Imidazopyridine chalcones as potent anticancer agents: Synthesis, single‐crystal X‐ray, docking, DFT and SAR studies

Abstract New imidazopyridine–chalcone analogs were synthesized through the Claisen–Schmidt condensation reaction. The newly synthesized imidazopyridine‐chalcones ( S1–S12 ) were characterized using spectroscopic and elemental analysis. The structures of compounds S2 and S5 were confirmed by X‐ray crystallography. The global chemical reactivity descriptor parameter was calculated using theoretically (DFT‐B3LYP‐3‐211, G) estimated highest occupied molecular orbital and lowest unoccupied molecular orbital values and the results are discussed. Compounds S1–S12 were screened on A‐549 (lung carcinoma epithelial cells) and MDA‐MB‐231 (M.D. Anderson‐Metastatic Breast 231) cancer cell lines. Compounds S6 and S12 displayed exceptional antiproliferative activity against lung A‐549 cancer cells with IC 50 values of 4.22 and 6.89 µM, respectively, compared to the standard drug doxorubicin (IC 50 = 3.79 μM). In the case of the MDA‐MB‐231 cell line, S1 and S6 exhibited exceptionally superior antiproliferative activity with IC 50 of 5.22 and 6.50 μM, respectively, compared to doxorubicin (IC 50 = 5.48 μM). S1 was found to be more active than doxorubicin. Compounds S1–S12 were tested for their cytotoxicity on human embryonic kidney 293 cells, which confirmed the nontoxic nature of the active compounds. Further molecular docking studies verified that compounds S1–S12 have a higher docking score and interacted well with the target protein. The most active compound S1 interacted well with the target protein carbonic anhydrase II in complex with pyrimidine‐based inhibitor, and S6 with human Topo IIα ATPase/AMP‐PNP. The results suggest that imidazopyridine‐chalcone analogs may serve as new leads as anticancer agents.