Synthesis, In Vitro Anticancer Activity, Molecular Docking, and Dynamic Simulation Study of Thiazole‐Conjugated Pyrazole Derivatives

In this study, we successfully designed and developed novel hybrid compounds integrating thiazole and pyrazole pharmacophores through a molecular hybridization approach. The synthesis was carried out through the Vilsmeier-Haack reaction, and the structural elucidation of these hybrids was achieved using FTIR, ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry (HRMS). The in vitro anticancer potency was evaluated against the MCF-7 cell line. Notably, compound IVc exhibited the highest anticancer activity among all tested compounds, with an IC₅₀ value of 126.98 µM, compared to standard 5-fluorouracil (IC₅₀ = 69.64 µM). Molecular docking studies with VEGFR-2 kinase (PDB ID: 4ASD) revealed the strong interactions between compound IVc and key residues, including CYS919A, LEU840A, VAL848A, VAL848A, ALA866A, VAL916A, PHE918A, LEU1035A, and PHE1047A. These findings were further validated by molecular dynamic simulations, which confirmed the structural stability of ligand-receptor complex over the entirety of the 100 ns simulation. Additionally, ADMET predictions indicated favorable pharmacokinetic properties, including excellent intestinal absorption, absence of hepatotoxicity, and strong drug-like characteristics. Collectively, this work provides valuable insights for designing thiazole-pyrazole derivatives as promising candidates for breast cancer treatment.