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It is identified for the first time Deferasirox, a well\u2010known FDA\u2010approved iron chelator (DFX) as an initial hit for kallikrein's (KLK) inhibition and proposed here the design and synthesis of a small library of molecules using DFX as chemical scaffold. Resulting subseries of compounds are evaluated against lead central nervous system KLK's, namely, KLK1, KLK6, and KLK8 using targeted pharmacomodulations on DFX. Beyond DFX, several reversible micromolar inhibitors of these KLKs have been identified as hits and are shown to be devoid of any noticeable cytotoxicity toward neural cell lines commonly used in the field of neurodegenerative diseases. Their ability to chelate iron is also assessed in comparison to DFX and preformed iron\u2010compound complexes displayed slightly improved inhibition potency for some derivatives with a KLK\u2010dependent manner. Hence, several DFX derivatives are identified as promising starting points for the development of dual therapeutic agents in the context of neurodegenerative diseases where both deregulated KLK's proteolysis and iron dysregulation are involved.<\/jats:p>","DOI":"10.1002\/cmdc.202500187","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T17:02:27Z","timestamp":1744045347000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Deferasirox Derivatives as Inhibitors of Kallikrein\u2010Related Peptidases Associated to Neurodegenerative Diseases"],"prefix":"10.1002","volume":"20","author":[{"given":"Ril\u00e8s","family":"Boumali","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9 CNRS INSERM Institut de Biologie Paris\u2010Seine Biological Adaptation and Ageing (B2A\u2010IBPS)  Paris F\u201075252 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