title: Design and Synthesis of Butenolide-based Novel Benzyl Pyrrolones: Their TNF-α based Molecular Docking with In vivo and In vitro Anti-inflammatory Activity.
abstract: A focused library of novel benzyl pyrrolones has been synthesized and their in silico molecular docking studies carried out against TNF-α target. Among all the docked molecules, compound 3f showed 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 their in vitro TNF α expression. Compounds 3b and 2b were 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. Compounds 3b and 2b also suppressed TNF α level by 65.03% and 60.90% as compared indomethacin, which showed 68.84% of inhibition. Compound 3b showed significant analgesic activity of 60.04%, and its activity was comparable with indomethacin (64.04%). Compounds 3b and 2b were also tested for their effect on protein expression of COX-2 and NF-κB in the liver tissues. Compounds 3b and 2b were further evaluated for their gastric risk and lipid peroxidation action and showed superior GI safety along with reduction of LPO as compared to indomethacin. Hepatotoxicity study showed that these two compounds did not cause any damage to liver.
authors.affiliation: Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, 110 062, India.
authors.forename: Yakub
authors.initials: Y
authors.lastname: Ali
authors.affiliation: Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, 110 062, India.
authors.forename: Mohammad Sarwar
authors.initials: MS
authors.lastname: Alam
authors.affiliation: Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, 110 062, India.
authors.forename: Hinna
authors.initials: H
authors.lastname: Hamid
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, 110 062, India.
authors.forename: Asif
authors.initials: A
authors.lastname: Husain
authors.affiliation: Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, 110 062, India.
authors.forename: Syed
authors.initials: S
authors.lastname: Shafi
authors.affiliation: CSIR Unit for Research and Development of Information Products, Pune, 411038, India.
authors.forename: Abhijeet
authors.initials: A
authors.lastname: Dhulap
authors.affiliation: Department of Chemistry, Faculty of Science, Delhi University, New Delhi, India.
authors.forename: Firasat
authors.initials: F
authors.lastname: Hussain
authors.affiliation: Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, 110 062, India.
authors.forename: Sameena
authors.initials: S
authors.lastname: Bano
authors.affiliation: Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, 110 062, India.
authors.forename: Chetna
authors.initials: C
authors.lastname: Kharbanda
authors.affiliation: Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, 110 062, India.
authors.forename: Syed
authors.initials: S
authors.lastname: Nazreen
authors.affiliation: Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, 110 062, India.
authors.forename: Saqlain
authors.initials: S
authors.lastname: Haider
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002351:Carrageenan / Q000633:toxicity; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D051381:Rats; D013276:Stomach Ulcer / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D014409:Tumor Necrosis Factor-alpha; C004511:butenolide; D002351:Carrageenan; D015107:4-Butyrolactone
keywords: TNF-α; analgesic; anti-inflammatory; benzyl pyrrolones; hepatotoxicity; immunohistochemistry; ulcerogenic