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The multifactorial etiology of age-related complex diseases, including Alzheimer's disease (AD), cancer, and type 2 diabetes mellitus (T2DM), challenges the efficacy of single-target therapeutics. The development of multi-target-directed ligands (MTDLs) represents a promising strategy to address these overlapping pathological networks. In this study, we employed a high-throughput phenotypic screening platform integrated with artificial intelligence (AI) to evaluate the pharmacological potential of a novel thiazolone derivative, Compound M. Consensus clustering analysis of zebrafish behavioral and physiological phenotypes against 103 clinical drugs predicted that Compound M possesses anti-AD activity at low concentrations and antitumor/antihyperglycemic effects at higher concentrations. Subsequent in vivo and in vitro validations confirmed these pleiotropic activities. In a zebrafish xenograft model, Compound M significantly inhibited Jurkat tumor cell proliferation (P < 0.001), exhibiting an in vitro cell viability IC50 of 10.7 μM. Furthermore, the compound demonstrated potent hypoglycemic effects in a high-fat diet-induced zebrafish model, comparable to the standard drug metformin. In an AlCl 3 -induced AD zebrafish model, Compound M significantly reduced acetylcholinesterase (AChE) activity by 38% (P < 0.001). In silico ADMET profiling predicted favorable intestinal absorption but limited blood-brain barrier (BBB) permeability and a potential risk for cardiac toxicity (hERG). Molecular docking studies revealed that Compound M engages the active sites of AChE and BACE1 primarily through hydrophobic interactions, acting as a partial-site binder. These findings establish Compound M as a promising lead scaffold for MTDL development, while highlighting specific structural optimization strategies—such as scaffold extension and physicochemical tuning—to enhance its CNS penetration and safety profile.
Cheng et al. (Fri,) studied this question.