title: Design, synthesis and biological evaluation of novel anti-cytokine 1,2,4-triazine derivatives.
abstract: A series of 16 novel 1,2,4-triazine derivatives bearing hydrazone moiety (7a-7p) have been designed, synthesized and evaluated for their activity to inhibit IL-1β and TNF-α production. All compounds are reported for the first time. The chemical structures of all compounds were confirmed by spectroscopic methods and elemental analyzes. Most of the synthesized compounds were proved to have potent anti-cytokine activity and low toxicity on PBMC and MCF-7 cell lines. Compounds 7f, 7k, 7l and 7j presented simultaneously good levels of inhibition of both cytokines. Moreover, compound 7l exhibited good anti-inflammatory effect in carrageenan-induced rat paw edema. The results of Western blotting demonstrated that the anti-cytokine potential of compound 7l is mainly mediated through the inhibition of p38 MAPK signaling pathway. Molecular docking was performed to position compound 7l into p38α binding site in order to explore the potential target. The information of this work might be helpful for the design and synthesis of novel scaffold toward the development of new therapeutic agent to fight against inflammatory diseases.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Khoshneviszadeh
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Ghahremani
authors.forename: Alireza
authors.initials: A
authors.lastname: Foroumadi
authors.forename: Ramin
authors.initials: R
authors.lastname: Miri
authors.forename: Omidreza
authors.initials: O
authors.lastname: Firuzi
authors.forename: Armin
authors.initials: A
authors.lastname: Madadkar-Sobhani
authors.forename: Najmeh
authors.initials: N
authors.lastname: Edraki
authors.forename: Maliheh
authors.initials: M
authors.lastname: Parsa
authors.forename: Abbas
authors.initials: A
authors.lastname: Shafiee
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D001665:Binding Sites; D002351:Carrageenan / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D006835:Hydrazones / Q000737:chemistry; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D006835:Hydrazones; D053583:Interleukin-1beta; D014227:Triazines; D014409:Tumor Necrosis Factor-alpha; C093444:1,2,4-triazine; D002351:Carrageenan; D048051:p38 Mitogen-Activated Protein Kinases
keywords: 1,2,4-Triazine; Anti-inflammatory activity; IL-1β; TNF-α; p38 MAPK