Synthesis, crystal structure, DFT, Hirshfeld surface analysis, energy framework, docking and molecular dynamic simulations of (E)-4-(4-methylbenzyl)-6-styrylpyridazin-3(2H)-one as anticancer agent

In this work, a novel crystal, (E)-4-(4-methylbenzyl)-6-styrylpyridazin-3(2H)-one (E-BSP) was synthesized via Knoevenagel condensation of benzaldehyde and (E)-6-(4-methoxystyryl)-4,5-dihydropyridazin-3(2H)-one. The molecular structure of E-BSP was confirmed by using FT-IR, H-1-NMR, C-13-NMR, UV-vis, ESI-MS, TGA/DTA thermal analyses and single crystal X-ray diffraction. The DFT/B3LYP methods with the 6-311++G(d,p) basis set were used to determine the vibrational modes over the optimized structure. Potential energy distribution (PED) and the VEDA 4 software were used to establish the theoretical mode assignments. The same approach was used to compute the energies of frontier molecular orbitals (HOMO-LUMO), global reactivity descriptors, and molecular electrostatic potential (MEP). Additionally, experimental and computed UV spectral parameters were determined in methanol and the obtained outputs were supported by FMO analysis. Molecular docking and molecular dynamics (MD) simulation analyses of the E-BSP against six proteins obtained from different cancer pathways were carried out. The proteins include; epidermal growth factor receptor (EGFR), Estrogen receptor (ER alpha), Mammalian target of rapamycin (mTOR), Progesterone receptor (PR) (Breast cancer), Human cyclin-dependent kinase 2 (CDK2) (Colorectal cancer), and Survivin (Squamous cell carcinoma/Non-small cell lung cancer). The results of the analyses showed that the compound had less binding energies ranging between -6.30 to -9.09 kcal/mol and formed stable complexes at the substrate-binding site of the proteins after the 50 ns MD simulation. Therefore, E-BSP was considered a potential inhibitor of different cancer pathways and should be used for the treatment of cancer after experimental validation and clinical trial.Communicated by Ramaswamy H. Sarma

Automated summary

A novel crystal (E)-4-(4-methylbenzyl)-6-styrylpyridazin-3(2H)-one (E-BSP) was synthesized and its molecular structure was confirmed through various analyses. The vibrational modes and energies of frontier molecular orbitals (HOMO-LUMO) were determined using DFT methods. The compound exhibited binding to six different cancer pathway proteins, indicating its potential as an inhibitor for cancer treatment. Experimental validation and clinical trials are necessary for further development.