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

Bukhari Syed Nasir Abbas, Gianluigi Lauro, Ibrahim Jantan, Giuseppe Bifulco, Muhammad Wahab Amjad

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4151-4161
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number15
DOIs
Publication statusPublished - 1 Aug 2014

Fingerprint

Secretory Phospholipase A2
Lipoxygenase
Prostaglandin-Endoperoxide Synthases
Interleukin-6
Pharmacology
Cytokines
Arachidonic Acid
Inhibitory Concentration 50
Anti-Inflammatory Agents
Enzyme inhibition
Cyclooxygenase 1
Macrophages
Enzymes
Cyclooxygenase 2
Metabolites
Soybeans
Metabolism
Screening
Research Personnel
Inflammation

Keywords

  • Claisen-Schmidt condensation
  • Curcumin
  • Lipopolysaccharides
  • Tumor necrosis factor alpha

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Pharmacological evaluation and docking studies of α,β- unsaturated carbonyl based synthetic compounds as inhibitors of secretory phospholipase A2, cyclooxygenases, lipoxygenase and proinflammatory cytokines. / Syed Nasir Abbas, Bukhari; Lauro, Gianluigi; Jantan, Ibrahim; Bifulco, Giuseppe; Amjad, Muhammad Wahab.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 15, 01.08.2014, p. 4151-4161.

Research output: Contribution to journalArticle

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