Pyrrolidin-2-one Linked Benzofused Heterocycles as Novel Small Molecule Monoacylglycerol Lipase Inhibitors and Antinociceptive Agents.

Eighteen pyrrolidin-2-one linked benzothiazole, and benzimidazole derivatives (10-27) were designed and synthesized. The structure of the compounds was confirmed by elemental and spectral (IR, 1 H-NMR, and MS) data analysis. All the compounds were screened by human monoacylglycerol lipase (hMAGL) inhibition assay. Three benzimidazole compounds, 22 (4-Cl phenyl), 23 (3-Cl,4-F phenyl), and 25 (4-methoxy phenyl) were found to be the most potent, having an IC50 value of 8.6 nM, 8.0 nM and 9.4 nM, respectively. Among them, the halogen-substituted phenyl derivatives, compound 22 (4-Cl phenyl) and compound 23 (3-Cl,4-F phenyl), showed micromolar potency against fatty acid amide hydrolase (FAAH), having an IC50 value of 35 µM and 24 µM, respectively. Benzimidazole derivative having 4-methoxyphenyl substitution (compound 25) was found to be a selective MAGL inhibitor (IC50 = 9.4 nM), with an IC50 value above 50 µM against FAAH. In the formalin-induced nociception test, compound 25 showed a dose-dependent reduction of pain response in both acute and late phases. At 30 mg/kg dose, it significantly reduced the pain response and showed greater potency than the reference drug gabapentin (GBP).