title: Synthesis, biological evaluation and molecular docking studies of 3-(triazolyl)-coumarin derivatives: effect on inducible nitric oxide synthase.
abstract: A series of 3-(triazolyl)-coumarins were synthesized and tested as anti-inflammatory agents. It was possible to infer that these compounds do not alter the interaction of LPS with TLR-4 or TLR-2, as the intracellular pathways involved in the TNF-α secretion and COX-2 activity were not affected. Nevertheless, the compounds inhibited iNOS-derived NO production, without affecting the eNOS activity. The outcome of the docking studies showed that π···π interactions with the heme group are important for the iNOS inhibition, thus making compound 3c a promising lead. Moreover, the efficacy of this compound was visualized by the reduced number of neutrophils in the LPS-inflamed subcutaneous tissue. Together, biological and docking data show that triazolyl-substituted coumarins, that can act on iNOS, are a good scaffold to be explored.
authors.affiliation: Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brazil. hstefani@usp.br
authors.forename: Hélio A
authors.initials: HA
authors.lastname: Stefani
authors.forename: Karina
authors.initials: K
authors.lastname: Gueogjan
authors.forename: Flávia
authors.initials: F
authors.lastname: Manarin
authors.forename: Sandra H P
authors.initials: SH
authors.lastname: Farsky
authors.forename: Julio
authors.initials: J
authors.lastname: Zukerman-Schpector
authors.forename: Ignez
authors.initials: I
authors.lastname: Caracelli
authors.forename: Sergio R
authors.initials: SR
authors.lastname: Pizano Rodrigues
authors.forename: Marcelo N
authors.initials: MN
authors.lastname: Muscará
authors.forename: Simone A
authors.initials: SA
authors.lastname: Teixeira
authors.forename: José R
authors.initials: JR
authors.lastname: Santin
authors.forename: Isabel D
authors.initials: ID
authors.lastname: Machado
authors.forename: Simone M
authors.initials: SM
authors.lastname: Bolonheis
authors.forename: Rui
authors.initials: R
authors.lastname: Curi
authors.forename: Marco A
authors.initials: MA
authors.lastname: Vinolo
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D003374:Coumarins; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D014230:Triazoles; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II