Synthesis and antiproliferative activity of 2-oxo-3-phenylquinoxaline derivatives and related compounds against colon cancer

Abstract

We have designed 17 new 2-oxo-3-phenylquinoxalines <i>via</i> the chemoselective Michael reaction of 3-phenylquinoxalin-2(1<i>H</i>)-one with acrylic acid derivatives. The ester, ethyl 3-(2-oxo-3-phenylquinoxalin-1(2<i>H</i>)-yl)propanoate, was reacted with hydroxylamine and hydrazine to produce <i>N</i>-hydroxy-3-(2-oxo-3-phenylquinoxalin-1(2<i>H</i>)-yl)propanamide and hydrazide, respectively. Further modifications were made through reactions with isothiocyanates and azide coupling with amines, yielding thiosemicarbazides and <i>N</i>-alkyl derivatives. Molecular docking studies identified compound 7j as the most potent binder, fitting well into the active site, with the phenyl ring occupying the S1 pocket and the amino acid chain positioned in the S2 pocket. The synthesized compounds (2a, 4, 7a, 7g, 7d, 7h, 7e, 7b, 7c, 7f, and 7j) were evaluated for their anti-cancer activity on colorectal cancer (HCT-116) cells. Compounds 2a and 7j showed significant reductions in cell viability, with IC50 values of 28.85 ± 3.26 μg mL^-1 and 26.75 ± 3.50 μg mL^-1, respectively. Image analysis of HCT-116 cells treated with 60 μg mL^-1 of compound 7j for 48 hours revealed notable morphological changes in both nuclei and cells. The number of cells reduced from 447 in the control to 238 in the treated group, with a corresponding reduction in the area covered by cells from 41.9% to 17.6%. Nuclear disintegration and chromatin fragmentation were observed, confirming apoptosis. These results highlight the potent cytotoxic effect of compound 7j.