Novel N-substituted indole Schiff bases as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase enzymes: Synthesis, biological activities in vitro and docking study

Phoebe F Lamie; Waleed A M Ali; Vaclav Bazgier; Lucie Rárová

doi:10.1016/j.ejmech.2016.08.013

Novel N-substituted indole Schiff bases as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase enzymes: Synthesis, biological activities in vitro and docking study

Eur J Med Chem. 2016 Nov 10:123:803-813. doi: 10.1016/j.ejmech.2016.08.013. Epub 2016 Aug 10.

Authors

Phoebe F Lamie¹, Waleed A M Ali², Vaclav Bazgier³, Lucie Rárová⁴

Affiliations

¹ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt. Electronic address: feby.farag@yahoo.com.
² BioChemistry Department, Cairo General Hospital, Egypt.
³ Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Institute of Experimental Botany ASCR & Palacký University, Šlechtitelů 27, 783 71, Olomouc, Czech Republic; Department of Physical Chemistry, Faculty of Science, Palacký University, 17. Listopadu 1192/12, 771 46, Olomouc, Czech Republic.
⁴ Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Institute of Experimental Botany ASCR & Palacký University, Šlechtitelů 27, 783 71, Olomouc, Czech Republic. Electronic address: lucie.rarova@upol.cz.

PMID: 27541263
DOI: 10.1016/j.ejmech.2016.08.013

Abstract

Two new series of N-substituted indole derivatives 4a-l and 5a-h were synthesized. Their chemical structures were confirmed using spectroscopic tools including IR, (1)H NMR, (13)C NMR mass spectroscopy and elemental analyses. The results showed no significant cytotoxic activity on either cancer or normal human cells. Anti-inflammatory activity for all target compounds was evaluated in vitro. Compounds 5a-h were found to have better anti-inflammatory activity than 4a-l. The inhibitory activity of COX-2 and 5-LOX were tested for 5a-h. Three compounds, 5c, 5d and 5f showed excellent COX-2 inhibitory activity with IC50 ranging from 0.98 to 1.23 μM compared to the reference celecoxib (1.54 μM). These compounds had a reasonable selectivity index between 7.03 and 8.05. Additionally, p-methylbenzoyl derivative 5g (IC50 = 5.78 μM) had superior 5-LOX inhibitory activity, higher than quercetin. 5e was close to quercetin in its LOX inhibitory activity. Compounds 5a-h were docked inside the active site of COX-2 and 5-LOX enzymes.

Keywords: Anti-inflammatory activity; Antiproliferative activity; Cyclooxygenase enzymes; Indole derivatives; Molecular docking study.

MeSH terms

Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / chemistry
Anti-Inflammatory Agents / metabolism
Anti-Inflammatory Agents / pharmacology
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Arachidonate 5-Lipoxygenase / chemistry
Arachidonate 5-Lipoxygenase / metabolism*
Catalytic Domain
Cell Line, Tumor
Chemistry Techniques, Synthetic
Cyclooxygenase 1 / metabolism
Cyclooxygenase 2 / metabolism*
Cyclooxygenase 2 Inhibitors / chemical synthesis
Cyclooxygenase 2 Inhibitors / chemistry
Cyclooxygenase 2 Inhibitors / metabolism
Cyclooxygenase 2 Inhibitors / pharmacology
Drug Design*
Humans
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / metabolism
Indoles / pharmacology*
Lipoxygenase Inhibitors / chemical synthesis
Lipoxygenase Inhibitors / chemistry
Lipoxygenase Inhibitors / metabolism
Lipoxygenase Inhibitors / pharmacology
Molecular Docking Simulation*
Schiff Bases / chemistry

Substances

Anti-Inflammatory Agents
Antineoplastic Agents
Cyclooxygenase 2 Inhibitors
Indoles
Lipoxygenase Inhibitors
Schiff Bases
Arachidonate 5-Lipoxygenase
Cyclooxygenase 1
Cyclooxygenase 2