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

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 IC₅₀ values of 4.22 and 6.89 µM, respectively, compared to the standard drug doxorubicin (IC₅₀  = 3.79 μM). In the case of the MDA-MB-231 cell line, S1 and S6 exhibited exceptionally superior antiproliferative activity with IC₅₀ of 5.22 and 6.50 μM, respectively, compared to doxorubicin (IC₅₀  = 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.