2. Academic Validation
  3. Discovery of reversible monoacylglycerol lipase (MAGL) inhibitors based on ortho-hydroxyanilide scaffold

Discovery of reversible monoacylglycerol lipase (MAGL) inhibitors based on ortho-hydroxyanilide scaffold

  • Bioorg Chem. 2025 Aug:163:108698. doi: 10.1016/j.bioorg.2025.108698.
Giulia Bononi 1,  Francesca Gado 2,  Samuele Masoni 1,  Diana Scalabrini 1,  Larissa Della Vedova 3,  Miriana Di Stefano 1,  Lisa Piazza 1,  Clarissa Poles 4,  Chiara Lonzi 1,  Eva Landucci 5,  Chiara Vagaggini 6,  Federica Poggialini 6,  Annalaura Brai 6,  Isabella Caligiuri 7,  Flavio Rizzolio 8,  Kawthar A Mohamed 9,  Simone Bertini 1,  Ersilia De Lorenzi 10,  Elena Dreassi 6,  Marco Macchia 1,  Filippo Minutolo 1,  Robert B Laprairie 9,  Carlotta Granchi 11,  Tiziano Tuccinardi 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
  • 2 Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milano, Italy; Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy.
  • 3 Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milano, Italy; Department of Biomolecular Health Sciences, Division of Cell Biology, Metabolism & Cancer, University of Utrecht, Yalelaan 2, 3584, CM, Utrecht, the Netherlands.
  • 4 Genomics and Experimental Medicine Program, Scuola Superiore Meridionale (SSM, School of Advanced Studies), Via Mezzocannone 4, 80078 Napoli, Italy; Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078 Napoli, Italy.
  • 5 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy; Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
  • 6 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 2, 53100 Siena, Italy.
  • 7 Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy.
  • 8 Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; Department of Molecular Sciences and Nanosystems, Ca' Foscari University, 30123 Venezia, Italy.
  • 9 College of Pharmacy and Nutrition, University of Saskatchewan, 107 Wiggins Road, S7N 5E5 Saskatoon, SK, Canada.
  • 10 Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy.
  • 11 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy. Electronic address: carlotta.granchi@unipi.it.
PMID: 40554889 DOI: 10.1016/j.bioorg.2025.108698
Abstract

Monoacylglycerol Lipase (MAGL) represents a key enzyme in the regulation of the endocannabinoid system and arachidonic acid signaling, emerging as a promising target for the treatment of inflammation, neurodegeneration, and Cancer. Herein, we report the design, synthesis, and biological evaluation of a novel series of o-hydroxyanilide derivatives as reversible MAGL inhibitors. Starting from a known salicylketoxime scaffold, we introduced strategic modifications to reduce lipophilicity and enhance selectivity and potency. Among the synthesized compounds, 4-phenylbutanamide 40 exhibited the most potent inhibitory activity against human MAGL (IC50 = 0.34 μM), outperforming reference compound 8 (IC50 = 0.68 μM), and showing good selectivity over FAAH and cannabinoid receptors CB1R and CB2R. Biochemical characterization confirmed a reversible and competitive mechanism of inhibition. Molecular modeling studies supported the key interactions of compound 40 with the MAGL oxyanion hole and hydrophobic pocket. In cellular assays, compound 40 activated the Nrf2 antioxidant pathway and significantly inhibited NFκB-mediated inflammation, without inducing cytotoxic effects. ADME profiling revealed good membrane permeability and excellent plasma stability, despite moderate metabolic stability in human liver microsomes. Taken together, these findings highlight compound 40 as a promising reversible MAGL Inhibitor endowed with anti-inflammatory and antioxidant properties, representing a valuable lead for the development of therapeutics targeting the endocannabinoid system.

Keywords

Inhibitors; MAGL; Monoacylglycerol lipase; Ortho-hydroxyanilide; Phenylbutanamide.

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