title: Pharmacological evaluation and docking studies of α,β-unsaturated carbonyl based synthetic compounds as inhibitors of secretory phospholipase A₂, cyclooxygenases, lipoxygenase and proinflammatory cytokines.
abstract: Arachidonic acid and its metabolites have generated high level of interest among researchers due to their vital role in inflammation. The inhibition of enzymes involved in arachidonic acid metabolism has been considered as synergistic anti-inflammatory effect. A series of novel α,β-unsaturated carbonyl based compounds were synthesized and evaluated for their inhibitory activity on secretory phospholipase A₂ (sPLA₂), cyclooxygenases (COX), soybean lipoxygenase (LOX) in addition to proinflammatory cytokines comprising IL-6 and TNF-α. Six α,β-unsaturated carbonyl based compounds (2, 3, 4, 12, 13 and 14) exhibited strong inhibition of sPLA₂ activity, with IC₅₀ values in the range of 2.19-8.76 μM. Nine compounds 1-4 and 10-14 displayed inhibition of COX-1 with IC₅₀ values ranging from 0.37 to 1.77 μM (lower than that of reference compound), whereas compounds 2, 10, 13 and 14 strongly inhibited the COX-2. The compounds 10-14 exhibited strong inhibitory activity against LOX enzyme. All compounds were evaluated for the inhibitory activities against LPS-induced TNF-α and IL-6 release in the macrophages. On the basis of screening results, five active compounds 3, 4, 12, 13 and 14 were found strong inhibitors of TNF-α and IL-6 release in a dose-dependent manner. Molecular docking experiments were performed to clarify the molecular aspects of the observed COX and LOX inhibitory activities of the investigated compounds. Present findings increases the possibility that these α,β-unsaturated carbonyl based compounds might serve as beneficial starting point for the design and development of improved anti-inflammatory agents.
authors.affiliation: Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia. Electronic address: snab@pharmacy.ukm.my.
authors.forename: Syed Nasir Abbas
authors.initials: SN
authors.lastname: Bukhari
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Lauro
authors.affiliation: Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia. Electronic address: ibj@pharmacy.ukm.my.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Jantan
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
authors.affiliation: Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
authors.forename: Muhammad Wahab
authors.initials: MW
authors.lastname: Amjad
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D008084:Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D064801:Phospholipase A2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013025:Glycine max / Q000201:enzymology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D003474:Curcumin; D016861:Cyclooxygenase Inhibitors; D015850:Interleukin-6; D008084:Lipoxygenase; D016859:Lipoxygenase Inhibitors; D064801:Phospholipase A2 Inhibitors; D054497:Phospholipases A2, Secretory; D011451:Prostaglandin-Endoperoxide Synthases; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors
keywords: Claisen–Schmidt condensation; Curcumin; Lipopolysaccharides; Tumor necrosis factor alpha