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

• Published in: Journal of fluorine chemistry 2023-08, Vol.270, p.110163, Article 110163
• Main Authors: Mphahlele, Malose J., Magwaza, Nontokozo M., Gildenhuys, Samantha, More, Garland K., Zamisa, Sizwe J., Maluleka, Morole M.
• Format: Article
• Language: English
• Subjects: 2-(arylsulfonamido)acetophenones; computational studies; Crystal structure; Cyclooxygenase-1/2; tyrosine kinase (VEGFR-2)
• ISSN: 0022-1139; 1873-3328
• DOI: 10.1016/j.jfluchem.2023.110163

•A base- and solvent-free reaction of 2-aminoacetophenone and benzenesulfonyl chlorides afforded the N-(2-acetylphenyl)benzenesulfonamides.•X-ray analysis was confirmed the presence of intramolecular NH⋯O bond suggested by the 1H NMR data.•The intermolecular interactions in the crystal structures of these compounds were studied using computational techniques.•The compounds were evaluated for inhibitory effect against COX-1/2 and VEGFR-2. 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 ± 0.001 µM) and strongly so against COX-2 (IC50 = 0.84 ± 0.002 µM) activity compared to celecoxib (IC50 = 8.17 ± 0.006 µM and 2.78 ± 0.003 µM, respectively). This compound was also found to be the most active against VEGFR-2 tyrosine kinase activity with an IC50 value of 5.73 ± 0.012 µM compared to nintedanib (IC50 = 2.10 ± 0.014 µM) and staurosporine (IC50 = 3.54 ± 0.025 µM). 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. [Display omitted]