title: Synthesis and pharmacological activity of chalcones derived from 2,4,6-trimethoxyacetophenone in RAW 264.7 cells stimulated by LPS: quantitative structure-activity relationships.
abstract: Inhibition of nitric oxide (NO) production by altering the expression of induced enzymes involved is potentially an important strategy for obtaining antiinflammatory agents. In the search for hits to obtain lead compounds for new drugs of this class, 14 synthetic chalcones derived from 2,4,6-trimethoxyacetophenone were evaluated in terms of their inhibitory action, in vitro, in relation to NO production in murine macrophages of the line RAW 264.7 induced by bacterial lipopolysaccharides (LPS). All the compounds were obtained by aldolic condensation between the acetophenone and corresponding aldehydes, under basic conditions. The mean IC(50) values, calculated through dose versus inhibitory effect curves, in four independent experiments, varied between 1.34 and 27.60microM, and were compared with the positive control, compound 1400W (IC(50)=3.78microM), a highly selective inhibitor of iNOS (induced nitric oxide synthase). Eight chalcones gave mean IC(50) values less than or equal to those obtained for 1400W, which suggests that these molecules may act as inhibitors of inflammatory process. The QSAR study reveals that electron-withdrawing groups in the B-ring seem to increase the inhibition of nitrite production, mainly when in position 2. A substitution in the ortho position of the A-ring seems to be necessary for the activity.
authors.affiliation: Universidade Federal de Santa Catarina, Departamento de Química, Campus Trindade, 88040-900 Florianópolis, SC, Brazil. louisedc@gmail.com
authors.forename: Louise Domeneghini
authors.initials: LD
authors.lastname: Chiaradia
authors.forename: Rodrigo
authors.initials: R
authors.lastname: dos Santos
authors.forename: Carlos Eduardo
authors.initials: CE
authors.lastname: Vitor
authors.forename: André Alexandre
authors.initials: AA
authors.lastname: Vieira
authors.forename: Paulo César
authors.initials: PC
authors.lastname: Leal
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Nunes
authors.forename: João Batista
authors.initials: JB
authors.lastname: Calixto
authors.forename: Rosendo Augusto
authors.initials: RA
authors.lastname: Yunes
mesh_terms: D000098:Acetophenones / Q000737:chemistry*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship
chemical_list: C526406:2,4,6-trimethoxyacetophenone; D000098:Acetophenones; D000893:Anti-Inflammatory Agents; D047188:Chalcones; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse