Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase
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 com...
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MDPI AG
2021-04-01
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| author | Obaid Afzal Abdulmalik Saleh Alfawaz Altamimi Mir Mohammad Shahroz Hemant Kumar Sharma Yassine Riadi Md Quamrul Hassan |
| author_facet | Obaid Afzal Abdulmalik Saleh Alfawaz Altamimi Mir Mohammad Shahroz Hemant Kumar Sharma Yassine Riadi Md Quamrul Hassan |
| author_sort | Obaid Afzal |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T12:09:18Z |
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| id | doaj.art-13ab781a6f144215803b0962d70b061b |
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| spelling | doaj.art-13ab781a6f144215803b0962d70b061b2023-11-21T16:20:07ZengMDPI AGMolecules1420-30492021-04-01268238910.3390/molecules26082389Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol LipaseObaid Afzal0Abdulmalik Saleh Alfawaz Altamimi1Mir Mohammad Shahroz2Hemant Kumar Sharma3Yassine Riadi4Md Quamrul Hassan5Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, Sri Satya Sai University of Technology and Medical Sciences, Sehore 466001, Madhya Pradesh, IndiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, Sri Satya Sai University of Technology and Medical Sciences, Sehore 466001, Madhya Pradesh, IndiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi ArabiaDepartment of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, IndiaTen 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.https://www.mdpi.com/1420-3049/26/8/2389analgesicanticancerpyrrolidin-2-onebenzoxazoleMAGL inhibitorsmolecular docking |
| spellingShingle | Obaid Afzal Abdulmalik Saleh Alfawaz Altamimi Mir Mohammad Shahroz Hemant Kumar Sharma Yassine Riadi Md Quamrul Hassan Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase Molecules analgesic anticancer pyrrolidin-2-one benzoxazole MAGL inhibitors molecular docking |
| title | Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase |
| title_full | Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase |
| title_fullStr | Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase |
| title_full_unstemmed | Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase |
| title_short | Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase |
| title_sort | analgesic and anticancer activity of benzoxazole clubbed 2 pyrrolidinones as novel inhibitors of monoacylglycerol lipase |
| topic | analgesic anticancer pyrrolidin-2-one benzoxazole MAGL inhibitors molecular docking |
| url | https://www.mdpi.com/1420-3049/26/8/2389 |
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