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Acetylcholinesterase (AChE) is an important drug target in neurological disorders like Alzheimer's disease, Lewy body dementia, and Parkinson's disease dementia as well as for other conditions like myasthenia gravis and anticholinergic poisoning. In this study, we have used a combination of high-throughput screening, machine learning, and docking to identify new inhibitors of this enzyme. Bayesian machine learning models were generated with literature data from ChEMBL for eel and human AChE inhibitors as well as butyrylcholinesterase inhibitors (BuChE) and compared with other machine learning methods. High-throughput screens for the eel AChE inhibitor model identified several molecules including tilorone, an antiviral drug that is well-established outside of the United States, as a newly identified nanomolar AChE inhibitor. We have described how tilorone inhibits both eel and human AChE with IC 50 's of 14.4 nM and 64.4 nM, respectively, but does not inhibit the closely related BuChE IC 50 > 50 μM. We have docked tilorone into the human AChE crystal structure and shown that this selectivity is likely due to the reliance on a specific interaction with a hydrophobic residue in the peripheral anionic site of AChE that is absent in BuChE. We also conducted a pharmacological safety profile (SafetyScreen44) and kinase selectivity screen (SelectScreen) that showed tilorone (1 μM) only inhibited AChE out of 44 toxicology target proteins evaluated and did not appreciably inhibit any of the 485 kinases tested. This study suggests there may be a potential role for repurposing tilorone or its derivatives in conditions that benefit from AChE inhibition.