Abstract
Within the framework of our attempts to synthesize pleiotropic anti-inflammatory agents, we have synthesized some chalcones and their corresponding 3,4-pyrrolyl derivatives. Chalcones constitute a class of compounds with high biological impact. They are known for a number of biological activities, including anti-inflammatory and free radical scavenging activities. They inhibit several enzymes implicated in the inflammatory process, such as lipoxygenase, cyclooxygenase (COX) and lysozymes. The synthesized pyrroles have been studied for: (1) their in vitro inhibition of lipoxygenase; (2) their in vitro inhibition of COX; (3) their in vitro inhibition of lipid peroxidation; (4) their interaction with the stable, N-centered, free radical, 2,2-diphenyl-1-picrylhydrazyl (DPPH); (5) their inhibition on interleukin-6 (IL-6); (6) their anti-proteolytic activity; and (7) their in vivo anti-inflammatory activity using carrageenan-induced rat paw edema. Their physicochemical properties were determined to explain the biological results. Lipophilicity was experimentally determined. 2i and 2v were found to be promising multifunctional molecules with high antiproteolytic and anti-inflammatory activities in combination with anti-interleukin-6 activity.
Highlights
Inflammation is the natural response of the biological system to various stimuli
Upon appropriate stimulation of neutrophils, arachidonic acid is cleaved from membrane phospholipids through the enzymatic activity of phospholipase A2, and it is metabolized by two enzymes: cyclooxygenase (COX) and lipoxygenase leading to pro-inflammatory mediators, prostanoids and leukotrienes, respectively [5]
Chalcones were used as precursors for the synthesis of aryl-aroyl-substituted pyrrolyl derivatives via a van Leusen reaction [38] with tosylmethyl isocyanide (TosMIC) to give 3-aroyl-4-arylpyrroles in an intermolecular cyclization
Summary
Upon appropriate stimulation of neutrophils, arachidonic acid is cleaved from membrane phospholipids through the enzymatic activity of phospholipase A2, and it is metabolized by two enzymes: cyclooxygenase (COX) and lipoxygenase leading to pro-inflammatory mediators, prostanoids and leukotrienes, respectively [5]. COX-1 is traditionally considered as a house-keeping enzyme, and it is responsible for the production of prostanoids and proinflammatory prostaglandins, implicated in homeostatic functions. COX-2 is the induced isoform, which catalyzes the production of prostaglandins during the inflammatory response [7]. The differential expression of the two isoforms, together with the fact that COX-1 is the main isoform expressed in the gastrointestinal track, led to the design and synthesis of selective COX-2 inhibitors as potent anti-inflammatory agents that would lack the gastro-intestinal side effects of traditional NSAIDs. Despite the initial success of selective
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