Pyrrolidin-2-one linked benzofused heterocycles as novel small molecule monoacylglycerol lipase inhibitors and antinociceptive agents.
Abdulmalik Saleh Alfawaz AltamimiSandhya BawaFareeda AtharMd Quamrul HassanYassine RiadiObaid AfzalPublished in: Chemical biology & drug design (2020)
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, 8.0 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 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).
Keyphrases
- molecular docking
- small molecule
- data analysis
- chronic pain
- neuropathic pain
- fatty acid
- photodynamic therapy
- drug induced
- pain management
- endothelial cells
- magnetic resonance
- magnetic resonance imaging
- liver failure
- mass spectrometry
- high throughput
- emergency department
- spinal cord
- intensive care unit
- high glucose
- spinal cord injury
- extracorporeal membrane oxygenation
- acute respiratory distress syndrome
- light emitting
- aortic dissection
- mechanical ventilation