Synthesis and Pharmacological Evaluation of 2,4-Dinitroaryldithiocarbamate Derivatives as Novel Monoacylglycerol Lipase Inhibitors

Abstract

Monoacylglycerol lipase (MAGL) is responsible for signal termination of 2-arachidonoylglycerol (2-AG), an endocannabinoid neurotransmitter endowed with several physiological effects. Previously, we showed that the arylthioamide scaffold represents a privileged template for designing MAGL inhibitors. A series of 37 compounds resulting from pharmacomodulations around the arylthioamide template were synthesized and tested to evaluate their inhibitory potential on MAGL activity as well as their selectivity over fatty acid amide hydrolase (FAAH), another endocannabinoid-hydrolyzing enzyme. We have identified 2,4-dinitroaryldithiocarbamate derivatives as a novel class of MAGL inhibitors. Among the synthesized compounds, we identified [2,4-dinitrophenyl-4-(4-tert-butylbenzyl)piperazine-1-carbodithioate] (CK37), as the most potent MAGL inhibitor within this series (IC(50) = 154 nM). We have also identified [2,4-dinitrophenyl-4-benzhydrylpiperazine-1-carbodithioate] (CK16) as a selective MAGL inhibitor. These compounds are irreversible MAGL inhibitors that probably act by interacting with Cys208 or Cys242 and Ser122 residues of the enzyme. Moreover, CK37 is able to raise 2-arachidonoylglycerol (2-AG) levels in intact cells.

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

“…175 Moreover, the modification of the amide moiety and the introduction of the sulfur atom appended to the thioamide group was performed based on an arylthioamide scaffold. 176 Especially, compounds 159 (CK16) and 160 The different effects on the alteration of 2-AG levels could be attributed to the differences in stability of 159 and 160. 176 Dilution studies indicated that 160 might covalently and irreversibly inactivate MAGL.…”

“…176 Especially, compounds 159 (CK16) and 160 The different effects on the alteration of 2-AG levels could be attributed to the differences in stability of 159 and 160. 176 Dilution studies indicated that 160 might covalently and irreversibly inactivate MAGL. 176 In 2009, two natural terpenoids 161 (pristimerin) and 162 (euphol) ( Figure 58) were reported to inhibit MAGL at submicromolar concentrations (IC50 = 0.093 and 0.315 µM, respectively).…”

“…176 Dilution studies indicated that 160 might covalently and irreversibly inactivate MAGL. 176 In 2009, two natural terpenoids 161 (pristimerin) and 162 (euphol) ( Figure 58) were reported to inhibit MAGL at submicromolar concentrations (IC50 = 0.093 and 0.315 µM, respectively). 47 Specifically, compound 161 rather than 162 was shown to elevate 2-AG levels without alteration of AEA concentrations.…”

Transition-Metal-Free C–S Bond Formation: Aqueous Synthesis of S-Aryl Dithiocarbamates by The use of Stable Arenediazonium Salts Mediated by Nano-Magnetic Supported Silica Sulfonic Acid

“…In order to optimize the reaction condition, as a model reaction, aniline (1 mmol) was homogenized by mixing 0.8 g of Fe 3 O 4 @SiO 2 -SO 3 H and 0.2 mL water into a mortar with a ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT 6 pestle until the aniline had disappeared as monitored by TLC. Then sodium nitrite (2 mmol) was added with continues grinding; the diazotation proceeded in few minutes and stable phenyldiazonium nano-magneto silica sulfate was prepared (Scheme 1, step 1).…”

“…[1][2][3][4][5][6] The formation of a carbon-sulfur (C-S) bond is a fundamental approach to introduce sulfur into organic compounds. Traditionally, various metal-based catalysts in combination with different ligands are generally used for the C-S bond formation by cross coupling of their halides.…”