Discovery of long-chain salicylketoxime derivatives as monoacylglycerol lipase (MAGL) inhibitors

European Journal of Medicinal Chemistry
Giulia BononiTiziano Tuccinardi

Abstract

Monoacylglycerol lipase (MAGL) is the enzyme hydrolyzing the endocannabinoid 2-arachidonoylglycerol (2-AG) to free arachidonic acid and glycerol. Therefore, MAGL is implicated in many physiological processes involving the regulation of the endocannabinoid system and eicosanoid network. MAGL inhibition represents a potential therapeutic target for many diseases, including cancer. Nowadays, most MAGL inhibitors inhibit this enzyme by an irreversible mechanism of action, potentially leading to unwanted side effects from chronic treatment. Herein, we report the discovery of long-chain salicylketoxime derivatives as potent and reversible MAGL inhibitors. The compounds herein described are characterized by a good target selectivity for MAGL and by antiproliferative activities against a series of cancer cell lines. Finally, modeling studies suggest a reasonable hypothetical binding mode for this class of compounds.

Citations

Jan 31, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Giulio PoliCarlotta Granchi
Apr 21, 2019·International Journal of Molecular Sciences·Laura MicheliLorenzo Di Cesare Mannelli
Jul 10, 2020·Biomolecules·Francesco BalestriAntonella Del Corso
Mar 2, 2019·International Journal of Molecular Sciences·Margherita LapilloGiulio Poli
Oct 28, 2019·Antioxidants·Francesco BalestriRoberta Moschini
Oct 22, 2020·Expert Opinion on Therapeutic Patents·Giulia BononiCarlotta Granchi
Jan 15, 2021·Scientific Reports·Salvatore SantamariaJosefin Ahnström
Dec 29, 2020·Frontiers in Oncology·Wenjun WangJiuwei Cui
Mar 27, 2021·Bioorganic & Medicinal Chemistry Letters·Fengmin XiongHeng Xu
Jul 5, 2021·European Journal of Medicinal Chemistry·Giulia BononiTiziano Tuccinardi
Dec 5, 2021·Chemical Biology & Drug Design·Jia-Zhu ChiganKe-Wu Yang
Sep 14, 2021·Annual Review of Pharmacology and Toxicology·Daniele Piomelli, Alex Mabou Tagne

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