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Targeting MGL through allosteric mechanisms is a promising strategy to modulate 2\u2010AG levels while avoiding limitations associated with active site\u2013directed inhibitors. In this study, we aimed to develop selective MGL inhibitors based on isothiazolinone (ITZ) and benzisothiazolinone (BTZ) scaffolds that covalently target the regulatory cysteine residues Cys201 and Cys208 forming disulfide adducts. Two complementary approaches were explored. First, a mechanism\u2010based strategy was designed to exploit MGL\u2010mediated hydrolysis of\n                    <jats:italic>O<\/jats:italic>\n                    \u2010substituted (benz)isothiazol\u20103\u2010ol derivatives, enabling localized release of the reactive warhead in proximity to the target cysteines. Second, to enhance molecular recognition, tailored substituents were introduced on the BTZ scaffold to promote selective interactions with residues surrounding the allosteric site. Although several compounds displayed nanomolar inhibitory activity, structure\u2013activity relationship analysis indicated that inhibitory potency is primarily driven by intrinsic warhead reactivity rather than specific protein\u2013ligand interactions. Overall, these findings highlight both the potential and the challenges of developing selective covalent allosteric MGL inhibitors, emphasizing the need for strategies that better balance reactivity and molecular recognition.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70414","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T07:43:03Z","timestamp":1787643783000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Iso\u2010 and Benzisothiazolinone Inhibitors of Monoacylglycerol Lipase: Exploring On\u2010Target Activity Through Scaffold Decoration and In Situ Warhead Generation"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4364-3409","authenticated-orcid":false,"given":"Edoardo","family":"Rocca","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze degli Alimenti e del Farmaco Universit\u00e0 degli Studi di Parma  Parma 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