University Clinic, TU Dresden, 01307 Dresden, Germany., Sipahi H; Department of Toxicology, Faculty of Pharmacy, Yeditepe University, 34755 Istanbul, Turkey., Schepmann D; Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, D-48149 Münster, Germany., Junker A; European Institute for Molecular Imaging (EIMI), der Westfälischen Wilhelms-Universität, D-48149 Münster, Germany., Wünsch B; Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, D-48149 Münster, Germany., Sippl W; Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-Universität Halle-Wittenberg, 6099 Halle (Saale), Germany., Gulcan HO; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Eastern Mediterranean University, TRNC, via Mersin 10, 99628 Famagusta, Turkey., Kizil C; German Centre for Neurodegenerative Diseases (DZNE), Helmholtz Association, 01307 Dresden, Germany.; Department of Neurology, Columbia University Irving Medical Center, 10032 New York, United States., Yarim M; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, 34755 Istanbul, Turkey.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2022 Sep 22; Vol. 65 (18), pp. 12292-12318. Date of Electronic Publication: 2022 Sep 09.
DOI: 10.1021/acs.jmedchem.2c01003
Abstrakt: Drug development efforts that focused on single targets failed to provide effective treatment for Alzheimer's disease (AD). Therefore, we designed cholinesterase inhibition (ChEI)-based multi-target-directed ligands (MTDLs) to simultaneously target AD-related receptors. We built a library of 70 compounds, sequentially screened for ChEI, and determined σ 1 R, σ 2 R, NMDAR-GluN2B binding affinities, and P2X7R antagonistic activities. Nine fulfilled in silico drug-likeness criteria and did not display toxicity in three cell lines. Seven displayed cytoprotective activity in two stress-induced cellular models. Compared to donepezil, six showed equal/better synaptic protection in a zebrafish model of acute amyloidosis-induced synaptic degeneration. Two P2X7R antagonists alleviated the activation state of microglia in vivo . Permeability studies were performed, and four did not inhibit CYP450 3A4, 2D6, and 2C9. Therefore, four ChEI-based lead MTDLs are promising drug candidates for synaptic integrity protection and could serve as disease-modifying AD treatment. Our study also proposes zebrafish as a useful preclinical tool for drug discovery and development.
Databáze: MEDLINE