Synthesis, structure, in vitro and in silico enzyme (COX-1/2 and VEGFR-2) inhibition studies of the 2-arylsulfonamidoacetophenones

A secondary sulfonamido group (-NHSO2R) is prevalent in small organic molecules of pharmacological importance including non-steroidal anti-inflammatory agents. These drugs have benefited from the strategic incorporation of fluorine atom/s or fluorine-containing group/s on the aromatic ring. With these considerations in mind, we synthesised ortho-arylsulfonamidoacetophenone derivatives 2a-f (70-85% yield) substituted with either a fluorine atom or fluorine-containing (-CF3 or -OCF3) group on the benzenesulfonyl moiety. The N-4(trifluoromethylbenzene)sulfonyl derivative 2e exhibited increased inhibitory activity against COX-1 (IC50 = 3.14 & PLUSMN; 0.001 & mu;M) and strongly so against COX-2 (IC50 = 0.84 & PLUSMN; 0.002 & mu;M) activity compared to celecoxib (IC50 = 8.17 & PLUSMN; 0.006 & mu;M and 2.78 & PLUSMN; 0.003 & mu;M, respectively). This compound was also found to be the most active against VEGFR-2 tyrosine kinase activity with an IC50 value of 5.73 & PLUSMN; 0.012 & mu;M compared to nintedanib (IC50 = 2.10 & PLUSMN; 0.014 & mu;M) and staurosporine (IC50 = 3.54 & PLUSMN; 0.025 & mu;M). Molecular docking predicted the fluorine atom/s, phenylacetyl and benzenesulfonamido groups to engage in increased hydrophilic and hydrophobic bonding interactions with the amino acid residues in the active sites of these enzymes consistent with the design strategy.

Automated summary

The secondary sulfonamido group is important in pharmacologically active organic molecules, and the incorporation of fluorine atom/s or fluorine-containing group/s on the aromatic ring can enhance their efficacy. In this study, ortho-arylsulfonamidoacetophenone derivatives substituted with fluorine atom/s or fluorine-containing group/s were synthesized, and the N-4(trifluoromethylbenzene)sulfonyl derivative showed the highest inhibitory activity against COX-1, COX-2, and VEGFR-2 tyrosine kinase compared to standard drugs.