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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / administration & dosage
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / chemistry
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Isoindoles / chemistry
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Isoindoles / therapeutic use
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Lipopolysaccharides / toxicity
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Mice
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Phthalimides* / administration & dosage
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Phthalimides* / chemical synthesis
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Pneumonia* / chemically induced
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Pneumonia* / drug therapy
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Pneumonia* / pathology
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Structure-Activity Relationship
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Sulfonamides* / administration & dosage
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Sulfonamides* / chemical synthesis
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Sulfonamides* / chemistry
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Tumor Necrosis Factor-alpha* / antagonists & inhibitors
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Tumor Necrosis Factor-alpha* / metabolism
Substances
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Anti-Inflammatory Agents
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Isoindoles
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LASSBio-468
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Lipopolysaccharides
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Phthalimides
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Sulfonamides
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Tumor Necrosis Factor-alpha