ETD

• Cancer
• Cancer cells
• Endocannabinoid system
• Enzymatic Modulation
• MAGL
• Monoacylglycerol Lipase
• Reversible inhibitors

Monoacylglycerol lipase (MAGL) is a key enzyme of the endocannabinoid system, responsible for the hydrolysis of 2-arachidonoylglycerol and the generation of arachidonic acid, thereby linking endocannabinoid signaling to lipid metabolism. Dysregulation of MAGL activity has been associated with several pathological conditions, including inflammatory and metabolic disorders as well as cancer, making this enzyme an attractive pharmacological target. This thesis focused on the synthesis and optimization of novel reversible MAGL inhibitors. Starting from the irreversible inhibitor SAR127303, structural modifications were introduced to remove the covalent warhead while preserving the main pharmacophoric features required for the enzyme recognition, leading to a series of sulfonamide derivatives. A further series of 1,2,3-triazole derivatives was also synthesized through bioisosteric replacement of the sulfonamide moiety. The resulting compounds were investigated to expand structure-activity relationships and support the development of potent reversible MAGL modulators with potential therapeutic applications.