Synthesis, molecular modeling and bioactivity of new bis-thiazole, thiazole-pyrazole, and thiazole-pyridine analogues

Abstract

Several new thiazole derivatives linked pyrazole and/or pyridine rings were synthesized based on the versatile precursor 2-(5-acetyl-4-methyl-3-phenylthiazol-2(3H)-ylidene)acetonitrile (1). The synthesized derivatives were optimized using DFT approach in order to inspect the configurations and energies of the HOMO-LUMO orbitals. The data disclosed low energy gap (ΔEH-L), 0.99–2.54 eV, following the order 9 < 3 = 4 ≈ 2 ≈ 8 < 5 < 1 < 7 ≈ 6. The in vitro anticancer activity of the new thiazole hybrids was tested against three cancer cell lines (HepG2, HCT-116, and MCF-7) as well as standard fibroblast cells (WI38) using Doxorubicin as a reference drug. The thiazole-pyridine hybrids 8 and 9 exhibited high cytotoxic efficacies against the MCF-7 cell line, IC50 28.53 ± 0.39 and 25.47 ± 0.54 µM. Moreover, the synthesized hybrids were docked against the crystal structure of (PDB: 3rcd) as a representative protein for the human epidermal growth factor receptor (HER2) to approve the relationship between the in vitro cytotoxicity results and inhibitor binding interactions. The docking study showed that thiazole-pyridine hybrids 8 and 9 displayed the highest score of bindings, which was compatible with the results of the cytotoxicity results.

Keywords

• Thiazole derivatives
• DFT optimization
• Anticancer activity
• Molecular docking