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

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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Güngör T,Ozleyen A,Yılmaz YB,Siyah P,Ay M,Durdağı S,Tumer TB

doi

10.1016/j.ejmech.2021.113566

keywords:

["Amide","Anti-inflammatory","Anticancer","Binary QSAR models","Docking","MD simulations","Nimesulide","Sulfonamide","Synthesis"]

subject

Has Abstract

pub_date

2021-10-05 00:00:00

pages

113566

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(21)00415-3

journal_volume

221

pub_type

杂志文章

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