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.
Highlights
Inflammation is the body’s response to insults, including trauma, infections and hypersensitivity
Acute lung inflammation is present in pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), whereas chronic lung inflammation is represented by asthma and chronic obstructive pulmonary disease (COPD) [1,4,5]
In a continuing effort to identify new anti-inflammatory and immunomodulatory drug candidates, we report in this paper the design, synthesis and pharmacological evaluation of novel phenyl sulfonamide derivatives 2a–h and 3–8 planned by structural modifications on the prototype 1
Summary
Inflammation is the body’s response to insults, including trauma, infections and hypersensitivity In the lung, this response is usually induced by pathogens, toxins, pollutants, irritants and allergens [1]. The acute inflammatory response is disrupted once the triggering insult is eliminated, the infection is cleared and the damaged tissue is repaired, but if the stimulus is not properly eliminated, the inflammatory process persists and acquires new characteristics, becoming detrimental due to its negative effects on tissue function. In some cases this undesirable inflammatory response results in overt tissue damage [2]. Acute lung inflammation is present in pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), whereas chronic lung inflammation is represented by asthma and chronic obstructive pulmonary disease (COPD) [1,4,5]
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