| Summary: | Ten benzoxazole clubbed 2-pyrrolidinones (<b>11</b>–<b>20</b>) as human monoacylglycerol lipase inhibitors were designed on the criteria fulfilling the structural requirements and on the basis of previously reported inhibitors. The designed, synthesized, and characterized compounds (<b>11</b>–<b>20</b>) were screened against monoacylglycerol lipase (MAGL) in order to find potential inhibitors. Compounds <b>19</b> (4-NO<sub>2</sub> derivative) and <b>20</b> (4-SO<sub>2</sub>NH<sub>2</sub> derivative), with an IC<sub>50</sub> value of 8.4 and 7.6 nM, were found most active, respectively. Both of them showed micromolar potency (IC<sub>50</sub> value above 50 µM) against a close analogue, fatty acid amide hydrolase (FAAH), therefore considered as selective inhibitors of MAGL. Molecular docking studies of compounds <b>19</b> and <b>20</b> revealed that carbonyl of 2-pyrrolidinone moiety sited at the oxyanion hole of catalytic site of the enzyme stabilized with three hydrogen bonds (~2 Å) with Ala51, Met123, and Ser122, the amino acid residues responsible for the catalytic function of the enzyme. Remarkably, the physiochemical and pharmacokinetic properties of compounds <b>19</b> and <b>20</b>, computed by QikProp, were found to be in the qualifying range as per the proposed guideline for good orally bioactive CNS drugs. In formalin-induced nociception test, compound <b>20</b> reduced the pain response in acute and late stages in a dose-dependent manner. They significantly demonstrated the reduction in pain response, having better potency than the positive control gabapentin (GBP), at 30 mg/kg dose. Compounds <b>19</b> and <b>20</b> were submitted to NCI, USA, for anticancer activity screening. Compounds <b>19</b> (NSC: 778839) and <b>20</b> (NSC: 778842) were found to have good anticancer activity on SNB-75 cell line of CNS cancer, exhibiting 35.49 and 31.88% growth inhibition (% GI), respectively.
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