Design, synthesis and biological evaluation of second-generation benzoylpiperidine derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors

Granchi, Carlotta; Bononi, Giulia; Ferrisi, Rebecca; Gori, Eleonora; Mantini, G.; Glasmacher, Sandra; Poli, Giulio; Palazzolo, Stefano; Caligiuri, Isabella; Rizzolio, Flavio; Canzonieri, Vincenzo; Perin, Tiziana; Gertsch, Jürg; Sodi, Andrea; Giovannetti, Elisa; Macchia, Marco; Minutolo, Filippo; Tuccinardi, Tiziano; Chicca, Andrea

doi:10.1016/j.ejmech.2020.112857

Cited by 34 publications

(33 citation statements)

References 59 publications

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“…The minimized complexes were used as input structures for the MD simulations, which were run using Particle Mesh Ewald (PME) electrostatics, a cutoff of 10 Å for the nonbonded interactions and periodic boundary conditions. The SHAKE algorithm was used to constrain all bonds involving hydrogen atoms and a time step of 2.0 fs was thus used for the simulations, following a protocol optimized from previous studies [ 21 ]. Initially, a heating stage of 1 ns, in which the temperature of the system was raised from 0 to 300 K, was performed using constant-volume periodic boundary conditions.…”

Section: Methodsmentioning

confidence: 99%

New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds

et al. 2022

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NAD+-dependent deacetylase SIRT1 regulates many different biological processes, thus being involved in pathogenic conditions such as metabolic diseases, neurogenerative disorders and cancer. Notably, experimental evidence underlined that the activation of SIRT1 had promising cardioprotective effects. Consequently, many efforts have been so far devoted to finding new SIRT1 activators, both derived from natural sources or prepared by synthetic procedures. Herein, we discovered new SIRT1-activating derivatives, characterized by phenolic rings spaced by sulfur, nitrogen or oxygen-based central linkers. The newly synthesized derivatives were analyzed in enzymatic assays to determine their ability to activate SIRT1, as compared with that of resveratrol. Among the tested molecules, bisarylaniline compound 10 proved to be the most efficient SIRT1 activator. An evaluation of the effects caused by focused structural variations revealed that its para-hydroxy-substituted diphenyl moiety of 10 was the fundamental structural requirement for achieving good SIRT1 activation. Compound 10 was further investigated in ex vivo studies in isolated and perfused rat hearts submitted to ischemia/reperfusion (I/R), where it showed significant protection of the myocardium against I/R injury. Molecular modeling studies suggest the binding mode of 10 within SIRT1 in the presence of the p53-AMC peptide. Our findings reveal that this chemical scaffold may be used as the starting point to develop a new class of more potent SIRT1 activators as cardioprotective agents.

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Section: Methodsmentioning

confidence: 99%

New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds

et al. 2022

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“…Hence, these four new nanomolar inhibitory benzoylpiperidine derivatives offer new prospects for the development of MAGL inhibitors as anticancer agents. [60]…”

Section: Anticancer Potential Of Magl Inhibitorsmentioning

confidence: 99%

“…The enzymatic and cell line assay results unveil that the potency of these compounds resides on the phenyl ring of the parent benzoyl piperidine moiety and particularly electronegative fluoro substituent greatly influences the MAGL inhibition properties. Hence, these four new nanomolar inhibitory benzoylpiperidine derivatives offer new prospects for the development of MAGL inhibitors as anticancer agents [60] …”

Section: Anticancer Potential Of Magl Inhibitorsmentioning

confidence: 99%

Anticancer Potential of Small‐Molecule Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase

Jaiswal

Ayyannan

2021

ChemMedChem

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Recently fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibitors have been in the limelight due to their anticancer potential. Both FAAH and MAGL are the endocannabinoid degrading enzymes that hydrolyze several endogenous ligands, mainly anandamide (AEA) and 2-arachidonic glycerol (2-AG), which regulate various pathophysiological conditions in the body such as emotion, cognition, energy balance, pain sensation, neuroinflammation, and cancer cell proliferation. FAAH and MAGL inhibitors block the metabolism of AEA and 2-AG, increase endogenous levels of fatty acid amides, and exert various therapeutic effects including chronic pain, metabolic disorders, psychoses, nausea and vomiting, depression, and anxiety disorders. FAAH and MAGL are primarily neurotherapeutic targets, but their contribution to various types of carcinomas are significant. Inhibitors of these enzymes either alone or as multitarget agents, or with supraadditive effects show the potential effect in ovarian, breast, prostate, and colorectal cancers. Besides highlighting the role of FAAH and MAGL in cancer progression, this review provides an update on the anticancer capabilities of known and newly discovered FAAH and MAGL inhibitors and also provides further directions to develop FAAH and MAGL inhibitors as new candidates for cancer therapy.

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“…The substitution of the chlorine in the structure of G1 with benzyl or phenylsulfide, but not phenylsulfone, improved the compounds’ potency. The addition of two fluorine atoms to the N-benzoyl fragment led to compound G3 ( Figure 8 ), a potent and reversible MAGL inhibitor with low effects on FAAH and ABHD6 [ 52 ]. Compounds G4 and G5 were obtained after testing various substituents on the phenylsulfide fragment of G3 [ 16 ].…”

Section: Magl Inhibitorsmentioning

confidence: 99%

Targeting Monoacylglycerol Lipase in Pursuit of Therapies for Neurological and Neurodegenerative Diseases

et al. 2021

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Neurological and neurodegenerative diseases are debilitating conditions, and frequently lack an effective treatment. Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of 2-AG (2-arachidonoylglycerol), a neuroprotective endocannabinoid intimately linked to the generation of pro- and anti-inflammatory molecules. Consequently, synthesizing selective MAGL inhibitors has become a focus point in drug design and development. The purpose of this review was to summarize the diverse synthetic scaffolds of MAGL inhibitors concerning their potency, mechanisms of action and potential therapeutic applications, focusing on the results of studies published in the past five years. The main irreversible inhibitors identified were derivatives of hexafluoroisopropyl alcohol carbamates, glycol carbamates, azetidone triazole ureas and benzisothiazolinone, whereas the most promising reversible inhibitors were derivatives of salicylketoxime, piperidine, pyrrolidone and azetidinyl amides. We reviewed the results of in-depth chemical, mechanistic and computational studies on MAGL inhibitors, in addition to the results of in vitro findings concerning selectivity and potency of inhibitors, using the half maximal inhibitory concentration (IC50) as an indicator of their effect on MAGL. Further, for highlighting the potential usefulness of highly selective and effective inhibitors, we examined the preclinical in vivo reports regarding the promising therapeutic applications of MAGL pharmacological inhibition.

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Design, synthesis and biological evaluation of second-generation benzoylpiperidine derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors

Cited by 34 publications

References 59 publications

New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds

New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds

Anticancer Potential of Small‐Molecule Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase

Targeting Monoacylglycerol Lipase in Pursuit of Therapies for Neurological and Neurodegenerative Diseases

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