P-TSA-catalyzed green synthesis of new 1,4-dihydropyrimidine derivatives inhibitor for HER2 receptor as anti-cancer agents: Molecular docking, ADME-Tox analysis, DFT calculation & MD simulation

Breast cancer (BC) is among the most prevalent forms of cancer affecting women. The human epidermal growth factor receptor-2 (HER2) accounts for 20% of all BC cases. Novel 1,4-dihydropyrimidine Schiff base derivatives were synthesized using a grinding stone method, combining 1,4-dihydropyrimidine, substituted aromatic aldehyde, and p-toluenesulphonic acid (p-TSA) as a catalyst. The resulting compounds underwent characterization through FT-IR, NMR ( 13 C, 1 H), GC–MS, and CHNS analysis. Furthermore, these new 1,4-dihydropyrimidine analogues were assessed for their cytotoxicity against cancer and normal cell lines, with Doxorubicin serving as the reference drug. Notably, 1,4-dihydropyrimidine compound 1 h exhibited potent cytotoxic activity (HepG2, LC 50 –0.06 μM, MCF-7, LC 50 –0.70 μM, HeLa, LC 50 –0.76 μM). The synthesized compounds demonstrated safety based on their IC 50 values against normal cell lines (HEK-293, LO2, and MRC5). The compound 1 h demonstrated an inhibitory effect on HER2 (PDBID: 1Z11 ) with a binding energy of (−9.7Kcal/mol compared to Doxorubicin (−7.8Kcal/mol). ADME-Tox properties and pharmacokinetics studies were predicted for the synthesized analogs. Optimal shape and dimensions were determined using DFT with the B3LYP/6–311++G (DP) basis set. HOMO-LUMO analysis revealed that compound 1 h (−8.2883 eV) to (−5.821 eV) possessed a significant energy gap (2.4632 eV for compound 1 h ). Molecular dynamics (MD) simulations of the HER2 (PDB ID: 1Z11 ) receptor and compound 1 h demonstrate stable binding, with minimal fluctuations observed over 50 ns, confirming the stability of the ligand–receptor interaction, particularly in the treatment of HER2-positive breast cancer. Given these findings, compound 1 h may be used as a potential anti-cancer drug. • New 1,4-dihydropyrimidine derivatives were synthesis. • Molecular docking analysis. • ADME-Tox. • DFT calculation. • MD-Simulation. • Compound 1 h is highly active in cytotoxic activity.