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Pyrrolidin‐2‐one linked benzofused heterocycles as novel small molecule monoacylglycerol lipase inhibitors and antinociceptive agents
Author(s) -
Altamimi Abdulmalik Saleh Alfawaz,
Bawa Sandhya,
Athar Fareeda,
Hassan Md Quamrul,
Riadi Yassine,
Afzal Obaid
Publication year - 2020
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13751
Subject(s) - monoacylglycerol lipase , fatty acid amide hydrolase , chemistry , benzimidazole , thiazole , benzothiazole , stereochemistry , potency , pharmacology , biochemistry , agonist , endocannabinoid system , in vitro , organic chemistry , medicine , cannabinoid receptor , receptor
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 ( h MAGL) 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 IC 50 value of 8.6, 8.0 and 9.4 n m , 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 IC 50 value of 35 and 24 µ m , respectively. Benzimidazole derivative having 4‐methoxyphenyl substitution (compound 25 ) was found to be a selective MAGL inhibitor (IC 50 = 9.4 n m ), with an IC 50 value above 50 µ m 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).