Comprehensive molecular docking, cytotoxicity, and ADMET analysis of documented curcuminoid derivatives on the A549 cell line

Various novel curcuminoids (1–7) and pyrazole derivatives of curcuminoids (8–14) were synthesized and characterized using spectrum analysis. The compounds produced were evaluated for antiproliferative effects against the A549 lung cancer cell line. Compound 2 exhibited notable cytotoxicity at 10.38 μg/mL, whereas compounds 4, 5, and 7 showed considerable cytotoxicity, with IC₅₀ concentrations of 47.1, 23.4, and 82.4 μg/mL, respectively. Conversely, the other synthesized compounds exhibited only modest cytotoxicity. Moreover, in silico molecular docking analyses of EGFR (PDB ID: 4HJ0) demonstrated that compounds 2 and 6 displayed the lowest binding energies, −11.52 kcal/mol and −11.47 kcal/mol, respectively, indicating a higher affinity for the active pocket of the receptor, characterized by robust hydrogen bond interactions. Compound 12 had the highest binding energy (−8.42 kcal/mol) and the weakest affinity (KI = 670.04 nM). SwissADME analysis revealed satisfactory drug-likeness among all compounds, with no violations of Lipinski’s rules and modest synthetic accessibility. ProTox-II indicated tolerable oral toxicity (LD₅₀: 1300–4000 mg/kg), although elevated immunotoxicity scores imply the need for additional safety assessment. These data identify compound 2 as a promising candidate for future optimization and preclinical development.