Design, Synthesis, X‐ray, Hirshfeld, DFT, Anticancer Efficacy, Molecular Docking and Molecular Dynamic for <i>N</i> ‐methyl‐ <i>C</i> ‐aryl Aldonitrones

Abstract

ABSTRACT Anticancer small molecule candidates N ‐methyl‐ C ‐3‐nitrophenyl aldonitrone 1 , N ‐methyl‐ C ‐9‐phenanthryl aldonitrone 2 and N ‐methyl‐ C ‐1‐pyrenyl aldonitrone 3 , were successfully synthesized and characterized by different spectroscopic methods. Hirshfeld analysis predicted O…H interactions are the most important in 1 , while for 2 the H…H, C…H and O…H contacts are the most important. Their percentages are 42.1, 47.4, 36.3 and 9.5%, respectively. Compounds 1 and 2 process IC 50 values of 99.1 and 95.6 µg/mL against MCF‐7, and 494.0 and 259.5 µg/mL against T47D, respectively. Compound 3 exhibits the lowest IC 50 values against both cancer cell lines. Compound 3 processes IC 50 (17.5 and 11.0 µg/mL) against MCF‐7 and T47D, respectively, which is mostly identical to the IC 50 of cisplatin , indicating that compound 3 has a good potential for use as an anticancer medication. Furthermore, compound 3 showed the highest docking score against the selected targets compared to 1 and 2 which confirm the cytotoxicity results. The selectivity index results suggested that compound 3 may possess cell line–specific selectivity, particularly favoring T47D cells. Density functional theory (DFT) calculations, including frontier molecular orbital analysis and molecular electrostatic potential (MEP) maps, provided an electronic basis for the observed activities. The superior potency of compound 3 is attributed to its low global hardness, high softness, and a large π‐basic aromatic surface that facilitates interactions with biological targets. Finally, a potential DNA/compound 3 binding was further explored by a molecular docking investigation. The resulted molecular confirmations showed that compound 3 binds to DNA minor groove with an average inhibition constant of 0.8 ± 0.1 µM.