title: Synthesis and pharmacological evaluation of novel phenyl sulfonamide derivatives designed as modulators of pulmonary inflammatory response.
abstract: In this paper we report the design, synthesis and pharmacological evaluation of a new series of phenyl sulfonamide derivatives 2a-h and 3-8 planned by structural modification on the anti-inflammatory prototype LASSBio-468 (1). Among the synthesized analogues, the tetrafluorophthalimide LASSBio-1439 (2e) stands out showing an in vitro anti-TNF-α effect similar to the standard thalidomide. The relevance of tetrafluorination of the phthalimide nucleus was also confirmed by the anti-inflammatory profile of 2e, through oral administration, in a murine model of pulmonary inflammation. The corresponding tetrafluorocarboxyamide metabolite LASSBio-1454 (15), generated from partial hydrolysis of the derivative 2e, presented a significant in vitro effect and a pronounced anti-inflammatory activity in vivo.
authors.affiliation: Laboratory of Evaluation and Synthesis of Bioactive Substances-LASSBio®, Federal University of Rio de Janeiro, P.O. Box 68024, 21944-971 Rio de Janeiro, RJ, Brazil.
authors.forename: Maria Letícia de Castro
authors.initials: ML
authors.lastname: Barbosa
authors.forename: Thiago José Figueira
authors.initials: TJ
authors.lastname: Ramos
authors.forename: Ana Carolina Santos
authors.initials: AC
authors.lastname: de Arantes
authors.forename: Marco Aurélio
authors.initials: MA
authors.lastname: Martins
authors.forename: Patrícia Machado Rodrigues E
authors.initials: PM
authors.lastname: Silva
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Lídia Moreira
authors.initials: LM
authors.lastname: Lima
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D054833:Isoindoles / Q000737:chemistry / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D010797:Phthalimides / Q000008:administration & dosage / Q000138:chemical synthesis; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D054833:Isoindoles; C503834:LASSBio-468; D008070:Lipopolysaccharides; D010797:Phthalimides; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha