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 alpha,beta-unsaturated carbonyl based compounds were synthesized and evaluated for their inhibitory activity on secretory phospholipase A(2) (sPLA(2)), cyclooxygenases (COX), soybean lipoxygenase (LOX) in addition to proinflammatory cytokines comprising IL-6 and TNF-alpha. Six alpha,beta-unsaturated carbonyl based compounds (2, 3, 4, 12, 13 and 14) exhibited strong inhibition of sPLA(2) activity, with IC50 values in the range of 2.19-8.76 mu M. Nine compounds 1-4 and 10-14 displayed inhibition of COX-1 with IC50 values ranging from 0.37 to 1.77 mu M (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-alpha 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-alpha 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 alpha,beta-unsaturated carbonyl based compounds might serve as beneficial starting point for the design and development of improved anti-inflammatory agents. (C) 2014 Elsevier Ltd. All rights reserved.

Pharmacological evaluation and docking studies of α,β-unsaturated carbonyl based synthetic compounds as inhibitors of secretory phospholipase A2, cyclooxygenases, lipoxygenase and proinflammatory cytokines

LAURO, GIANLUIGI;BIFULCO, Giuseppe;
2014

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 alpha,beta-unsaturated carbonyl based compounds were synthesized and evaluated for their inhibitory activity on secretory phospholipase A(2) (sPLA(2)), cyclooxygenases (COX), soybean lipoxygenase (LOX) in addition to proinflammatory cytokines comprising IL-6 and TNF-alpha. Six alpha,beta-unsaturated carbonyl based compounds (2, 3, 4, 12, 13 and 14) exhibited strong inhibition of sPLA(2) activity, with IC50 values in the range of 2.19-8.76 mu M. Nine compounds 1-4 and 10-14 displayed inhibition of COX-1 with IC50 values ranging from 0.37 to 1.77 mu M (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-alpha 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-alpha 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 alpha,beta-unsaturated carbonyl based compounds might serve as beneficial starting point for the design and development of improved anti-inflammatory agents. (C) 2014 Elsevier Ltd. All rights reserved.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11386/4504858
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