Design and Synthesis of Butenolide‐based Novel Benzyl Pyrrolones: Their TNF‐αbased Molecular Docking withIn vivoandIn vitroAnti‐inflammatory Activity

• DOI: 10.1111/cbdd.12522
• Publication Date: 2015-01-28T11:33:52Z
• Authors: Yakub Ali; Mohammad Sarwar Alam; Hinna Hamid; Asif Husain; Syed Shafi; Abhijeet Dhulap; Firasat Hussain; Sameena Bano; Chetna Kharbanda; Syed Nazreen; Saqlain Haider
• Keywords: Male; 0301 basic medicine; Tumor Necrosis Factor-alpha; Anti-Inflammatory Agents, Non-Steroidal; Drug Evaluation, Preclinical; Carrageenan; Rats; 3. Good health; Molecular Docking Simulation; Mice; Structure-Activity Relationship; 03 medical and health sciences; 0302 clinical medicine; 4-Butyrolactone; Liver; Drug Design; Animals; Female; Lipid Peroxidation; Stomach Ulcer

A focused library of novel benzyl pyrrolones has been synthesized and theirin silicomolecular docking studies carried out againstTNF‐αtarget. Among all the docked molecules, compound3fshowed best glide score of −6.89. All the synthesized compounds were evaluated for in vivo anti‐inflammatory activity by carrageenan‐induced paw edema model. Compounds showing significant anti‐inflammatory activity were further tested for theirin vitroTNFαexpression. Compounds3band2bwere found to show significant inhibition of 76.22% and 71.47%, respectively after 5 h in comparison with standard drug indomethacin, which showed 80.98% inhibition of inflammation. Compounds3band2balso suppressedTNFαlevel by 65.03% and 60.90% as compared indomethacin, which showed 68.84% of inhibition. Compound3bshowed significant analgesic activity of 60.04%, and its activity was comparable with indomethacin (64.04%). Compounds3band2bwere also tested for their effect on protein expression ofCOX‐2 andNF‐κB in the liver tissues. Compounds3band2bwere further evaluated for their gastric risk and lipid peroxidation action and showed superiorGIsafety along with reduction ofLPOas compared to indomethacin. Hepatotoxicity study showed that these two compounds did not cause any damage to liver.