title: Indole based peptidomimetics as anti-inflammatory and anti-hyperalgesic agents: Dual inhibition of 5-LOX and COX-2 enzymes.
abstract: The indoles bearing a tosyl group at N-1 and a dipeptide substituent at C-3 were screened for anti-inflammatory and anti-hyperalgesic activities. Some of the compounds made significant reduction in the dextran induced swelling and capsaicin induced pain in the albino mice. About 95% reversal in capsaicin induced pain occurred in the presence of 5 mg kg(-1) of compound 7b, 7d and 7h while diclofenac showed 90% reversal when its 10 mg kg(-1) dose was used. In order to examine the mode of action of these compounds; COX-1, COX-2 and 5-LOX enzyme immunoassays were performed. The IC50 of compound 7b for COX-2 and 5-LOX were in the nM range: 5-LOX, IC50 = 2.0 nM; COX-2, IC50 = 6.3 nM, selectivity for COX-2 over COX-1 was 351. The interactions of the compounds with COX-2 and 5-LOX were supported by the physical parameters including Ki, Ka and ΔG. The most potent compounds 7b, 7d and 7h showed no toxicity to the animals and were identified as the promising leads for anti-inflammatory drugs.
authors.affiliation: UGC Sponsored Centre for Advanced Studies, Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India.
authors.forename: Palwinder
authors.initials: P
authors.lastname: Singh
authors.affiliation: UGC Sponsored Centre for Advanced Studies, Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India.
authors.forename: Parteek
authors.initials: P
authors.lastname: Prasher
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, India.
authors.forename: Parvirti
authors.initials: P
authors.lastname: Dhillon
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, India.
authors.forename: Rajbir
authors.initials: R
authors.lastname: Bhatti
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D057786:Peptidomimetics
chemical_list: D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D057786:Peptidomimetics; C030374:indole
keywords: 5-LOX inhibitors; Anti-hyperalgesic; Anti-inflammatory; COX-2; Peptidomimetics