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

Abstract Herein, a Cs 2 CO 3 ‐promoted N ‐alkylation of 3‐cyano‐2(1 H )‐pyridones containing alkyl groups with diverse alkyl halides to synthesize N ‐alkyl‐2‐pyridones over O ‐alkylpyridines is reported. The use of 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(1 H )‐pyridone ring, as evidenced by the preferential formation of O ‐alkylpyridines upon the introduction of aryl groups. Remarkably, we efficiently employed CuAAC and Ti(O i ‐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 10 b and 10 d 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 10 b and 10 d to the PIM‐1 kinase enzyme were determined through molecular docking studies.