2. Academic Validation
  3. New nimesulide derivatives with amide/sulfonamide moieties: Selective COX-2 inhibition and antitumor effects

New nimesulide derivatives with amide/sulfonamide moieties: Selective COX-2 inhibition and antitumor effects

  • Eur J Med Chem. 2021 Oct 5:221:113566. doi: 10.1016/j.ejmech.2021.113566.
Tuğba Güngör 1,  Adem Ozleyen 2,  Yakup Berkay Yılmaz 3,  Pinar Siyah 4,  Mehmet Ay 5,  Serdar Durdağı 4,  Tugba Boyunegmez Tumer 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Sciences and Arts, Natural Products and Drug Research Laboratory, Çanakkale Onsekiz Mart University, Çanakkale, 17020, Turkey. Electronic address: tgungor@comu.edu.tr.
  • 2 Graduate Program of Biomolecular Sciences, School of Graduate Studies, Canakkale Onsekiz Mart University, 17020, Çanakkale, Turkey; School of Chemistry, University of Leicester, LE1 7RH, Leicester, United Kingdom.
  • 3 Graduate Program of Biomolecular Sciences, School of Graduate Studies, Canakkale Onsekiz Mart University, 17020, Çanakkale, Turkey; Department of Molecular Biology and Genetics, Faculty of Arts and Science, Çanakkale Onsekiz Mart University, 17020, Çanakkale, Turkey.
  • 4 Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahçeşehir University, 34353, Istanbul, Turkey.
  • 5 Department of Chemistry, Faculty of Sciences and Arts, Natural Products and Drug Research Laboratory, Çanakkale Onsekiz Mart University, Çanakkale, 17020, Turkey.
  • 6 Department of Molecular Biology and Genetics, Faculty of Arts and Science, Çanakkale Onsekiz Mart University, 17020, Çanakkale, Turkey. Electronic address: tumertb@comu.edu.tr.
PMID: 34077833 DOI: 10.1016/j.ejmech.2021.113566
Abstract

Seventeen new amide/sulfonamide containing nimesulide derivatives were synthesized and characterized by several spectroscopic techniques and primarily investigated for their inhibitory potential on COX Enzymes and Other pro-inflammatory factors. Experimental analyses showed that among seventeen compounds, N8 and N10 have remarkable potency and selectivity for the COX-2 Enzyme over COX-1 at very low doses as compared to nimesulide. Moreover, both N8 and N10 selectively reduced the Lipopolysaccharide (LPS)-stimulated COX-2 mRNA expression level while the COX-1 level remained stable. Both PGE2 release and nitric oxide production in macrophage cells were significantly suppressed by the N8 and N10 treatment groups. In silico ADME/Tox, molecular docking and molecular dynamics (MD) simulations were also conducted. Additionally, all compounds were also screened in a panel of Cancer cell lines for their antiproliferative properties by MTT and SRB assays. Compound N17 exhibited a considerable antiproliferative effect on the colon (IC50: 9.24 μM) and breast (IC50: 11.35 μM) Cancer cell lines. N17 exposure for 48 h decreased expression of anti-apoptotic protein Bcl-2 and increased the expression of apoptogenic Bax. Besides, the Bax/Bcl-2 ratio was increased with visible ultrastructural changes and apoptotic bodies under scanning electron microscopy. In order to investigate the structural and dynamical properties of selected hits on the target structures, multiscale molecular modeling studies are also conducted. Our combined in silico and in vitro results suggest that N8 and N10 could be further developed as potential nonsteroidal anti-inflammatory drugs (NSAIDs), while cytotoxic N17 might be studied as a potential lead compound that could be developed as an Anticancer agent.

Keywords

Amide; Anti-inflammatory; Anticancer; Binary QSAR models; Docking; MD simulations; Nimesulide; Sulfonamide; Synthesis.

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