Synthesis of phenyl-substituted amides with antioxidant and anti-inflammatory activity as novel lipoxygenase inhibitors.
Lipoxygenases (LO) have been implicated in several inflammatory diseases such as asthma, immune disorders, and cancers. Lipoxygenases play an essential role in the biosynthesis of the leukotrienes. Leukotrienes have been implicated as mediators in the pathophysiology of inflammatory diseases, host defense reactions and they were found to play important role in the propagation of the diseases states, exacerbating the local events and ultimately leading to tissue damage. As a consequence of these broad biological implications, there is a great interest in synthesising new compounds with this activity. The synthesis of new amides of aryl acetic acid is described. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Since lipophilicity is a significant physicochemical property determining distribution, bioavailability, metabolic activity and elimination, their lipophilicity is experimentally determined from RPTLC method. Several parameters were theoretically calculated and were used for a QSAR study. The compounds are tested in vitro on: a) soybean lipoxygenase inhibition, b) interaction with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical, c) the HO* mediated oxidation of DMSO, d) inhibition of lipid peroxidation, e) scavenging of superoxide anion radicals f) interaction with glutathione and g) in vivo for the inhibition of carrageenin induced rat paw edema. The compounds present significant antioxidant activities, medium anti-inflammatory activity and potent inhibition of soybean lipoxygenase as a result of their physicochemical features.
Pontiki
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Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece.
Hadjipavlou-Litina
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D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology*; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002351:Carrageenan; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005260:Female; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000494:pharmacology; D005978:Glutathione / Q000737:chemistry; D017665:Hydroxyl Radical; D007202:Indicators and Reagents; D015227:Lipid Peroxidation / Q000187:drug effects; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016877:Oxidants; D010851:Picrates / Q000737:chemistry; D051381:Rats; D011916:Rats, Inbred F344; D013056:Spectrophotometry, Ultraviolet; D013481:Superoxides / Q000737:chemistry
D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D001713:Biphenyl Compounds; D016166:Free Radical Scavengers; D007202:Indicators and Reagents; D016859:Lipoxygenase Inhibitors; D016877:Oxidants; D010851:Picrates; D013481:Superoxides; D017665:Hydroxyl Radical; D002351:Carrageenan; C004931:1,1-diphenyl-2-picrylhydrazyl; D005978:Glutathione