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

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...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2012-12, Vol.17 (12), p.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: Article
Language:English
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-&#945
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor Necrosis Factor-alpha - metabolism
Tumor necrosis factor-TNF
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Summary: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.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules171214651