Synthesis, molecular docking and biological evaluation of new Mannich base derivatives as potential anticancer agents

In the present study, a new series of Mannich base compounds (M1-M12) derived from paracetamol were prepared via the Mannich reaction by reacting the active hydrogen of paracetamol with anhydrous aldehydes (like: formaldehyde, benzaldehyde, and acetaldehyde) and secondary amines (like: morpholine, piperidine, pyrrolidine, and diethylamine) in the presence of a catalytic amount of concentrated hydrochloric acid. The prepared compounds were characterized based on physical properties, including melting point and elemental analysis, as well as spectroscopic data (FT-IR, NMR (1H &13C). The anticancer potential of these compounds was screened using the MTT assay on A549 cancer cells at different concentrations (250–50 μg/mL). Several derivatives showed promising cytotoxic activity, with IC₅₀ values ranging from (74.80 ± 1.08 to 183.4 ± 1.07 μg/mL). Among them, compounds M5, M6, M7, and M8, showed significant cytotoxicity comparable to the standard drug Pemetrexed. Furthermore, molecular docking studies were also conducted to evaluate the potential interaction pattern of the active compounds with the enzyme active site. Among the series, analogues M1, M5, M6, M7, M8, and M10 exhibit good interaction with the target protein 1TUP, which is the crystal structure of the tumour suppressor protein p53 bound to DNA. These results indicate that modification of paracetamol with Mannich base improves its pharmacological properties. Further investigations, including mechanistic and in vivo studies, are warranted to validate their therapeutic potential.