Synthesis and pharmacological evaluation of novel phenyl sulfonamide derivatives designed as modulators of pulmonary inflammatory response

• Published in: Molecules (Basel, Switzerland) Vol. 17; no. 12; pp. 14651 - 14672
• Main Authors: Barbosa, Maria Letícia de Castro, Ramos, Thiago José Figueira, de Arantes, Ana Carolina Santos, Martins, Marco Aurélio, Silva, Patrícia Machado Rodrigues E, Barreiro, Eliezer J, Lima, Lídia Moreira
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10-12-2012; MDPI
• Subjects: Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Asthma; Chronic obstructive pulmonary disease; Design; Inflammation; Isoindoles - chemistry; Isoindoles - therapeutic use; LASSBio-468; LASSBio-596; Lipopolysaccharides - toxicity; Mice; phthalimide; Phthalimides - administration & dosage; Phthalimides - chemical synthesis; Pneumonia - chemically induced; Pneumonia - drug therapy; Pneumonia - pathology; Reagents; Signal transduction; Structure-Activity Relationship; Sulfonamides - administration & dosage; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; TNF-α Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Brazil; Rio de Janeiro Brazil
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules171214651

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.