Cs₂CO₃‐Promoted Alkylation of 3‐Cyano‐2(1H)‐Pyridones: Anticancer Evaluation and Molecular Docking

Abstract

Herein, a Cs2CO3‐promoted N‐alkylation of 3‐cyano‐2(1H)‐pyridones containing alkyl groups with diverse alkyl halides to synthesize N‐alkyl‐2‐pyridones over O‐alkylpyridines is reported. Alkyl dihalides resulted in complex mixtures of N‐ and O‐alkylated products. The primary factor influencing regioselectivity in these reactions is the electronic effects of substituents on the 2(1H)‐pyridone ring, as evidenced by the preferential formation of O‐alkylpyridines upon the introduction of aryl groups. Remarkably, we efficiently employed CuAAC and Ti(Oi‐Pr)4‐catalyzed amidation reactions to functionalize N‐alkyl‐2‐pyridones containing propargyl and ester groups, leading to the synthesis of 1,2,3‐triazoles and amides, respectively. Moreover, O‐alkylpyridines 10b and 10d displayed remarkable selectivity toward the A‐498 renal cancer cell line with growth inhibition percentages (%GI) of 54.75 and 67.64, respectively. The binding modes of compounds 10b and 10d to the PIM‐1 kinase enzyme were determined through molecular docking studies.