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

• Published in: Journal of medicinal chemistry Vol. 65; no. 18; pp. 12292 - 12318
• Main Authors: Turgutalp, Bengisu, Bhattarai, Prabesh, Ercetin, Tugba, Luise, Chiara, Reis, Rengin, Gurdal, Enise Ece, Isaak, Andreas, Biriken, Derya, Dinter, Elisabeth, Sipahi, Hande, Schepmann, Dirk, Junker, Anna, Wünsch, Bernhard, Sippl, Wolfgang, Gulcan, Hayrettin Ozan, Kizil, Caghan, Yarim, Mine
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.09.2022; Amer Chemical Soc
• Subjects: Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Animals; Chemistry, Medicinal; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Cholinesterase Inhibitors - therapeutic use; Cholinesterases; Donepezil - therapeutic use; Lead - therapeutic use; Life Sciences & Biomedicine; Ligands; Pharmacology & Pharmacy; Science & Technology; Zebrafish - metabolism; P2X7 RECEPTOR; TARGET; EXCITOTOXICITY; NMDA RECEPTORS; MOUSE MODEL; SIGMA-1 RECEPTOR; D-ASPARTATE RECEPTOR; SYNAPTIC PLASTICITY; BINDING; LIFE EXPECTANCY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01003

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 σ1R, σ2R, 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.