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a class of synthetic new psychoactive substances (NPSs), continue to emerge and pose public threats. Government control efforts often lead to the emergence of new isomers, which have adverse repercussions on NPSs identification and risk prediction. This work reports on the synthesis and structural characterization of twenty chloro-cathinones, including different isomers, to create analytical data to facilitate their identification in forensic and clinical contexts. Additionally, the potential of these cathinones to cause neuronal damage was evaluated. In vitro cytotoxicity was assessed using a differentiated human neuroblastoma cell line (SH-SY5Y) as a dopaminergic neuronal model. The tested cathinones showed LC50 values from 0.6 to 2.5 mM, with 4-CBC being the most cytotoxic. The most toxic cathinones increase reactive oxygen species levels and\/or cause mitochondrial membrane potential depolarization. Furthermore, this study explored, for the first time, the effect of cathinones on the cholinergic system through acetylcholinesterase (AChE) inhibition. All tested cathinones inhibited AChE with IC50 values between 0.1 and 2 mM. Molecular docking analysis revealed that the most inhibitory cathinones interacted with the CASs and PASs in AChE\u2019s active gorge. These findings provide valuable insights into the effects of cathinones, highlighting potential health risks and structural features that may influence their toxicity towards the cholinergic system and neuronal damage.<\/jats:p>","DOI":"10.3390\/ijms26083540","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T12:05:56Z","timestamp":1744200356000},"page":"3540","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Synthesis, Characterization, and Biological Effects of Chloro-Cathinones: Toxicity and Potential Neurological Impact"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2286-9817","authenticated-orcid":false,"given":"Ana Patr\u00edcia","family":"Gomes","sequence":"first","affiliation":[{"name":"BioISI\u2014Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal"},{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal"},{"name":"Departamento de Engenharia Qu\u00edmica, Instituto Superior de Engenharia de Lisboa, Av. Conselheiro Em\u00eddio Navarro, 1959-007 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2300-0711","authenticated-orcid":false,"given":"Raquel","family":"Ferro","sequence":"additional","affiliation":[{"name":"BioISI\u2014Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal"}]},{"given":"Daniela","family":"Pinto","sequence":"additional","affiliation":[{"name":"BioISI\u2014Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1224-1699","authenticated-orcid":false,"given":"Joana","family":"Silva","sequence":"additional","affiliation":[{"name":"MARE\u2014Marine and Environmental Sciences Centre, ARNET\u2014Aquatic Research Network, ESTM, Polytechnic University of Leiria, 2520-614 Peniche, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1581-2127","authenticated-orcid":false,"given":"Celso","family":"Alves","sequence":"additional","affiliation":[{"name":"MARE\u2014Marine and Environmental Sciences Centre, ARNET\u2014Aquatic Research Network, ESTM, Polytechnic University of Leiria, 2520-614 Peniche, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5192-3006","authenticated-orcid":false,"given":"Rita","family":"Pacheco","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal"},{"name":"Departamento de Engenharia Qu\u00edmica, Instituto Superior de Engenharia de Lisboa, Av. Conselheiro Em\u00eddio Navarro, 1959-007 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1613-7023","authenticated-orcid":false,"given":"Helena","family":"Gaspar","sequence":"additional","affiliation":[{"name":"BioISI\u2014Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s00204-013-1163-9","article-title":"Khat and synthetic cathinones: A review","volume":"88","author":"Valente","year":"2014","journal-title":"Arch. Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1007\/s11101-015-9435-z","article-title":"Chemical composition of Catha edulis (khat): A review","volume":"15","author":"Getasetegn","year":"2016","journal-title":"Phytochem. 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