Novel Pyrrolopyrimidine Based Dual Heterocyclic Hybrids as Antiproliferative Agents: Synthesis, In-vitro Assessment, Docking, and ADME Exploration
The present work reports the synthesis of novel pyrrolo[2,3-d]pyrimidine and 1,3,4–oxadiazole hybrids bearing 1,2,3–triazole substituents, efficiently obtained via CuAAC click reactions. The results indicated that 1,2,3–triazole hybrids 5b and 5g demonstrated the highest cytotoxicity against A-549 and HCT-116 cells with IC50 values of 6.12±1.15 µM and 8.01±1.72 µM and 5.20±0.99 µM and 6.60±1.90 µM, respectively, compared with the reference drug doxorubicin (5.40±1.75 µM for A-549 and 6.60±1.23 µM for HCT-116). Molecular docking revealed the structural basis for this activity, showing compounds 5b, 5e and 5g strong binding to key target like EGFR mutant in lung cancer pocket of (PDB code: 8d76) via binding affinities ranging from −7.49 to −7.79 kcal/mol. The in-silico ADME/Tox analysis confirmed the drug-likeness of all the prepared compounds, indicating their potential for oral bioavailability and overall therapeutic efficacy. Collectively, these properties distinguish 5b, 5e and 5g, positioning it as the most potent and selective anticancer lead.