Design, Synthesis, Cytotoxicity, ADMET, and Molecular Docking Insights of Novel <i>Bis</i> ‐1,2,3‐Triazole‐Pyrimidinone Fused Compounds

ABSTRACT In this study, a series of novel bis ‐1,2,3‐triazole‐linked pyrimidinone hybrids were rationally designed and synthesized via tosylation reaction, Hantzsch reaction, and nucleophilic substitution, followed by Copper‐catalyzed azide‐alkyne cycloaddition (CuAAC) reactions, highlighting an environmentally sustainable and cost‐effective approach. The synthesized compounds were characterized through comprehensive analytical techniques, including nuclear magnetic resonance spectroscopy ( 1 H/ 13 C) and high‐resolution mass spectrometry analysis. The compounds were assessed for anticancer activity using the MTT assay against the human lung (NCI‐H69, A549), colon (HCT116), and breast cancer cell lines (T47D and MCF7). Key derivatives ( 8g and 8i ) showed significant activity on the NCI‐H69 and MCF7 cell lines with IC 50 values of 5.14 ± 0.76, 4.63 ± 0.64, 5.50 ± 0.73, and 6.09 ± 0.99 µM, respectively, comparable to the standard drug, and are nontoxic at their effective concentration as anticancer agents. Molecular docking studies were also conducted to assess the interaction profile of the active synthesized triazole hybrids with the human lung cytochrome P450 2A13 target receptor (PDB: 2P85). It was found through docking studies that the synthesized bis ‐triazole hybrids ( 8c , 8f , 8g, and 8i ) might interact with several amino acids, with binding energies of −6.25, −5.83, −6.80, and −6.40 kcal mol −1 , respectively. Drug likeness of the leading compounds was also evaluated through absorption, distribution, metabolism, excretion, and toxicity analysis.